4 chapter 4 Well-Being and Resilience


Specific citation information for the notes on this page can be found at this link:

REFERENCES (main file)




I urge caution in interpreting any perspectives on positive and negative emotional style or trait.  The research is, I am certain, being accomplished by people operating in either the secure attachment or the insecure organized attachment paradigms.  The continuum or spectrum of secure attachment, through the insecure organized attachment to the insecure disorganized attachment patterns reflects a parallel ability to experience positive affect and optimistic thinking.

We cannot “dissociate” emotional affect and cognitive perspective from the foundational construction of the brain that happened birth through age 2 – an onwards through childhood.  We have to be very careful not to be ignorant and self righteous, not to blame the victim, not to make assumptions that just because the optimal world defines functioning by one set of measurements means that these sets are either real or true for all equally.

I believe that the entire matrix of being human is planted within a secure-insecure, safe-unsafe experience-based world, and that this reality has evolved in expression of our entire being.


Rosenkranz et al 2003


Association between psychological states and immune function – mechanisms by which such states are instantiated in the brain and influence the immune system are poorly understood

I am not convinced that it doesn’t operate the other way around – that something is wrong in the body and we FEEL that in our emotions – attachment built into the brain at birth also builds the emotional centers of the brain – insecure attachment and its corresponding emotional patterns are built in – these studies are not measuring attachment or early traumatic/chronic traumas, information that modulates their findings if they asked the important questions – where do these supposed affective styles come from in the first place?  Emotional regulatory operations in the brain are build by and through early caregiver interactions

Present study – investigated relations of physiological measures of affective style, psychological well being and immune function – used autobiographical writing task –

“Higher levels of right-prefrontal electroencephalographic activation and greater magnitude of the startle reflex reliably predicted poorer immune response.  These data support the hypothesis that individuals characterized by a more negative affective style mount a weaker immune response and therefore maybe at greater risk for illness than those with a more positive affective style.” Rosenkranz et al 2003, p11148

Endocrine and immune products such as cortisol and proinflammatory cytokines have been implicated in the deleterious health consequences of psychosocial stress and negative affect.  Therefore, it is plausible that the etiology of the dysregulation of these molecules likely involves the central circuitry governing the processing of emotional information.”  Rosenkranz et al 2003, p11148

…..particular interest is prefrontal cortex (PFC) – its role in depression and associations with measures of immune function

“Affective styles refers to individual differences in valence-specific features of emotional reactivity and affect regulation….magnitude and duration of emotion as well as the efficacy of processes invoked to regulate emotion….”  Rosenkranz et al 2003, p11148

“Asymmetry in the activation of select territories of the PFC, assessed with measures of brain electrical activity, has been consistently related to individual differences in the tendency to experience negative affect…high levels of right-sided prefrontal activation at baseline exhibit higher levels of dispositional negative affect and also show increased reactivity to acute negative affective challenges…that their left-frontally activated counterparts….” Rosenkranz et al 2003, p11148

[activity and reactivity]

“Of particular interest, previous studies have linked right-prefrontal activation to both poorer natural killer cell activity…and a larger decrement in natural killer cell activity in vitro after an emotional stressor….” Rosenkranz et al 2003, p11148


….3 different physiological indicators of negative affective style predicted weaker antibody response to influenza vaccination

…..greater relative right-prefrontal EEG activation at baseline and

…….greater relative right-prefrontal EEG activation and

……..larger relative eye-blink startle magnitude in response to the negative affect induction.  Rosenkranz et al 2003, p11151

…specific pathways responsible for the association between negative affect and immune function cannot be determined in this study, data exist that suggest bidirectional communication between the PFC and certain immune cells

………mice studies:  asymmetric disruption in immune system: – right lesions = enhancement ———left lesions = suppression

…….previous studies also suggest “…interaction between the PFC and immune system, there are widespread connections to the immune system via the hypothalamic-pituitary-adrenal (HPA) axis, hippocampus, and amygdala….Functional manipulation of these regions has been shown to impact immune function.” Rosenkranz et al 2003, p11151

……mean basal salivary cortisol is an indicator of HPA-axis activation

….associations between HPA-axis function and asymmetric prefrontal activity in nonhuman primates has been shown, and in human infants

……….animals and humans showing greater right-sided activation exhibiting higher levels of basal cortisol compared with left-activated counterparts

………recent data from rhesus monkey studies – indicated animals with higher levels of right-sided frontal activation also exhibit higher levels of cerebrospinal fluid measures of corticotrophin-releasing hormone = molecule that initiates the cascade of changes in the HPA axis that culminate in release of cortisol — Rosenkranz et al 2003, p11151

“Interestingly, the physiological measures of affective style, prefrontal activation symmetry and emotion-modulated startle, themselves were not significantly correlated in this study.”  Rosenkranz et al 2003, p11151

……..measures of startle and frontal EEG symmetry activation – “…likely reflect different central routes that influence a final common pathway, perhaps hypothalamic activity, which then modulates immune function.”  Rosenkranz et al 2003, p11151




Ciocoiu, Colev-Luca & Bădescu 2003

Abstract – article in Romanian – Disciplina de Fiziopatologie, Facultatea de Medicină, Universitatea de Medicină şi Farmacie Gr.T. Popa Iaşi.

Hypothalamic-pituitary-adrenal [HPA] axis activity and cortisol release are consequences of central stress system activation, but they may also influence cognitive and emotional processes within the brain. Despite the importance of central stress response systems, little is known about the specific brain circuits through which psychosocial stimuli activate the hypothalamic-pituitary-adrenal axis and through which cortisol feedback modulates central processing. The authors used [(15)O]H(2)O positron emission tomography (PET) on subjects with posttraumatic stress disorder (PTSD) to study these circuits. METHOD: Participants were combat-PTSD patients, combat-exposed healthy comparison subjects, and noncombat-exposed healthy comparison subjects. Participants were scanned using [(15)O]H(2)O PET while they experienced a series of emotional-induction conditions, which included aversive pictures and autobiographic narratives. Blood samples were obtained 2 minutes before and 5 minutes after each activation scan in order to measure the subjects’ plasma adrenocorticotropic hormone and cortisol levels.

RESULTS: In voxel-wise analyses, the authors found that

adrenocorticotropic hormone responses were covaried with regional cerebral blood flow (rCBF) in the dorsal medial prefrontal cortex, rostral anterior cingulate cortex, and right insula, with some differences between PTSD patients and comparison subjects.

Prestimulus cortisol levels covaried with rCBF responses in the rostral anterior cingulate cortex. In combat-PTSD patients only, prestimulus cortisol levels covaried with rCBF in the subgenual anterior cingulate cortex.

CONCLUSIONS: These findings provide evidence of

cortical involvement in hypothalamic-pituitary-adrenal responses to psychological stimuli,

specifically implicating the


dorsal medial prefrontal cortex, and

rostral anterior cingulate cortex.

These findings also show, for the first time, that cortisol may modulate activity in specific brain areas such as the rostral and subgenual anterior cingulate cortices.

Differential patterns of covariation between combat veterans with and without PTSD potentially

implicate the dorsal medial prefrontal cortex

and subgenual anterior cingulate cortex

as areas of dysregulation in PTSD.


Meijer 2002

Abstract – Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, The Netherlands. o.meijer@lacdr.leidenuniv.nl

The corticosteroid hormones cortisol and corticosterone

are secreted by the adrenal gland in response to stress. They have profound effects on brain function, which are mediated

by the related mineralocorticoid (MR) and glucocorticoid (GR) receptors.

The MR and GR are ligand-activated transcription factors and

exert different, sometimes opposing effects on the brain.

The balance between these two receptor activities is considered essential for appropriate corticosteroid signaling and health.

An exciting recent insight in steroid biology is that the

nature and magnitude of steroid receptor-mediated responses depend not only on ligand and receptor availability,

but also in a critical manner on the presence of downstream mediator proteins (coregulators),

such as the steroid receptor coactivators and nuclear receptor corepressors.

Members of the coregulator families

differ in their specific interactions with steroid receptors,

as well as in their distribution throughout the brain and pituitary.

The activity of these proteins can be regulated both at the expression level, and by post-translational modifications. These characteristics make coregulator proteins of outstanding interest as determinants of receptor, cell and state-dependent effects of MR and GR signaling (and steroid receptor signaling in general) in the brain.


The following section immediately followed GR and MR on non-genomic level in attachment/cannabinoid



Eskandari & Sternberg 2002

Abstract – Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA..

Many lines of research have established the numerous routes by which the immune and central nervous systems (CNS) communicate. The CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through similar routes via immune mediators and cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal (HPA) axis, through the hormones of the neuroendocrine stress response.

The sympathetic nervous system regulates immune system function primarily via adrenergic neurotransmitters released through neuronal routes.

Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease.

Glucocorticoids are the main effector endpoint

of the neuroendocrine response system.


Webster, Tonelli & Sternberg 2002

Abstract – Section on Neuroimmune Immunology and Behavior, National Institute of Mental Health, Bldg 36, Room 1A 23 (MSC 4020), 36 Convent Drive, Bethesda, Maryland 20892-4020, USA. jwebster@codon.nih.gov

A reciprocal regulation exists

between the central nervous and immune systems

through which the CNS signals the immune system

via hormonal and neuronal pathways and

the immune system signals the CNS through cytokines.

The primary hormonal pathway by which the CNS regulates

the immune system is the

hypothalamic-pituitary-adrenal axis,

through the hormones of the neuroendocrine stress response.

The sympathetic nervous system

regulates the function of the immune system

primarily via adrenergic neurotransmitters

released through neuronal routes.

Neuroendocrine regulation of immune function

is essential for survival during stress or infection

and to modulate immune responses in inflammatory disease.

Glucocorticoids are the main effector end point

of this neuroendocrine system

and, through the glucocorticoid receptor,

have multiple effects on immune cells and molecules.

This review focuses on the regulation of the immune response

via the neuroendocrine system.

Particular details are presented on the effects of

interruptions of this regulatory loop

at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.


Barrett & Spelsberg 1998

Abstract – Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.

“Steroid receptors at the nexus of transcriptional regulation.”

During the past few years, our understanding of nuclear receptor action has dramatically improved as a result of the identification and functional analysis of co-regulators such as factors involved in chromatin remodeling, transcription intermediary factors (co-repressors and co-activators), and direct interactions with the basal transcriptional machinery.

Furthermore, the elucidation of the crystal structures of the empty ligand-binding domains of the nuclear receptor and of complexes formed by the nuclear receptor’s ligand-binding domain bound to agonists and antagonists has contributed significantly to our understanding of the early events of nuclear receptor action.

However, the picture of hormone- and hormone receptor-mediated mechanisms of gene regulation remain incomplete and extremely complicated when one also considers the “nontraditional” interactions of hormone-activated nuclear receptors, for example, interactions between the activated steroid receptors and components of the chromatin/nuclear matrix; and finally the nongenomic effects that steroid hormones can exhibit with other signaling pathways. In this prospectus on steroid receptors, we discuss the implications of various steroid hormone and nuclear receptor interactions and potential future directions of investigation.


Kelley, Weigent & Kooijman  2007

Abstract – Laboratory of Integrative Immunophysiology, Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES, 227 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL 61801, USA. kwkelley@uiuc.edu

A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information

from the immune system

to the neuroendocrine system

is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also.

In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems.

Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines.

This means that the brain functions

as an immune-regulating organ

participating in immune responses.

A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system.

Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that

neuroendocrine protein hormones

influence immunity and that

immune processes affect the neuroendocrine system.

New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level.

This communication system

is activated when inflammatory processes induced

by proinflammatory cytokines antagonize the function

of a variety of hormones,

which then causes endocrine resistance in both the periphery and brain.

Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.


O’Connor et al 2008

Abstract – Integrative Immunology and Behavior Program, Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

During the past decade, the

immune and endocrine systems

have been discovered to interact

in controlling physiologic processes as diverse as cell growth and differentiation, metabolism, and

even human and animal behavior.

The interaction between these two major physiological systems is a bi-directional process.

While it has been well documented that hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid-stimulating hormone (TSH), regulate a variety of immune events, a great deal of data have accumulated

supporting the notion that cytokines from the

innate immune system

also affect the neuroendocrine system.

Communication between these two systems coordinates processes that are necessary to maintain homeostasis.

Proinflammatory cytokines often act as negative regulatory signals that temper the action of hormones and growth factors.

This system of ‘checks and balances’

is an active, ongoing process, even in healthy individuals.

Dysregulation of this process has been implicated as a potential pathogenic factor in the development of co-morbid conditions associated with several chronic inflammatory diseases, including type 2 diabetes, cardiovascular disease, cerebrovascular disease, inflammatory bowel disease, rheumatoid arthritis, major depression, and even normal aging.

Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I). We also highlight that IGF-I can induce resistance or reduce sensitivity to brain TNFalpha and discuss how TNFalpha, IL-1beta, and IGF-I interact to regulate several aspects of behavior and cognition.


Richwine et al 2008

Abstract – Integrative Immunology and Behavior Program, University of Illinois, Urbana, IL 61801, USA; Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA.

The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal-dependent learning and memory is higher in the brains of aged mice compared to young adults after peripheral injection of lipopolysaccharide (LPS).[ (LPS) A compound containing lipid bound to a polysaccharide; often a component of microbial cells walls] In this study we investigated whether the exaggerated inflammatory cytokine response in the hippocampus of aged mice after IP injection of LPS is associated with architectural changes to dendrites of pyramidal neurons in the dorsal CA1 hippocampus. Compared to young adults, aged mice had higher basal expression of MHC class II, lower basal expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and a decrease in total dendritic length in both the basal and apical tree.

After IP LPS administration, expression of IL-1beta, IL-6, and TNFalpha mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that

a peripheral infection in the aged

can cause a heightened inflammatory cytokine response

in the hippocampus and atrophy of hippocampal neurons.

Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.


Ferencik et al 2007

Abstract – Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia. miroslav.ferencik@fmed.uniba.sk

Inflammation is a key component of the immune system. It has important functions in both defense and pathophysiological events maintaining the dynamic homeostasis of a host organism including its tissues, organs and individual cells.

On the cellular level it is controlled by more than

400 currently known genes.

Their polymorphisms and environmental conditions give rise to different genotypes in human population.

Pro-inflammatory genotype,

which dominates in the present population,

may be advantageous in childhood but not in elderly people because it is characterized by an increased vulnerability to,

and intensity of, inflammatory reactions.

These reactions may be the possible reasons of chronic inflammatory diseases, especially in old age. Better understanding of complex molecular and cellular inflammatory mechanisms is indispensable for detailed knowledge of pathogenesis of many diseases, their prevention and directed drug therapy. Here we summarize the basic current knowledge on these mechanisms.


Ferencik, Novak & Rovensky 1998

Abstract – article in Slovak – Imunologický ústav Lekárskej fakulty Univerzity Komenského v Bratislave.

For far too long, the immune system has been viewed in isolation from the rest of the body’s organ system. But now it is clear that the

immune system is an integral part of the organ and physiological systems of whole organism.

Especially, the immune and endocrine systems share many ligands and receptors that result in constant and important bidirectional communication.

A new and important function for the immune system is to serve as a sensory organ for noncognitive stimuli such as infectious agents and tumors. And any threat or “toxin” in the environment requiring adjustments to ensure survival

On the other hand the neuroendocrine system can perform important immunoregulatory activities.

It also suggest that brain is not more an immunologically privileged site.

Recent studies provide a new view of immunoreactivity to antigens from the nervous system and to immune and inflammatory responses in brain.

These may be influenced both by the circulating cytokines derived from the immune system and/or those endogenously produced within the neuroendocrine system.

……..There is a growing body of evidence that

cytokines are an integral part of the central nervous system

with an important neuromodulatory role in neural mechanisms regulating stress responses, hormonal changes and various kinds of behavior.

The mutual informatory circuit

inside of the immune, nervous and endocrine systems

suggest that they all form the superinformation system

with pivotal regulatory role in living organisms.

Overall, the recognition of the immune system as our sixth sense may ultimately provide the new understanding of physiology required for successful diagnostic and therapeutic programs against disease and stress involving immune-neuroendocrine communication. (Tab. 5, Ref. 35.)


Boranic, Savioncello & Garilovac 2008

Abstract – article in Croatian – ImunoIoski zavod, Zagreb. milivoj.boranic@zg.t-com.hr

Innate and acquired immune reactions are controlled by their intrinsic regulatory mechanisms, ie. by an array of cytokines that mediate communication among cells of the immune system itself and with other cells and tissues, e. g. in areas of inflammation.

In addition, the immune system is also subjected to systemic regulation by the vegetative and endocrine systems since immune cells express receptors for neurotransmitters and hormones.

Neuroendocrine signals may enhance or suppress the immune reaction, accelerate or slow it, but do not affect specificity.

Various stressful factors,

including the psychosocial ones,

affect immunity.

In turn, cytokines generated by the immune system influence hormonal secretion and central nervous system, producing specific behavioral changes (the “sickness behavior”) accompanying infectious and inflammatory diseases. Here is a useful link in my thinking, that both PTSD and depression are “sickness behaviors”

That includes somnolence, loss of appetite, depression or anxiety and decrease of cognitive abilities, attention and memory.

Local immune systems in skin and mucosa are also subjected to systemic neuroendocrine regulation and possess intrinsic neuroregulatory networks as well. These mechanisms render skin and respiratory and digestive tracts responsive to various forms of stress. Examples are neurodermitis, asthma and ulcerative colitis.

In children,

the immune and the neuroendocrine systems

are still developing,

particularly in fetal, neonatal and early infant periods,

and exposure to stressful experiences

at that time may result in late consequences in the form of

deficient immunity or greater risks for allergic or autoimmune reactions. Including vulnerabilities to cancer – influenced also by epigenetic factors that are reactions to previous generations’ exposure to toxins – and including all sorts of “mental” adjustments that may be far from ideal

Recognition of the participation of neuroendocrine mechanisms in regulation of immunity helps us understand alterations and disturbances of immune reactions under the influence of stressful factors but so far has not produced reliable therapeutic implications. Psychosocial interventions involving the child and its family may be useful.


Put yet another way, during this fetal, neonatal and early infant periods we are “coming down” into our bodies – if we believe in a soul, then our soul will adjust to fit our body and our body will adjust to fit the world.  While a little stress is vitally necessary, too much exposure to “stressful experiences” change us, our body, and our fit in both our body and in the world.  We will do the best we can.  Our body will do the best that it can.  But too much of the wrong stress, and the consequences are going to deviate from the ideal, but not from the possible.

I still don’t feel that I fit in the world.  What I WANT is probably here in the world, but it doesn’t feel like that.  It feels like I want what’s in the next world, because I never came into THIS world in the proper way in the first place from the beginning.

I think for some people it works the other way around, that they are too much in the world of the material and the physical without allowing sensitivities to operate – without their feelings.  While some talk of the hawks and the doves, I like the analogy that some (hawks) are geared genetically to be less anxious, pay less attention to details, be less sensitive, and more aware of “that which looms.”  The doves, on the other hand have highly sensitive systems, are more anxious genetically because they are geared to notice the little things, “that which flutters.”  On the grand scale, some of us would make better hunters and others better gatherers.  Our DNA pool has not let go of those possibilities or those predispositions.  Only in a world that would like to see us all the same would we not be able to understand that this sensitivity, this anxiety scale, has served the human species with advantage since our beginnings.  It results in part from being members of a complicated species that has retained within it the abilities within the many that could not possibly be available solely within the one.

While, as been shown with maternal stress changing vasopressin anxiety in offspring toward more middle and less extremes of high or low anxiety, I wonder if extreme stress postnatally can in fact make the low anxiety even lower anxiety, and the high anxiety ever higher.

In my case, I did not have a chance in the womb to adjust in any way developmentally for the extreme stress in myself or my mother once I was born.  I suspect the pregnancy was ideal – which I have always seen as an asset for my survival of the postnatal hardships – and it was.  Yet, if the mother is normally in a high stress environment, the characteristic stress of that environment will be communicated to the infant through the mother even before it is born, and adjustments will be made in the developing fetus to be somewhat better prepared for “what lies in wait” once it is born.  That is nature’s way.


Butts & Sternberg 2008

Abstract – Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health/NIH, 5625 Fishers Lane, Room 4N15, MSC 9401, Bethesda, MD 20892, USA.

An increasing body of evidence demonstrates that there is bidirectional communication between the neuroendocrine and immune systems.

Interaction between these systems results in a variety of outcomes, including the well documented sickness behavior” elicited by cytokines of the immune system that can enter the brain and activate second messengers that modify neuronal activity.

Crosstalk between the neuroendocrine and immune systems can also result in production of factors by the nervous and endocrine systems that alter immune cell function and subsequent modulation of immune responses against infectious agents and other pathogens. Continued exposure to molecules produced by the neuroendocrine system has also been known to increase susceptibility and/or severity of disease.

Furthermore, neuroendocrine factors are thought to play a major role in gender-specific differences in development of certain disorders, including autoimmune/inflammatory diseases that have a two to tenfold higher incidence in females compared to males.

Neuroendocrine factors can affect immune cells at the level of gene transcription but have also been shown to modify immune cell activity by interacting with intracellular molecules, resulting in modified ability of these cells to mount a potent immune response. In this review, we will consider various effects of the neuroendocrine system and its proteins on specific populations of immune cells and associated responses in host immunity against pathogens. We will further discuss how this modification of immune cell activity by the neuroendocrine system can contribute to susceptibility/severity of disease development.



Licinio & Frost 2000

Abstract – Department of Psychiatry and Neuropsychiatric Institute, School of Medicine, University of California, Los Angeles, CA 90095-1761, USA. licinio@ucla.edu

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80’s and 90’s our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain.

Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that

cytokines are potent regulators of

hypothalamic neuropeptidergic systems

that maintain neuroendocrine homeostasis

and which regulate the body’s response to stress.

The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.


Turnbull & Rivier 1999

Abstract – The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, USA.

Glucocorticoids are hormone products of the adrenal gland, which have long been recognized to have a profound impact on immunologic processes.

The communication between immune and neuroendocrine systems is, however, bidirectional. The endocrine and immune systems share a common “chemical language,” with both systems possessing ligands and receptors of “classical” hormones and immunoregulatory mediators. Studies in the early to mid 1980s demonstrated that monocyte-derived or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis, establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication between the immune and neuroendocrine systems. The subsequent 10-15 years have witnessed demonstrations that numerous members of several cytokine families increase the secretory activity of the HPA axis.

Because this neuroendocrine action of cytokines is mediated primarily at the level of the central nervous system, studies investigating the mechanisms of HPA activation produced by cytokines take on a more broad significance, with findings relevant to the more fundamental question of how cytokines signal the brain. This article reviews published findings that have documented which cytokines have been shown to influence hormone secretion from the HPA axis, determined under what physiological/pathophysiological circumstances endogenous cytokines regulate HPA axis activity, established the possible sites of cytokine action on HPA axis hormone secretion, and identified the potential neuroanatomic and pharmacological mechanisms by which cytokines signal the neuroendocrine hypothalamus.



“So you will find the smallest atoms in the universal system

are similar to the greatest beings of the universe.

It is clear that they come into existence

from one laboratory of might under one natural system,

one universal law;

therefore they may be compared to one another.”

‘Abdu’l-Baha, Page 299

in “Baha’I World Faith:  Selected Writings of Baha’u’llah and ‘Abdu’l-Baha,” Baha’I Publishing Trust, Wilmette, IL, 5th printing of 1956 edition, 1971


IMPORTANT – direct links between brain, HPA axis and immune system

Links depression to an immune response to environmental challenge

Related articles are included here


Walker, Knott & Hodgson 2008

Abstract – University of Newcastle, School of Biomedical Sciences, University Drive, Newcastle, NSW 2308, Australia. rohan.walker@newcastle.edu.au

Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress.

A variety of early life stressors have consistently been implicated in the development of psychopathology in adulthood.

The current study investigates a rarely considered form of early life stress, bacterial infection, for its ability to induce psychopathology-like symptoms in adult rat.

Specifically, neonatal rats were exposed to a simulated bacterial infection. In adulthood the acoustic startle response of these animals was evaluated both prior to and following exposure to restraint stress.

Our results indicate that animals neonatally exposed to infection exhibit a significantly exaggerated acoustic startle response but only following exposure to stress.

Additionally, we observed that adult animals neonatally exposed to infection, exhibited increased production of circulating corticosterone following stress, indicating potentiated hypothalamic pituitary adrenal axis activity as well as altered novelty seeking behavior and locomotor activity.

These results extend upon existing pre-clinical findings that indicate certain stressful early life events can predispose the adult animal to exhibit abnormal behavior in adulthood.

This piece of research demonstrates that the same kind of reaction is caused to the fetus from stress hormones in the mother’s body and by infection, thus showing me that I am right, that there is a direct link between the immune system response, the stress response, and alterations in the reaction of the body to traumas and toxins that affect the “animal” for the rest of its life – the body is making adaptations to life in a hostile, toxic environment.  This, to me, partly because of its subtlety scares me.  I started out looking for what happens as a consequence of direct abuse and neglect to an infant, and I am finding it goes so much further and deeper than I ever imagined.


This article is also a linking article between infection, stress response, epigenetics, response of the organism in its development to a toxic environment.

Rasmussen, Crites & Burke 2008

Abstract – VA Puget Sound Health Care System, Mental Illness Research, Education and Clinical Center, Seattle, WA 98108, USA. drasmuss@u.washington.edu

Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats.

Following exposure to trauma,

a vulnerable sub-population of individuals

develops post-traumatic stress disorder (PTSD)

with characteristic persistent autonomic hyper-responsivity, associated increased startle response, and commonly altered hypothalamo-pituitary-adrenal regulation.

A goal of this investigation was to identify a predictive marker for this vulnerability.

Previous investigators have developed a model for PTSD in which male mice were exposed to a single brief episode of inescapable footshock followed by 1-min contextual reminders of this trauma at weekly intervals for 6 weeks.

Exposure to these reminders induced a progressive and persistent increase in the amplitude of acoustic startle consistent with the persistently increased acoustic startle of individuals exhibiting PTSD.

We adapted this model to adult male Wistar rats, with added characterization of initial (pre-trauma) startle response. Here is where I wonder, also, about latent inhibition problems, where we cannot “let go of” the initial traumas.

After one episode of inescapable footshock (10 s, 2 mA) or control treatment followed by six weekly 1-min contextual reminders, acoustic startle was re-tested. Data were analyzed after dividing rats within each treatment into LOW vs MID vs HIGH (33% in each group) pre-treatment startle responders.

Rats which exhibited pre-treatment LOW- and MID-range acoustic startle responses did not develop increased acoustic startle responses following subsequent traumatic stress+reminders ([TS+R]) treatment.

However, rats which exhibited HIGH pre-treatment startle responses exhibited further significant (p<0.01) [TS+R]-induced persistent enhancement of this already elevated startle response.

Furthermore, rats exhibiting HIGH pre-treatment startle responses were also the only subgroup which exhibited increased basal plasma corticosterone levels following [TS+R] treatment.

These results suggest that initial pre-stress acoustic startle response can identify subgroups of rats which are predisposed to, or resistant to, developing a PTSD-like syndrome following subsequent trauma.

There is more information on acoustic startle in the language section.  Is this increase in acoustic startle sensitivity linked to the lateralization in the brain – i.e. handedness?


Haddad, Saade & Safieh-Garabedian 2002

Abstract – and article – Severinghaus-Radiometer Research Laboratories, Department of Anesthesia and Perioperative Care, University of California at San Francisco, School of Medicine, Medical Sciences, San Francisco, CA 94143-0542, USA. johnjhaddad@yahoo.co.uk

Cytokines and neuro-immune-endocrine interactions: a role for the hypothalamic-pituitary-adrenal revolving axis.

Cytokines, peptide hormones and neurotransmitters, as well as their receptors/ligands, are endogenous to the brain, endocrine and immune systems. These shared ligands and receptors are used as a common chemical language for communication within and between the immune and neuroendocrine systems.

Such communication suggests an immunoregulatory role for the brain

and a sensory function for the immune system.

Interplay between the immune, nervous and endocrine systems is most commonly associated with the pronounced effects of stress on immunity.

The hypothalamic-pituitary-adrenal (HPA) axis

is the key player in stress responses;

it is well established that both external and internal stressors activate the HPA axis.

Cytokines are chemical messengers that stimulate the HPA axis when the body is under stress or experiencing an infection.

This review discusses current knowledge of cytokine signaling pathways in neuro-immune-endocrine interactions as viewed through the triplet HPA axis. In addition, we elaborate on HPA/cytokine interactions in oxidative stress within the context of nuclear factor-kappaB transcriptional regulation and the role of oxidative markers and related gaseous transmitters.


Authors represent U of C at San Francisco, last 2 from American University of Beirut, Lebanon

“The HPA system communicates bidirectionally with neuro-immune-endocrine interactions….The neuro-immune-endocrine interface is mediated by cytokines acting as auto/paracrine or endocrine factors regulating pituitary development, cell proliferation, hormone secretion and feedback control of the HPA axis.  Soluble products that appear to transmit information from the immune compartments to the CNS act as immunotransmitters and function in immunomodulatory neuroendocrine circuits.”  Haddad, Saade & Safieh-Garabedian 2002, p 15

“There is now cumulating evidence that there are important interactions between the immune and neuroendocrine systems, which may explain, in (p 15) part, some of the effects on growth, thyroid, adrenal and reproductive functions which occur in the pathophysiology of acute and chronic disease [and epigenetics?].”  Haddad, Saade & Safieh-Garabedian 2002, p 16

“Cytokines are mediators of inter- and intracellular communications.”  Haddad, Saade & Safieh-Garabedian 2002, p 2

Cytokines are peptides, “…contribute to a chemical signaling language that regulates development, tissue repair, haemopoiesis, inflammation and the specific and nonspecific immune responses…”  Haddad, Saade & Safieh-Garabedian 2002, p 2

Potent cytokine polypeptide – interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-[I think that’s an alpha sign] – “…act in a complex, intermingled network where one cytokine can influence the production of, and response to, many other cytokines….the pathophysiology of inflammatory hyperalgesia, infection and autoimmune and malignant diseases can be explained, at least in part, by the induction of cytokines and the subsequent protracted cellular responses…..[quotes refs here].”  Haddad, Saade & Safieh-Garabedian 2002, p 2

“The mechanisms,

from both the neural and immunological perspective,

involved in stress-induced alterations of immune function

are being studied….”

[quotes refs here, Haddad, Saade & Safieh-Garabedian 2002, p 2

“The immune system is regulated in part by the central nervous system (CNS), acting principally via the hypothalamic-pituitary adrenal (HPA) axis and the sympathetic nervous system (SNS)….In recent years, our understanding ot the interactions between the HPA axis and immune-mediated inflammatory reactions has expanded enormously.  This review outlines the influences that the HPA axis and immune-mediated inflammatory reactions exert on each other and discusses the mechanisms whereby these interactions are mediated.  Furthermore, we discuss HPA interactions and oxidative stress evolution within the context of a potential role for the transcription factor NF-[upside down 8?]-B, which regulates a plethora of cellular functions including proinflammatory-mediated processes, and the role of gaseous transmitters.”  Haddad, Saade & Safieh-Garabedian 2002, p 2

“The neuroendocrine and immune systems communicate bidirectionally….

The neuro-immune-endocrine interface is mediated by cytokines,

such as IL-1 and TNF-[alpha],

acting as auto/paracrine factors regulating pituitary development, cell proliferation, hormone secretion, and feedback control of the HPA axis….”  Haddad, Saade & Safieh-Garabedian 2002, p 2

hypothesis increasingly supported that “…there are bidirectional circuits between the CNS and the immune system.”  Haddad, Saade & Safieh-Garabedian 2002, p 2

information is transmitted from “the immune compartment to the CNS.”  Haddad, Saade & Safieh-Garabedian 2002, p 2

Opioid peptides,

adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH)

are additional products of lymphocytes that may function in immunomodulatory neuroendocrine circuits.”  Haddad, Saade & Safieh-Garabedian 2002, p 2

What kind of connection is this between opioids and the immune system and stress circuits?  I have been looking for this, wanting to know if attachment is implicated here.

“… the term ‘immuno-transmitter’

[is] used to describe molecules

that are produced predominantly by cells that comprise the immune system

but that transmit specific signals and information to neurons and other cell types….”  Haddad, Saade & Safieh-Garabedian 2002, p 2

major cytokines involved that “…affect the release of anterior pituitary hormones by an action on the hypothalamus and/or pituitary gland ….are IL-1, IL-2, IL-6, TNF-[alpha] and interferon (IFN)….The predominant effects of these cytokines are to stimulate the HPA axis and to suppress the hypothalamic-pituitary-thyroid (HPT) and gonadal axes, L(p. 2) and growth hormone (GH) release….There is accumulating evidence that there are significant interactions between the immune and neuroendocrine systems which may explain, at least in part, some of the effects on growth, thyroid, adrenal and reproductive functions which occur in acute and chronic disease..”    Haddad, Saade & Safieh-Garabedian 2002, p3

“…peculiar alterations in hormone secretion occur….[d]uring stimulation of the immune system (e.g. during infectious diseases)….The role of cytokines in these alterations is being elucidated and established….”  Haddad, Saade & Safieh-Garabedian 2002, p3

[hawks and doves]

“The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the HPA axis to the stimulatory influence of ILs and stress-related mediators….It is thus reasonable to assume that inappropriate responses of the HPA axis to ILs might play a role in modulating the onset of pathological conditions such as infections and related pathologies.”  Haddad, Saade & Safieh-Garabedian 2002, p3

researchers have found supporting evidence “…that IL-1 acts as a neurotransmitter neuromodulator in brain….[and that] IL-1 mediated activation of the HPA axis occurs primarily at the level of the brain and/or pituitary gland….”  Haddad, Saade & Safieh-Garabedian 2002, p3

“IL-1 and other related proinflammatory cytokines are potent activators of the HPA axis….there is a clear-cut differential response to IL-1[alpha] and IL-1[beta]….[latter one increases, in rat studies] the plasma levels of ACTH in a dose-related manner, whereas IL-1[alpha] did not, suggesting that the two members of the IL-1 family may have a different spectrum of biological actions…..IL-1 activates the HPA axis.”  Haddad, Saade & Safieh-Garabedian 2002, p 3

“…IL-1 acts centrally in the brain to stimulate the secretion of CRF, thereby eliciting ACTH release….a direct action of IL-1 on the pituitary gland is unlikely.”  Haddad, Saade & Safieh-Garabedian 2002, p4

In mice, IL-1 has been shown to increase “…the cerebral concentration of the norepinephrine (NE) catabolite….probably reflecting increased activity of noradrenergic neurons….This effect was dose-dependent and was largest in the hypothalamus, especially the medial division….[and] paralleled the increase of plasma corticosterone.”  Haddad, Saade & Safieh-Garabedian 2002, p4

“Noradrenergic neurons with terminals in the hypothalamus are known to regulate the secretion of CRF, thus suggesting that IL-1 activates the HPA axis by activating these neurons.  Because the initiation of an immune response is known to cause systemic release of IL-1, this cytokine may be an immuno-transmitter communicating the immunologic activation to the brain.  The IL-1 induced changes in hypothalamic …[the norepinephrine (NE) catabolite] may explain the increases of electrophysiological activity, the changes of hypothalamic NE metabolism and the increases in circulating glucocorticoids reported to be associated with immunologic activation and frequently observed in infected animals….”  Haddad, Saade & Safieh-Garabedian 2002, p4

….immune regulators interact with the HPA axis

….”IL-1 can cause the release of ACTH….”

….”…IL-1[beta] produced an immediate increase in plasma corticosterone and ACTH….”

….”…differential action of IL-1[beta] on macrophage cytokine production….”

“These results supported the concept of a negative feedback on macrophage IL-1 secretion [“suppression was mediated by adrenocortical activation”]by the central action of IL-1[beta] and indicated that both the HPA axis and the sympathetic nervous system mediate this effect.”  – Haddad, Saade & Safieh-Garabedian 2002, p4

“…IL-1-induced corticosterone release was shown to occur by an adrenergic mechanism (p 4) from rat adrenal gland….”  Haddad, Saade & Safieh-Garabedian 2002, p5

“An interest [sic] mechanism was recently reported for IL-1-mediated regulation of the HPA axis. A primary route of peripheral cytokine signaling was proposed through the stimulation of

peripheral vagal afferents

rather than or in addition to direct cytokine access to brain….

suggesting that IL-1 activates the HPA axis via the stimulation of peripheral vagal afferents and further support the hypothesis that

peripheral cytokine signaling to the CNS

is mediated primarily by stimulation of peripheral afferents….”  Haddad, Saade & Safieh-Garabedian 2002, p5

“…an interesting mechanism implicated the vagus nerve (Hosoi et al., 2000 [see below]).  For instance, direct electrical stimulation of the central end of the vagus nerve induced increases in the expression of mRNA and protein levels of IL-1[beta] in the hypothalamus and the hippocampus.  Furthermore, expression of CRF mRNA was increased in the hypothalamus after vagal stimulation (Hosoi et al., 2000).  Plasma levels of ACTH and corticosterone (CORT), in addition, were also increased by this stimulation, indicating that the activation of the afferent vagus nerves can induce production of cytokines in the brain and activate the HPA axis.  Therefore, the afferent vagus nerve may play an important role in transmitting peripheral signals to the brain in the infection and inflammation.”  Haddad, Saade & Safieh-Garabedian 2002, p5

“In concert, dorsal and ventral medullary catecholamine cell groups were reported to contribute differentially to systemic IL-1[beta]-induced HPA axis responses.  Medial parvocellular paraventricular corticotropin-releasing hormone…cells are critical in generating HPA axis responses to systemic IL-1[beta]….The authors [Buller et al., 2001, see abstract below] examined the role of nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM) catecholamine cells in the activation of mPVN…lesions, which selectively depleted catecholaminergic terminals, reduced IL-1[beta]-induced mPVN CRH cell activation….Both VLM and NTS lesions reduced the mPVN CRH and OT [oxytocin] cell response to IL-1[beta]. Unlike VLM lesions, NTS lesions also suppressed the recruitment of central amygdala neurons….both the NTS and VLM catecholamine cells have important, but differential, contributions to the generation of IL-[beta]-induced HPA axis responses….”  Haddad, Saade & Safieh-Garabedian 2002, p5

“Another major mechanism reported for the action of IL-1 on the HPA axis involved the amygdala.  For example, bilateral ibotenic acid lesions of the central amygdala substantially reduced ACTH release and hypothalamic corticotropin-releasing factor and


cell c-fos expression responses to IL-1 and IL-8, suggesting a facilitatory role for this structure in the generation of HPA axis responses to an immune challenge (XU et al, 1999).”  Haddad, Saade & Safieh-Garabedian 2002, p5 [see abstract below]

“…only a small number of central amygdala cells project directly to the paraventricular nucleus, the authors then examined the effect of central amygdala lesions on the activity of other brain nuclei that might act as relay sites in the control of the HPA axis function.  It was found that bilateral central amygdala lesions significantly reduced IL-1[beta]-induced c-fos expression in cells of the ventromedial and ventrolateral subdivisions of the bed nucleus of the stria terminals and brainstem catecholamine cell groups of the nucleus tractus solitarius (A2 noradrenergic cells) and ventrolateral medulla (A1 noradrenergic and C1 adrenergic cells).  These findings, in conjunction with previous evidence of bed nucleus of the stria terminalis and catecholamine cell group involvement in HPA axis regulation, indicated that ventromedial and ventrolateral bed nucleus of the stria terminalis cells and medullary catecholamine cells might mediate the influence of the central amygdala on the HPA axis responses to an immune challenge….the central amygdala influences HPA axis responses to a systemic immune challenge…it primarily acts by modulating the activity of other control mechanisms.”  Haddad, Saade & Safieh-Garabedian 2002, p5

suggested:  “…an involvement of endogenous prostaglandins [hormone-like substances that play a part in inflammation] in the effect of cytokines on the HPA axis….(p 5)….primarily mediated through corticosteroid feedback….”  Haddad, Saade & Safieh-Garabedian 2002, p6

“…the ability of IL-1[alpha] to activate the HPA axis might be partially dependent on the release of prostaglandins….[there is] a role for prostaglandins in IL-1-mediated activation of the HPA axis….”  Haddad, Saade & Safieh-Garabedian 2002, p6

“…more than one mechanism could be involved in the HPA response to IL-1:  the more rapid one…[and the] slower one….glucocorticoids, known to modulate CRF release by negative feedback inhibition, have been postulated to exert a permissive action the IL-1 effect on CRF secretion….IL-1 does not seem to induce CRF secretion by interfering with an impeding action of glucocorticoids, although the cytokine effect is negatively modulated by corticosteroids.”  Haddad, Saade & Safieh-Garabedian 2002, p6

“…IL-1 and glucocorticoid hormones represent two key mediators involved in the modulation of the neuro-immuno-endocrine response to stress.

In the immune system, glucocorticoids modulate IL-1 production and a number of IL-1 receptors.”  Haddad, Saade & Safieh-Garabedian 2002, p6

“…glucocorticoids inhibit the autoregulatory loop of IL-1…and constitute a mechanism for controlling IL-1 feedback stimulation….”  Haddad, Saade & Safieh-Garabedian 2002, p7

“In contrast, proinflammatory cytokines can reduce glucocorticoid receptor translocation and function.  Specifically, several studies have found that cytokines induce a decrease in glucocorticoid receptor (GR) function, as evidenced by reduced sensitivity to glucocorticoid effects on functional end points….cytokines produced during an inflammatory response may induce GR resistance in relevant cell types by direct effects on the GR, thereby providing an additional pathway by which the immune system can influence the HPA axis….”  Haddad, Saade & Safieh-Garabedian 2002, p7

Glucocorticoids are widely used in the therapy of inflammatory, autoimmune and allergic diseases.  As the end-effectors of the HPA axis, endogenous glucocorticoids also play an important role in suppressing innate and cellular immune responses.” Haddad, Saade & Safieh-Garabedian 2002, p. 10

“Recent studies have indicated that IL-12 promotes Th1 cell-mediated immunity, while IL-4 stimulates Th2 humoral-mediated immunity….The regulatory effect of glucocorticoids on key elements of IL-12 and IL-4 signaling were…examined.  On the analysis of the effect of Dex on IL-12-inducible genes….”  Haddad, Saade & Safieh-Garabedian 2002, p11

“…suppressive action of glucocorticoids on the Th1 cellular immune response and … the glucocorticoid-induced shift toward the Th2 humoral immune response….”   Haddad, Saade & Safieh-Garabedian 2002, p 12

“…the upregulation of IL-10 production could be involved in the prolonged clinical benefit.  [talking about Dex treatment or rheumatoid arthritis (RA) patients]  The strong immunosuppressive effect is…accompanied by a relative shift towards T2 cell activity….this shift in T cell balance was a direct effect of Dex and thus independent of the HPA axis….the antiinflammatory activity of corticosteroids….. Haddad, Saade & Safieh-Garabedian 2002, p. 10

[LPS – lipopolysaccharide – compound containing lipid bound to a polysaccharide; often a component of microbial cells walls]

[polysaccharide – a complex carbohydrate composed of three or more simple carbohydrate molecules joined together – Any of a class of carbohydrates, such as starch and cellulose]

“Administration of LPS results in the activation of the HPA axis….The mechanisms through which LPS stimulates the HPA axis are not well understood, however….”  Haddad, Saade & Safieh-Garabedian 2002, p7

results of studies suggest “…that LPS activates the HPA axis through a mechanism involving the activation of IL-1 receptors and that the effect of IL-1[beta], but not IL-1[alpha]….LPS acts both at the level of the brain and the gonads to stimulate the HPA axis, and inhibits the hypothalamic-pituitary-gonadal (HPG) axis….”  Haddad, Saade & Safieh-Garabedian 2002, p7

“Further elaborating on the mechanisms related to LPS-mediated regulation of the HPA axis, a role for hippocampal mineralocorticoid (type 1) receptor has been reported….binding properties of the corticosteroid receptor system, which mediates feedback inhibition of the HPA axis….an impaired feedback of the HPA axis via deficient hippocampal MRs contributes to stimulate corticosterone [in rats, cortisol in humans] secretion from the adrenals during infection.”  Haddad, Saade & Safieh-Garabedian 2002, p8

“Exogenously administered IL-1 mimics most of the effects of LPS on pituitary activity.  In addition, antibodies against IL-1 receptors can interfere with LPS-induced ACTH secretion, indicating that at least part of the ability of LPS to alter endocrine functions appears to depend upon endogenous IL-1….Of interest, IL-1 and IL-6 share a number of biological functions.  Because IL-1 induces IL-6 in vivo, the extent to which IL-6 mediates the effects of IL-1 has come under investigation….The stimulation of the HPA axis by IL-1 and IL-6 is recognized as a critical component of the inflammatory response…suboptimal amounts of IL-1[alpha] and IL-6 to induce an early (30 – 60 min) ACTH response and produces a later (2 – 3 h) response that was similar to the one observed after IL-1[alpha] was administered alone, suggesting that the late response to IL-1 may be dependent on synergy with the endogenous IL-6 it induces systemically and in the CNS (including the hypothalamus and the pituitary gland)….  Haddad, Saade & Safieh-Garabedian 2002, p7

IL-1, IL-6 and TNF [tumor necrosis factor-alpha (TNF alpha) — by controlling gene expression, TNF alpha orchestrates the cutaneous responses to environmental damage and inflammation.]      —   “…all three inflammatory cytokines are obligatory for LPS-induced elevation of plasma ACTH….play different roles in LPS-induced ACTH release….LPS stimulates hypothalamic CRH by a mechanism that involves the action of IL-1 within the CNS and may proceed independently of peripheral actions of IL-1 circulating in the bloodstream….”  Haddad, Saade & Safieh-Garabedian 2002, p8

“…cytokines synergize the stimulatory effect of IL-1 on the HPA axis….interaction between IL-6 and IL-1, and between IL-6 and stress on the activation of the HPA axis…..findings indicate a modulatory role for IL-6 stimulated HPA axis activity in response to IL-1 or a novelty psychological stressor, but not for restraint stress….Although a considerable amount of evidence has shown that physical and psychological stress elevates the plasma IL-6 levels, the physiological significance of such an elevation remains to be elucidated….restraint stress-induced elevation of plasma IL-6 negatively regulates the plasma TNF-[alpha] levels and may thus contribute to the maintenance of homeostasis….”  Haddad, Saade & Safieh-Garabedian 2002, p8

IL-10 is a modulator of proinflammatory cytokines, IL-1 and TNF-alpha — Haddad, Saade & Safieh-Garabedian 2002, p. 11

“IL-10, has been shown to have a wide range of activities in the immune system…. [and] is produced in pituitary, hypothalamic and neural tissues in addition to lymphocytes….IL-10 enhances CRF and ACTH production in hypothalamic and [ACTH] pituitary tissues, respectively.  Further downstream in the HPA axis endogenous IL-10 has the potential to contribute to regulation of glucocorticosteroid production both tonically and following stressors.  Evidence indicated that IL-10 might be an important endogenous regulator in HPA axis activity and in CNS pathologies.  Thus, in addition to its more widely recognized role in immunity, as anti-inflammatory cytokine, IL-10’s neuroendocrine activities point to its role as an important regulator in communication between the immune and neuroendocrine systems….” Haddad, Saade & Safieh-Garabedian 2002, p. 11

“Another mechanisms reported implicated histamine receptors in LPS/IL-1-induced activation of the HPA axis and ACTH release.  LPS and LPS-derived cytokines stimulate the release of histamine (HA).  HA is a known hypothalamic neurotransmitter and activates the HPA axis.”  Haddad, Saade & Safieh-Garabedian 2002, p8

“…the cytokine IL-2 …[activates] the human HPA axis….ET [big-endothelinEndothelin–amino acid peptide produced in a variety of tissues including endothelial and vascular smooth-muscle cells, neurons and astrocytes in the central nervous system, and endometrial cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production.] might be a link between cytokines and CRH, most probably functioning as a cytokine-induced neuromodulator controlling pituitary functions….”  Haddad, Saade & Safieh-Garabedian 2002, p9

“The cytokine IL-2 exerts numerous effects within the immune as well as the central nervous system and is thought to serve as a humoral signal in their communicationA major role for IL-2 has been noted in the regulation of the HPA axis responses. Brain-derived or blood-borne IL-2 may also control the activity of the HPA axis at various levels of regulation.  IL-2, for example, caused a dose-dependent stimulation of AVP [vasopressin] secretion from both the intact rat hypothalamus in vitro and hypothalamic cell cultures….IL-s, however, did not increase the secretion of CRH in either preparation, nor did it prime the cells to respond to a subsequent dose of IL-2….[providing] yet another line of communication between the immune and neuroendocrine systems.”  Haddad, Saade & Safieh-Garabedian 2002, p9

Accumulating evidence indicates that IL-3 can activate the HPA axis….IL-3 and IL-6 directly stimulate the steroidogenesis at the adrenal level through activation of different, cAMP-independent pathways.  While the stimulatory effect of IL-6 on cortisol secretion from adult human adrenocortical cells seems to be mediated through the COX pathway, the effect of IL-3 on adrenocortical cortisol secretion is dependent on the lipoxygenase [an enzyme?] pathway….both IL-3 and IL-6 stimulated basal cortisol secretion dose-dependently to a similar extent at a similar time course [in studies] ….While the stimulatory effect of IL-3 seems to be dependent on the lipoxygenase pathway, the effect of IL-6 on adrenocortical cortisol secretion is mediated through the COX pathway.”  Haddad, Saade & Safieh-Garabedian 2002, p10

“Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways.  The CNS regulates systemic inflammatory responses to LPS, for instance, through humoral mechanisms….Activation of afferent vagus nerve fibers by LPS or cytokines specifically stimulates HPA anti-inflammatory responses.  In this respect, it was described that a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to LPS is active at the level of the HPA axis…..Acetylcholine, the principle vagal neurotransmitter, significantly attenuated [lessened] the release of proinflammatory cytokines, including IL-18, but not the anti-inflammatory cytokine IL-10, in LPS-stimulated human macrophage cultures.  Furthermore, direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock….Similarly, increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF-[alpha], IL-1[beta], IL-6 and IL-18….[there is] a close relationship between the inflammatory process and the HPA axis….” ….”  Haddad, Saade & Safieh-Garabedian 2002, p. 12

cytokine – “messenger” molecule that allows cells to communicate and alter one another’s function – Cytokine: A small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal molecules, such as tumor necrosis factor and the interferons, which trigger inflammation and respond to infections.


“The Mammalian stress response evokes a series of neuroendocrine responses that activate the HPA axis and the SNS….Coordinated interactions between stress response systems, occurring at multiple levels including the brain, pituitary gland, adrenal gland and peripheral tissues, are required for the maintenance of homeostatic plateau. Adaptation to stress evokes a variety of biological responses, including activation of the HPA axis and synthesis of a panel of stress-response proteins at cellular levels.”  Haddad, Saade & Safieh-Garabedian 2002, p. 12

“For example, expression of thioredoxin (TRX), a non-thiol antioxidant, is significantly induced under oxidative conditions….TRX expression….negatively [modulates] GR function and [decreases] glucocorticoid-inducible gene expression.”  Haddad, Saade & Safieh-Garabedian 2002, p. 12

“…impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most possibly through the functional replenishment of the GR….Moreover, not only the ligand-binding domain but also the DNA binding domain of the GR was also suggested to be a direct target of TRX.  Together, these observations presented conclusive evidence showing that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level and, thereby, it was proposed that cross talk between neuroendocrine control of stress responses and cellular antioxidant systems may be essential for mammalian adaptation processes.”  Haddad, Saade & Safieh-Garabedian 2002, p. 13

“…CRH has a neuroprotective activity in CRH-receptor type 1 (CRH-R1)-expressing neurons against oxidative cell death ….protective effect of CRH…..observations strongly demonstrated a novel cytoprotective effect of CRH that is mediated by CRH-R1 and …indicate CRH as an endogenous protective neuropeptide against oxidative cell death in addition to its function in the HPA system.  Moreover, the protective function of CRH proposes a molecular link between oxidative stress-related degenerative events and the CRH-R1 system.”  Haddad, Saade & Safieh-Garabedian 2002, p. 13

NO and CO and oxidative stress and HPA interactions

“…the brain has the capacity to synthesize impressive amounts of the gases nitric oxide (NO) and carbon monoxide (CO)….There is growing evidence that these gaseous molecules function as novel neural messengers in the brain….”  Haddad, Saade & Safieh-Garabedian 2002, p. 13

“NO has an important role in the control of reproduction ….and also appears to mediate the action of one of the major transmitters…glutamate…..Evidence also suggests that NO act to restrain the HPA axis, as it inhibits HPA stimulation by various stimulants such as IL-1, vasopressin (VP) and inflammation.  This effect fits a proinflammatory role of NO as it leads to suppression of the release of the anti-inflammatory corticosteroids from the adrenal…..NO is an unusual chemical messenger.  NO mediates blood vessel relaxation when produced by endothelial cells.  When produced by macrophages, NO contributes to the cytotoxic function of these immune cells.  NO also functions as a neurotransmitter and neuromodulator in the central and peripheral nervous systems.  The effects on blood vessel tone and neuronal function form the basis for an important role of NO on neuroendocrine function and behavior.  NO mediates hypothalamic portal blood flow and, (p 13) thus, affects OT and VP secretion; furthermore, NO mediates neuroendocrine functions in the HPG and HPA axes.  NO influences several motivated behaviors including sexual, aggressive and ingestive behaviors.  NO also influences learning and memory….NO, thus, is emerging as an important chemical mediator of neuroendocrine function and behavior.”  Haddad, Saade & Safieh-Garabedian 2002, p. 14

“NOS, the enzyme responsible for NO formation, is found in hypothalamic neurons containing OT, VP and, to a lesser extent, CRF.” Haddad, Saade & Safieh-Garabedian 2002, p. 14

“…stress-induced increase in NO synthesis in the adrenal cortex can modify the stress-induced corticosterone response to facilitate the recovery from the elevated CORT secretion by stress in the adrenal cortex to the resting basal level…..the immobilization stress can cause changes in the enzyme activity and gene expression of neuronal NOS in the hypothalamus, pituitary and adrenal gland in vivo…..A significant increase of NOS enzyme activity in the anterior pituitary, adrenal cortex and adrenal medulla was observed in the stressed animals, as compared to control rats….Upregulation of NOS mRNA expression in anterior pituitary and adrenal cortex was already detectable after stress.  The NOS mRNA signals in PVN increased after the stress imposed….suggesting that psychological and/or physiological stress causes NO release in the HPA axis and in the sympatho-adrenal system….It was proposed that NO may modulate a stress-induced activation of the HPA axis and the sympatho-adrenal medullary system….The different duration of stress-induced NOS activity in HPA axis and the adrenal medulla may suggest NO synthesis is controlled by separate mechanism in the two HPA and sympatho-adrenal systems….”  Haddad, Saade & Safieh-Garabedian 2002, p. 14

molecular mechanisms reported for the action of NO with the HPA axis

“…NO stimulates the activity of PVN neurons that control the HPA axis…..the determination whether this effect was direct or mediated through PVN afferents….{could not be determined}”  Haddad, Saade & Safieh-Garabedian 2002, p. 15

“Although not as intensely studied as NO, CO has been shown to suppress stimulated CRH release and may also function to restrain the HPA axis….Evidence implicating NO in the control of prolactin (PRL) and GH secretion is plausible, as is the possible role of NO acting directly at the anterior pituitary.”  Haddad, Saade & Safieh-Garabedian 2002, p. 13

“Taken as a whole, the current data suggest that the diffusible gases, NO and CO, act as novel transmitters in the neuroendocrine axis and mediate a variety of important neuroendocrine functions.”  Haddad, Saade & Safieh-Garabedian 2002, p. 13


”Further elaborating on the role of transcriptional regulation in HPA responses, dysregulation of the serotonergic system and abnormalities of the HPA axis function have been implicated to be involved in neuropsychiatric disorders. ….[see Wissink et al 2000 below]  Corticosteroid hormones in a variety of animal models suppress serotonin-1A receptors.  This effect may play a central role in the pathophysiology of depression. However, little is known about the molecular mechanism underlying this suppressive effect of CORT [on transcription]….Remarkably, only the GR and not the MR was able to mediate this repressive effect of CORT, thus arguing that negative cross-talk between the GR and ….[elements mediating induction of transcription that CORT represses]….may provide a basis for the molecular mechanism underlying the negative action of CORT on serotonin signaling in the brain….”  Haddad, Saade & Safieh-Garabedian 2002, p. 13

So does this link have something to do with the GR aspect not working right due to interference of some kind with immune system activation effects?

Here are some more articles that relate to this:


Wissink et al 2000

Abstract – Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.

Regulation of the rat serotonin-1A receptor gene by corticosteroids.

Dysregulation of the serotonergic system and abnormalities of the hypothalamic-pituitary-adrenal axis function have been implicated to be involved in neuropsychiatric disorders.

Serotonin-1A receptors

have been shown to be suppressed

by corticosteroid hormones

in a variety of animal studies.

This effect may play a central role in the pathophysiology of depression.

However, little is known about the molecular mechanism underlying this suppressive effect of corticosteroids

Here, we show by functional analysis of the promoter region of the rat serotonin-1A receptor gene that two NF-kappaB elements in the promoter contribute to induced transcription of the rat serotonin-1A receptor gene. Furthermore, we show that


repress this NF-kappaB-mediated induction of transcription.

Remarkably, we observed that

only the glucocorticoid receptor

and not the mineralocorticoid receptor

was able to mediate this repressive effect of corticosteroids.

[see below, context dependent action: Meijer et al 2000]

We argue that negative cross-talk between the glucocorticoid receptor and NF-kappaB may provide a basis for the molecular mechanism underlying the negative action of corticosteroids on serotonin signaling in the brain.


Meijer et al 2000

Abstract – Department of Physiology, Division of Nephrology, University of California, San Francisco, CA, USA.

Transcriptional repression of the 5-HT1A receptor promoter by corticosterone via mineralocorticoid receptors depends on the cellular context.

The diverse effects of the corticosteroid hormones are mediated in large measure by the mineralocorticoid and glucocorticoid receptors, two closely related members of the nuclear receptor superfamily.

In the brain, corticosteroids regulate neuronal excitability and responses to neurotransmitters in a cell type-specific manner.

The 5-HT1A receptor, for example,

is highly expressed in the hippocampus and raphe

but transcription is repressed by corticosterone

(the principal glucocorticoid in rodents)

only in hippocampus.

We have used transient transfection of cultured cells to study the transcriptional regulation of the 5-HT1A receptor promoter by activators and repression by glucocorticoids. We find that

transcription factors Sp1 and NF-kB subunit p65, both of which are coexpressed in hippocampus with the 5-HT1A receptor in vivo, synergistically activate a reporter driven by receptor 5′-flanking region.

Primer extension data suggest that the multiple transcription initiation sites used in reporter gene transcription correlate with those used in transcription of the endogenous gene which has a TATA-less promoter.

Repression of transcription by corticosteroids was found to be mediated by both mineralocorticoid and glucocorticoid receptors, but not identically.

While glucocorticoid receptors potently inhibited both p65- and p65/Sp1-stimulated transcription, repression via mineralocorticoid receptors (MR) depended on the transcriptional activators that were present: p65-stimulated reporter activity was not repressed via MR, whereas a similar level of transcription resulting from synergistic activation by p65/Sp1-stimulation was repressed via MR.

The context-dependence

of these MR-mediated effects provides a model for the cell-type and state-dependent actions of corticosterone in the brain.


OU et al 2001

Abstract and article free online- Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario K1H-8M5, Canada.

Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene.

Negative regulation of neuronal serotonin (5-HT1A) receptor levels

by glucocorticoids in vivo may contribute to depression.

Both types I (mineralocorticoid) and II (glucocorticoid) receptors (MR and GR, respectively) participate in corticosteroid-induced transcriptional repression of the 5-HT1A gene; however, the precise mechanism is unclear.

A direct repeat 6-base pair glucocorticoid response element (GRE) half-site 5′-TGTCCT separated by 6 nucleotides was conserved in human, mouse, and rat 5-HT1A receptor promoters. In SN-48 neuronal cells that express MR, GR, and 5-HT1A receptors, deletion or inactivation of the nGRE (negative GRE) eliminated negative regulation of the rat 5-HT1A or heterologous promoters by corticosteroids, whereas its inclusion conferred corticosteroid-induced inhibition to a heterologous promoter. Bacterially expressed recombinant MR and GR preferentially bound to the nGRE as a heterodimer, as identified in nuclear extracts of MR/GR-transfected COS-7 cells, and with higher affinity than MR or GR homodimers. In SN48 and COS-7 cells, concentration-dependent coactivation of MR and GR was required for maximal inhibitory action by corticosteroids and was abrogated in the L501P-GR mutant lacking DNA binding activity. Corticosteroid-mediated transcriptional inhibition was greater for MR/GR in combination than for MR or GR alone.

These data represent the first identification of an nMRE/GRE and indicate that heterodimerization [Heterodimers are relatively common and it may be that the arrangement has the advantage that, for example: several different binding subunits may interact with a conserved signaling subunit] of MR and GR mediates direct corticosteroid-induced transrepression of the 5-HT1A receptor promoter.


“Adrenal corticosteroids readily enter the central nervous system to regulate a diversity of processes that involve the serotonergic system, including mood and emotion.”  OU et al 2001, p. 14299

“Limbic brain regions involved in mood control, such as the hippocampus and septum, are richly innervated by serotonergic neurons (6). Glucocorticoids exert strong negative regulation on the serotonergic system (7–9), and the limbic system is particularly sensitive to glucocorticoids because both high and low affinity glucocorticoid receptor types I and II (i.e. MR and GR) are present (10–12). The 5-HT1A receptor plays an important dual role in the serotonergic system, because it is expressed both postsynaptically in the limbic system and presynaptically as the primary somatodendritic autoreceptor of serotonergic raphe neurons (13, 14). The level of expression of somatodendritic 5-HT1A receptors determines serotonergic tone, in part, by inhibiting raphe firing activity and is thus implicated in mood disorders, such as depression and generalized anxiety, that involve the serotonergic system (11, 15, 16). Major depression has also been associated with disruption of the hypothalamic-pituitary-adrenal axis; as many as 50% of depressed patients fail to suppress corticotrophin and cortisol levels upon dexamethasone challenge. Interactions between glucocorticoids and the serotonin system may be critical in the origin or maintenance of the depressed state.”  OU et al 2001, p. 14299

“The 5-HT1A receptor is strongly expressed in the hippocampus, septum, and other limbic areas (17, 18) and functions as a key regulator of the limbic system. Transcription of the 5-HT1A receptor gene is negatively regulated by corticosteroids especially in the limbic system…. The extent of increase in 5-HT1A receptor gene transcription upon adrenalectomy was most robust in the hippocampus and septum, with smaller changes in the raphe nuclei.”  OU et al 2001, p. 14299

“Because interactions between MR and GR appear to play an important role in glucocorticoid-mediated regulation of 5-HT1A receptor transcription in vivo, gel shift and cotransfection experiments were designed to assess functional interactions at the 5-HT1A promoter. Our findings indicate that a novel nGRE confers direct negative regulation by corticosteroids to the rat 5-HT1A receptor or heterologous promoters and suggest that MR and GR form a novel head-to-tail heterodimeric complex with the nGRE to mediate glucocorticoid-induced gene repression.”  OU et al 2001, p. 14300

article’s discussion

“The level of expression of the 5-HT1A receptor has been implicated in mental illnesses such as major depression, anxiety, and related disorders. For example, gene knockout of the 5-HT1A receptor gene results in mice with increased anxiety-related behaviors (3–5). On the other hand, depressed suicides show elevated levels of 5-HT1A autoreceptors compared with nondepressed suicides (46). Dysregulation of glucocorticoids is observed in a large proportion of depressed patients, suggesting a link between regulation of the 5-HT1A receptor by glucocorticoids and the etiology or maintenance of depression.”  OU et al 2001, p. 14303

“The NFkB-dependent indirect pathway of glucocorticoid regulation may provide a complementary mechanism to regulate 5-HT1A receptor expression, especially in fibroblast or immune cells where NFkB is implicated in the stimulation of 5-HT1A receptor expression (49).”  OU et al 2001, p. 14304

“…the nMRE/ GRE of the MR1GR combination was significant higher than that of GR or MR alone. Corticosteroid repression of transcriptional activity of the rat 5-HT1A receptor gene proceeded through a mechanism involving preferential coactivation of both MR and GR. Cooperative interactions between MR and GR at a positive GRE have been reported in the nervous system

54), in which MR and GR activate transcription synergistically through heterodimer formation.”  OU et al 2001, p. 14304

“Thus, direct glucocorticoid-induced transrepression at the nGRE is likely to represent the dominant mechanism of basal regulation of the 5-HT1A gene. The NFkB-dependent indirect pathway of glucocorticoid regulation may provide a complementary mechanism to regulate 5-HT1A receptor expression, especially in fibroblast or immune cells where NFkB is implicated in the stimulation of 5-HT1A receptor expression (49).”  OU et al 2001, p. 14304

“The high affinity of MR for corticosterone would allow for high sensitivity to the actions of glucocorticoids in regions that express this receptor (55). The strong expression of 5-HT1A receptors in MR-enriched hippocampal CA1 pyramidal cells and the cooperative interactions between MR and GR at the 5-HT1A nGRE strongly suggest that heterodimerization is the key mechanism for inhibitory regulation by glucocorticoids of the 5-HT1A receptor gene in the brain.”  OU et al 2001, p. 14304

“In conclusion, we have identified a novel nMRE/GRE that demonstrates the crucial role of MR/GR heterodimers in mediating responses to corticosteroids, not only for transcriptional activation but also for transcriptional repression. This is consistent with the general importance of heterodimerization of the steroid receptor family of nuclear receptors (44, 63). Furthermore, our results provide a plausible mechanism for the sensitivity of the rat 5-HT1A receptor gene to corticosteroid induced transrepression, particularly in the hippocampus where MR and GR are both expressed.”  OU et al 2001, p. 14305


Stockmeier et al 1998

Abstract and free online article – Program in Basic and Clinical Neuroscience, Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity.

It has been hypothesized that a deficit in serotonin

may be a crucial determinant in the pathophysiology

of major depression.

Serotonin-1A receptors are located on serotonin cell bodies

in the midbrain dorsal raphe (DR) nucleus,

and the activation of these receptors

inhibits the firing of serotonin neurons

and diminishes the release of this neurotransmitter in the prefrontal cortex.

Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain.

The present study determined whether the binding of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [3H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [3H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.


“…changes in serotonin-1A receptors in the human midbrain may alter the release of serotonin in prefrontal cortex and thereby play a significant role in major depression.”  Stockmeier et al 1998, p 7394

significant increase in serotonin-1A receptors in depressed suicides

Our evidence in these subjects indicates that major depression, suicide, or the combination of these two factors is related to a significant and consistent increase in serotonin-1A receptors at several levels along the midbrain DR [dorsal raphe (DR)].” Stockmeier et al 1998, p 7395

midbrain DR was sampled at several rostral-to-caudal levels

“In contrast to presynaptic serotonin-1A receptors in the DR, serotonin-1A receptors in prefrontal cortex are located postsynaptically, and their involvement in depression and suicide awaits further clarification.”  Stockmeier et al 1998, p 7397

“The role that serotonin-1A receptors in the DR plays in depression and suicide may be related to the location of these receptors on serotonin neurons and the ability of these receptors to regulate the electrical activity of serotonin neurons. The serotonin-1A receptor protein is synthesized by serotonin neurons in the DR, and immunohistochemical evidence reveals that nearly all of these receptors are located on the perikarya and dendrites of serotonin neurons (Sotelo et al., 1990; Miquel et al., 1992). The serotonin-1A receptor has been classified functionally as an inhibitory autoreceptor, because the firing rate of serotonin neurons in the DR is inhibited by the direct application of 8-OH-DPAT, a serotonin-1A receptor agonist, into the DR (Sprouse and Aghajanian, 1986). Thus, the observed increase in presumably inhibitory serotonin-1A receptors in the DR of suicide victims with major depression may provide pharmacological evidence for diminished activity of serotonin neurons in these subjects.”  Stockmeier et al 1998, p 7397

“Serotonin-1A receptors in the midbrain DR may be critical to the therapeutic effect of some antidepressant treatments, as revealed by electrophysiological experiments. Serotonin-1A receptors in the DR are desensitized by the repeated treatment of experimental animals with a monoamine oxidase inhibitor or SSRI (Blier et al., 1986; Chaput et al., 1988), and that desensitization is coupled with a facilitation of serotonin output in the frontal cortex (Invernizzi et al., 1994). Thus, the therapeutic action of some antidepressant treatments in humans may involve the facilitation of serotonin neurotransmission in prefrontal cortex in response to desensitization of inhibitory serotonin-1A autoreceptors in the midbrain DR (Blier and De Montigny, 1994). In this study the observation of increased serotonin-1A receptors in the midbrain DR of suicide victims with major depression is consistent with the hypothesis that the therapeutic effect of antidepressant medications may involve at least physiological desensitization (if not downregulation) of these receptors on serotonin neurons.”  Stockmeier et al 1998, p 7400

“Future studies in subjects with major depression not dying by suicide and in suicide victims not meeting criteria for major depression will help to identify whether increased serotonin-1A receptors in the midbrain DR are associated with suicide per se, major depression, or an interaction between major depression and suicide.”  Stockmeier et al 1998, p 7400

of note in regard to action of antidepressants:

Serotonin-1A receptors in the midbrain DR may be critical to

the therapeutic effect of some antidepressant treatments…. Serotonin-1A receptors

in the DR are desensitized by the repeated treatment of

experimental animals with a monoamine oxidase inhibitor or

SSRI (Blier et al., 1986; Chaput et al., 1988), and that desensitization

is coupled with a facilitation of serotonin output in the

frontal cortex (Invernizzi et al., 1994). Thus, the therapeutic

action of some antidepressant treatments in humans may involve

the facilitation of serotonin neurotransmission in prefrontal cortex

in response to desensitization of inhibitory serotonin-1A

autoreceptors in the midbrain DR (Blier and De Montigny, 1994).

In this study the observation of increased serotonin-1A receptors

in the midbrain DR of suicide victims with major depression is

consistent with the hypothesis that the therapeutic effect of antidepressant

medications may involve at least physiological desensitization

(if not downregulation) of these receptors on serotonin


It has been suggested that serotonin-1A autoreceptors in the

midbrain play a role in hastening the antidepressant effect of

SSRIs (Artigas et al., 1996). Two open-label studies reported that

pindolol, an antagonist at b-adrenergic and serotonin-1A receptors,

induced a rapid improvement in depressive symptoms in

patients treated with an SSRI or monoamine oxidase inhibitor

(Artigas et al., 1994; Blier and Bergeron, 1995). Artigas et al.

(1996) suggest that the 2 week delay in the onset of the therapeutic

benefit of antidepressant medication may be attributable to

the ability of an SSRI to increase the extracellular concentration

of serotonin in the midbrain DR, thereby activating inhibitory

somatodendritic serotonin-1A autoreceptors. As a result of a

diminished firing of serotonin neurons, the extracellular concentration

of serotonin in the cerebral cortex would be diminished

early in the course of SSRI therapy. Cotreatment with pindolol, it

was hypothesized, would restore the firing of serotonin neurons

by blocking the inhibitory somatodendritic serotonin-1A autoreceptors

and increasing extracellular serotonin concentrations in

the forebrain, thereby decreasing the latency of the antidepressant

response (Blier and Bergeron, 1997). Most, but not all,

double-blind placebo-controlled studies of pindolol plus an SSRI

support the hypothesis that pindolol accelerates the antidepressant

response ….”
Stockmeier et al 1998, p 7400

It is hard to track through the research, switching from one research field to another.  If as the article above states, these serotonin alterations can be caused by corticosteroids from stress affecting the immune system, changing genetic transcription factors, then suicide can be an immune system response to an overly stressful environment?




Kawashima & Fujii 2000

Abstract – Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. kawashima-ki@kyoritsu-ph.ac.jp

Extraneuronal cholinergic system in lymphocytes.

Acetylcholine (ACh) is well known as a neurotransmitter in both the central and peripheral nervous systems in mammalian species.

Both muscarinic and nicotinic ACh receptors have been identified in lymphocytes isolated from thymus, lymph node, spleen, and peripheral blood, and their stimulation by muscarinic and nicotinic agonists elicits a variety of functional and biochemical effects.

On the basis of these findings, it has been

postulated that the parasympathetic nervous system

may play a role in immune-neurohumoral crosstalk.

However, ACh present in the blood of several species has been localized to lymphocytes from various origins using radioimmunoassay.

expression of choline acetyltransferase, an ACh synthesizing enzyme, has been identified in human blood mononuclear leukocytes, human leukemic T-cell lines, and rat lymphocytes. Stimulation of T-lymphocytes with phytohemagglutinin activates the lymphoid cholinergic system, as evidenced by increased synthesis and release of ACh, increased acetylcholinesterase activity, and the increased expression of mRNA encoding choline acetyltransferase and ACh receptors.

The observation that muscarinic receptor stimulation by ACh or agonists increases in [Ca(2)+](i) and up-regulates c-fos expression strongly argues that ACh synthesized and released from T-lymphocytes acts as an autocrine and/or paracrine factor regulating immune function.

In summary, these data present a compelling picture in which

immune function

is not only regulated by the cytokine system,

but is also under the control of an independent, lymphoid cholinergic system.


Fujii, Takada-Takatori & Kawashima 2007

Abstract – Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Tokyo 105-8512, Japan.

Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity.

Lymphocytes possess the essential components

of a cholinergic system,

including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).

Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity.


Kawashima & Fujii 2004

Abstract – Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. kawashima-ki@kyoritsu-ph.ac.jp

The lymphocytic cholinergic system and its biological function.

Lymphocytes are now known to possess the essential components for a non-neuronal cholinergic system.

These include acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).

Stimulating lymphocytes with phytohemagglutinin, a T-cell activator; Staphylococcus aureus Cowan I, a B-cell activator; or cell surface molecules enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. Activation of mAChRs and nAChRs on lymphocytes elicits increases in the intracellular Ca(2+) concentration and stimulates c-fos gene expression and nitric oxide synthesis. On the other hand, long-term exposure to nicotine down-regulates expression of nAChR mRNA. Abnormalities in the lymphocytic cholinergic system have been detected in spontaneously hypertensive rats and MRL-lpr mice, two animal models of immune disorders.

Taken together, these data present a compelling picture in which immune function is, at least in part, under the control of an independent non-neuronal lymphocytic cholinergic system.


Fujii 2004

Abstract – article in Japanese – Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan. fujii-tk@kyoritsu-ph.ac.jp

[An independent, non-neuronal cholinergic system in lymphocytes and its roles in regulation of immune function]

Acetylcholine (ACh) is classically thought of as a neurotransmitter in mammalian species.

However, lymphocytes express most of the cholinergic components found in the nervous system, including ACh, choline acetyltransferase (ChAT), high-affinity choline transporter, and acetylcholinesterase as well as both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).

Activation of T cells via the T cell receptor/CD3 complex, contact of T cells with antigen presenting cells, or activation of the adenylyl cyclase pathway in T cells modulates cholinergic activity, as evidenced by up-regulation of ChAT and M(5) mAChR mRNA expression. Stimulation of mAChRs on T and B cells with ACh or another mAChR agonists elicits intracellular Ca(2+) signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and interleukin-2-induced signal transduction via M(3) and M(5) mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca(2+) signaling in T and B cells, probably via alpha7 nAChRs subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Abnormalities in lymphocytic cholinergic system have been seen in animal models of immune deficiency and immune acceleration. Collectively, these data provided a compelling picture in which immune function is, at least partly, under the control of an independent, non-neuronal cholinergic system in lymphocytes.


Fujii & Kawashima 2001

Abstract – Department of Pharmacology, Kyoritsu College of Pharmacy, Tokyo, Japan.

An independent non-neuronal cholinergic system in lymphocytes.

Acetylcholine (ACh) is a well characterized neurotransmitter occurring throughout the animal kingdom.

In addition, both muscarinic and nicotinic ACh receptors have been identified on lymphocytes of various origin, and their stimulation by muscarinic or nicotinic agonists elicits a variety of functional and biochemical effects.

It was thus initially postulated that the parasympathetic nervous system may play a role in modulating immune system function. However, ACh in the blood has now been localized to lymphocytes; indeed expression of choline acetyltransferase (ChAT), an ACh synthesizing enzyme, has been shown in human blood mononuclear leukocytes, human leukemic T-cell lines and rat lymphocytes. Stimulation of T-lymphocytes with phytohemagglutinin activates the lymphoid cholinergic system, as evidenced by increased synthesis and release of ACh and increased expression of mRNAs encoding ChAT and ACh receptors. The observation that M3 muscarinic receptor stimulation by ACh and other agonists increases the intracellular free Ca2+ concentration and upregulates c-fos gene expression strongly argues that ACh, synthesized and released from T-lymphocytes, acts as an autocrine and/or paracrine factor regulating immune function. These findings present a compelling picture in which immune function is, at least in part, under the control of an independent lymphoid cholinergic system.


Kawashima & Fujii 2003

Abstract – Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. kawashima-ki@kyoritsu-ph.ac.jp

The lymphocytic cholinergic system and its biological function.

Lymphocytes are now known to possess the essential components for a non-neuronal cholinergic system.

These include acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulating lymphocytes with phytohemagglutinin, a T-cell activator; Staphylococcus aureus Cowan I, a B-cell activator; or cell surface molecules enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. Activation of mAChRs and nAChRs on lymphocytes elicits increases in the intracellular Ca(2+) concentration and stimulates c-fos gene expression and nitric oxide synthesis. On the other hand, long-term exposure to nicotine down-regulates expression of nAChR mRNA. Abnormalities in the lymphocytic cholinergic system have been detected in spontaneously hypertensive rats and MRL-lpr mice, two animal models of immune disorders. Taken together, these data present a compelling picture in which immune function is, at least in part, under the control of an independent non-neuronal lymphocytic cholinergic system


Dinan et al 2008 —

Abstract – Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

Enhanced cholinergic-mediated increase in the pro-inflammatory cytokine IL-6 in irritable bowel syndrome: role of muscarinic receptors.

OBJECTIVES: Irritable bowel syndrome (IBS) is a functional disorder, which has recently been linked to immune activation.

We tested the hypothesis that the pro-inflammatory cytokine profile in IBS is driven by the cholinergic system and determined if the responses are mediated by muscarinic receptors. METHODS: Eighty-eight subjects took part in two studies, 37 IBS patients (Rome II), 14 depressed patients, and 37 healthy volunteers. Eighteen IBS patients had diarrhea predominant IBS, 14 were alternators, and 5 were predominantly constipated. In study 1, blood was drawn for baseline measurement of growth hormone (GH) and cytokines IL-6, IL-8, and IL-10. Pyridostigmine 120 mg was administered orally and further blood sampling took place for 180 min. In study 2, patients with IBS, depressed patients, and healthy subjects underwent the pyridostigmine test on two separate occasions with procyclidine (antimuscarinic) pre-treatment on one test occasion. Both GH and IL-6 were monitored. RESULTS: In study 1, baseline IL-6 (P= 0.003) and IL-8 levels (P= 0.001) were higher in IBS than in controls. Pyridostigmine stimulated the release of IL-6 and GH, but not IL-8 or IL-10; these responses were significantly augmented in IBS patients relative to controls. The IL-6 level following pyridostigmine administration correlated significantly with the symptom score (P < 0.01). In study 2, IL-6 rose following pyridostigmine in IBS but not depression and procyclidine blocked the rise. The GH response was abolished by procyclidine in all three groups. CONCLUSIONS:

IBS and major depression are characterized

by a pro-inflammatory profile,

whereas IBS patients alone exhibit an exaggerated

muscarinic receptor-mediated IL-6 response.

I’m not convinced that depression is not an immune system response itself – a proinflammatory immune response –a reaction to when the immune system sensitivities are overwhelmed


Shah et al 2008

Abstract – University of Maryland School of Medicine.

Muscarinic receptors and ligands in cancer.

Emerging evidence indicates that

muscarinic receptors and ligands play key roles in regulating cellular proliferation and cancer progression.

Both neuronal and non-neuronal acetylcholine production results in neurocrine, paracrine and autocrine promotion of cell proliferation, apoptosis, migration, and other features critical for cancer cell survival and spread.

The present review comprises a focused critical analysis of evidence supporting the role of muscarinic receptors and ligands in cancer.

Criteria are proposed to validate the biological importance of muscarinic receptor expression, activation, and post-receptor signaling.

Likewise, criteria are proposed to validate the role of non-neuronal acetylcholine production in cancer.

Dissecting cellular mechanisms necessary for muscarinic receptor activation as well as those needed for acetylcholine production and release will identify multiple novel targets for cancer therapy. Key words: muscarinic receptors, cancer, cholinergic signaling, acetylcholine, bile acids.


Tata 2008

Abstract – Dept. of Cell and Developmental Biology, La Sapienza Università di Roma, Research Center of Neuroscience Daniel Bovet, P.le A. Moro, 5, 00185 Roma, Italy. adamaria.tata@uniroma1.it

Muscarinic acetylcholine receptors: new potential therapeutic targets in antinociception and in cancer therapy.

The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice.


in fact is synthesized not only in the nervous system

but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation).

The possible involvement of acetylcholine and muscarinic receptors in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer and Sjogren’s diseases).

This review will focus on the potential implications of muscarinic receptors in tumor progression and in nociception and the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin,; patent, US5096890; US6106864 ) have also been demonstrated to arrest tumor progression in nude mice.

Moreover muscarinic agonists such as vedaclidine, CMI- 936 and CMI-1145 have been demonstrated to have analgesic effects, in animal models comparable or more pronounced to those produced by morphine or opiates.


Cheng et al 2008

Abstract – Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Healthcare System, University of Maryland School of Medicine, Department of Pathology, 22 S. Greene St., N3W62, Baltimore, MD 21201, USA.

Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation.

Most colon cancers

overexpress M3 muscarinic receptors (M3R), and post-M3R signaling stimulates human colon cancer cell proliferation.

Acetylcholine (ACh),

a muscarinic receptor ligand traditionally regarded as a neurotransmitter, may be produced by nonneuronal cells.

We hypothesized that ACh release by human colon cancer cells results in autocrine stimulation of proliferation.

H508 human colon cancer cells, which have robust M3R expression, were used to examine effects of muscarinic receptor antagonists, acetylcholinesterase inhibitors, and choline transport inhibitors on cell proliferation. A nonselective muscarinic receptor antagonist (atropine), a selective M3R antagonist (p-fluorohexahydro-sila-difenidol hydrochloride), and a choline transport inhibitor (hemicholinum-3) all inhibited unstimulated H508 colon cancer cell proliferation by approximately 40% (P<0.005). In contrast, two acetylcholinesterase inhibitors (eserine-hemisulfate and bis-9-amino-1,2,3,4-tetrahydroacridine) increased proliferation by 2.5- and 2-fold, respectively (P<0.005). By using quantitative real-time PCR, expression of choline acetyltransferase (ChAT), a critical enzyme for ACh synthesis, was identified in H508, WiDr, and Caco-2 colon cancer cells. By using high-performance liquid chromatography-electrochemical detection, released ACh was detected in H508 and Caco-2 cell culture media. Immunohistochemistry in surgical specimens revealed weak or no cytoplasmic staining for ChAT in normal colon enterocytes (n=25) whereas half of colon cancer specimens (n=24) exhibited moderate to strong staining (P<0.005). We conclude that ACh is an autocrine growth factor in colon cancer. Mechanisms that regulate colon epithelial cell production and release of ACh warrant further investigation.

Song et al 2003

Abstract – Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA.

Synthesis of acetylcholine by lung cancer.

The role of autocrine growth factors in the stimulation of lung cancer growth is well established.


is an agonist for acetylcholine receptors

and stimulates lung cancer growth.

This suggests that if lung cancers synthesize acetylcholine (ACh), then ACh may be an autocrine growth factor for lung cancer.

Analysis of normal lung demonstrated that the cells of origin of lung cancers express the proteins necessary for non-neuronal ACh storage and synthesis.

Analysis of mRNA from squamous cell lung carcinoma, small cell lung carcinoma (SCLC) and adenocarcinoma showed synthesis of choline acetyltransferase (ChAT) and nicotinic receptors.

Immunohistochemical analysis of a retrospective series of SCLC and adenocarcinomas showed that more than 50% of the lung cancers screened expressed ChAT and nicotinic receptors.

To study the effect of endogenous ACh synthesis on growth, SCLC cell lines were studied. SCLC cell lines were found to express ChAT mRNA and to secrete ACh into the medium as measured by HPLC separation and enzymatically-coupled electrochemical detection. The SCLC cell line NCI-H82 synthesized highest levels of ACh. Showing that the endogenously synthesized ACh interacted with its receptors to stimulate cell growth, addition of muscarinic and nicotinic antagonists slowed H82 cell proliferation. These findings demonstrate that lung cancer cell lines synthesize and secrete ACh

to act as an autocrine growth factor.

The existence of a cholinergic autocrine loop in lung cancer provides a basis for understanding the effects of nicotine in cigarette smoke on lung cancer growth and provides a new pathway to investigate for potential therapeutic approaches to lung cancer.  Is this true also for patch, gum nicotine?


Song & Spindel 2008

Abstract – Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton 97006, USA.

Basic and clinical aspects of non-neuronal acetylcholine: expression of non-neuronal acetylcholine in lung cancer provides a new target for cancer therapy.

Lung cancer is the leading cause of cancer death worldwide and new treatment strategies are clearly needed.

The recent discovery that lung and other cancers synthesize and secrete acetylcholine (ACh) which acts as an autocrine growth factor suggests that this cholinergic autocrine loop may present new therapeutic targets.

In normal bronchial epithelium, small airway epithelium and pulmonary neuroendocrine cells synthesize Ach; and in squamous cell lung carcinoma, adenocarcinoma, and small cell lung carcinoma, the respective lung cancers that derive from those cell types similarly synthesize ACh.

ACh secreted by those cancers stimulates growth of the tumors by binding to nicotinic and muscarinic receptors expressed on lung cancers.

Thus antagonists to nicotinic and muscarinic receptors can inhibit lung cancer growth. The muscarinic receptor (mAChR) subtype utilized for cell proliferation is the M(3) subtype and consistent with this M(3) mAChR antagonists inhibit growth of SCLC and squamous cell carcinomas.

This is significant as M(3) mAChR antagonists have low toxicity and are in wide clinical use.

As multiple other cancer types besides lung carcinomas express both M(3) mAChR and acetylcholine, other cancer types besides lung carcinoma may respond to M(3) mAChR antagonists.


Sun et al 2008c

Abstract – (didn’t print) – Cardiovascular Biology Research Group, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.


modulation of immune cell function

is an important mechanism of neuro-immune intersystem crosstalk.

Substance P (SP)

is one such key neuropeptide involved.

In this study, we investigated the yet unexplored cellular mechanisms of SP-mediated inflammatory responses in macrophages using a mouse macrophage-like cell line RAW 264.7 and isolated peritoneal macrophages.


Sun et al 2008d

Abstract – (didn’t print) – Department of Pharmacology, National University of Singapore, Singapore.

Substance P enhances NF-kappaB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways.

The neuropeptide substance P (SP),

[A protein substance that stimulates nerve endings at an injury site and within the spinal cord, increasing pain messages — A short-chain polypeptide that functions as a neurotransmitter especially in the transmission of pain impulses from peripheral receptors to the central nervous system]

as a major mediator of neuroimmunomodulatory activity, modulates diverse functions of immune cells,

including macrophages.

In the current study, we focused on the yet uncertain role of SP in enhancing the inducible/inflammatory chemokine response of macrophages and the signaling mechanism involved. …. Among the chemokines examined, macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 are two major chemokines that were synthesized by macrophages in response to SP. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-kappaB activation.


Erin & Ulusoy 2008

Abstract – Department of Internal Medicine, Faculty of Medicine, Akdeniz University, Antalya, Turkey.

Differentiation of neuronal from non-neuronal Substance P.

Substance P (SP)

originally found as a neuropeptide in capsaicin [An ingredient in hot peppers that can be found in ointment form for use on the skin to relieve pain from diabetic neuropathy]-sensitive sensory neurons,

had more recently been identified in non-neuronal cells, especially under pathological conditions.

Neuronal and non-neuronal SP may perform distinct functions.

A simple technique to differentiate different SP sources is currently unavailable.

Herein, we describe a two-step sequential acetic acid extraction to differentiate SP source. The efficiency of this two-step extraction in differentiating SP in capsaicin-sensitive neurons was verified by using capsaicin as a tool to deplete SP in sensory neurons. Specifically, Balb-c mice were treated with high dose capsaicin (200 mg/kg). Skin was removed two weeks after treatment. In a separate experiment, lung and skin tissues from control animals (untreated) were incubated in-vitro with capsaicin, and sequential acetic acid extraction was performed. Following capsaicin treatment, both in-vivo and in-vitro, SP recovered in first extraction decreased significantly in lung and skin. Lastly, presence of capsaicin solvent (10% methanol and 10% Tween 80) or protease inhibitor cocktail in solution altered SP EIA test, yielding false positive results. These results demonstrated that SP in capsaicin sensitive sensory neurons was extracted in initial extraction of 15 min while non-neuronal SP was present in second extraction. Because SP in non-neuronal tissues may possibly be more important in pathological conditions, this technique could be useful in determining effects of various treatments on neuronal and non-neuronal SP levels and their consequences.


Dendritic cells (DCs) are immune cells and form part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells.  Dendritic cells are present in small quantities in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, the dendrites, that give the cell its name. However, these do not have any special relation with neurons, which also possess similar appendages. Immature dendritic cells are also called veiled cells, in which case they possess large cytoplasmic ‘veils’ rather than dendrites.


Janelsins et al 2008

Abstract (didn’t print) – Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

Pro-inflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity.

Dendritic cells (DCs)

are the preferred targets for immune-therapy protocols focused on stimulation of cellular immune responses.

However, regardless of initial promising results, ex vivo-generated DCs do not always promote immune-stimulatory responses.

The outcome of DC-dependent immunity

is regulated by pro-inflammatory

cytokines and neuropeptides.

Pro-inflammatory neuropeptides

of the tachykinin family,

including substance P (SP)

and hemokinin-1 (HK-1), bind the neurokinin 1 receptor (NK1R) and promote stimulatory immune responses.

Nevertheless, the ability of pro-inflammatory tachykinins to affect the immune functions of DCs remains elusive.

In the present work, we demonstrate that mouse bone marrow-derived DCs (BMDCs) generated in the presence of GM-CSF and IL-4, express functional NK1R. Signaling via NK1R with SP, HK-1 or the synthetic agonist [Sar(9)Met(O2)(11)]-SP (SarSP) rescues DCs from apoptosis induced by deprivation of GM-CSF and IL-4. Mechanistic analysis demonstrates that NK1R agonistic binding promotes DC survival via PI3K-Akt signaling cascade.

In adoptive transfer experiments, NK1R-signaled BMDCs loaded with Ag exhibit increased longevity in draining lymph nodes, resulting in enhanced and prolonged effector cellular immunity. Our results contribute to the understanding of the interactions between the immune and nervous systems that control DC function, and present a novel approach for ex vivo-generation of potent immune-stimulatory DCs.


Monday, December 01, 2008

Well, gee!  I think I’ve found a major connection I’ve been heading toward in my research that connects the immune system to mood and anxiety disorders – which are themselves, I believe, immune system responses to toxins in the world, including toxic fetal, infant and childhood circumstances that lead to changes in all the developing systems of the body.

If substance P is involved with physical pain sensation, my question has been, “Is it also involved with emotional pain?”  I guessed that it is.  Now to prove my point.  This has to do with the overwhelming sadness of infant and child abuse and the pain of broken attachment systems through problematic developmental experiences.  And yet following this hunch of mine feels a little like staring straight into the sun.


Holtzheimer & Nemeroff 2008

Abstract – Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle Northeast, Suite 4000, Atlanta, GA 30322, USA. pholtzh@emory.edu

Novel targets for antidepressant therapies.

Most depressed patients fail to achieve remission despite adequate antidepressant monotherapy, and a substantial minority show minimal improvement despite optimal and aggressive therapy. However, major advances have taken place in elucidating the neurobiology of depression, and several novel targets for antidepressant therapy have emerged. Three primary approaches are currently being taken:

1) optimizing the pharmacologic modulation of monoaminergic [of or pertaining to neurons that secrete monoamine neurotransmitters (e.g., dopamine, serotonin)] neurotransmission,

2) developing medications that target neurotransmitter systems other than the monoamines, and

3) directly modulating neuronal activity via focal brain stimulation.

We review novel therapeutic targets for developing improved antidepressant therapies, including triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, dopamine receptor agonists, corticotropin-releasing factor-1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, N-methyl-D-aspartate receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists.

Developments in therapeutic focal brain stimulation include vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, and deep brain stimulation.

There must be a connection between substance P as a pain signaler and the pain of depression?


IMPORTANT – immune system and mood disorder connection

Alburges et al 2009

abstract – Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Room 201, Salt Lake City, UT, USA, mario.alburges@utah.edu.

Responses of limbic and extrapyramidal substance P systems to nicotine treatment.

Neuropeptides are linked to the psychopathology of stimulants of abuse, principally through dopamine mechanisms.

Substance P (SP) is one of these neuropeptides and is associated with both limbic and extrapyramidal dopaminergic pathways and likely contributes to the pharmacology of these stimulants.

The effects of nicotine on these dopamine systems have also been extensively studied; however, its effects on the associated SP pathways have received little attention.

OBJECTIVES: In the present study, we elucidated the effects of nicotine treatment on limbic and extrapyramidal SP systems by measuring changes in associated SP tissue concentrations. MATERIALS AND METHODS: Male Sprague-Dawley rats received (+/-)nicotine 4.0 mg/kg/day (0.8 mg/kg, intraperitoneally; five injections at 2-h intervals) in the presence or absence of selective dopamine D(1) and D(2) receptor antagonists or a nonselective nicotinic acetylcholine receptor antagonist. RESULTS:

The nicotine treatment significantly but temporarily

decreased substance P-like [??]  immunoreactivity (SPLI)

content in the ventral tegmental area (VTA) and substantia nigra 12-18 h after drug exposure. This connects to the research on nicotine’s effects on sensory gating, and on increasing MAOA – aggression-like increases

The nicotine-mediated changes in SPLI were selectively blocked by pretreatment with mecamylamine as well as a dopamine D(1), D(2), or both receptor antagonists. Other brain areas that also selectively demonstrated nicotine-related declines in SPLI content included prefrontal cortex, the nucleus accumbens shell, and the very posterior caudate.

CONCLUSIONS: These findings indicate that

some limbic and basal ganglia SP systems

are significantly affected by exposure to nicotine

through processes mediated

by nicotinic and dopaminergic receptors,

suggesting a role for SP pathways in nicotine’s limbic and extrapyramidal effects.

With substance Ps connection to pain and to the immune system response, how is this information not in close conformity with my suspicion that mood disorders are immune system responses?


Alburges et al 2000

Abstract – Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E RM 201, Salt Lake City, UT 84112, USA. m.e.alburges@m.cc.utah.edu

Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments.

Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine.

The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity.

Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment.

However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug.

The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride).

Direct connection between dopamine and substance P effects – on immune response?  How do I connect these effects to the attachment system?  How do I connect what goes wrong in attachment to alterations in the immune response?

Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity.

These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.


Loonam et al 2003

Abstract – Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, New York 10021, USA.

Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum.

The mechanism of action of drugs of abuse like cocaine and amphetamines has been studied extensively in the dopamine terminal field areas of the caudate-putamen (CPu) and the nucleus accumbens (NAc) of the rodent brain.

These brain regions contain several neuropeptides that must play important roles in the normal physiological functions of these brain regions.

The study of neuropeptide physiology in the context of the neurobiological responses to drugs of abuse may shed some light on the intrinsic mechanism of action of neuropeptides of the CPu and the NAc.

The neuropeptides substance P (SP) and cholecystokinin (CCK) are present in the striatum where they could play an important role regulating the effects of psychostimulants like cocaine and amphetamines (methamphetamine [METH] is a long acting derivative of d-amphetamine).

These highly addictive agents induce the release of dopamine (DA) (and other catecholamines) from dopaminergic terminals of the striatum. As is nicotine highly addictive

The excessive release of DA in the striatum and the NAc has been implicated in the habit-forming properties of these drugs.

In order to study the contribution of SP and CCK in the striatum during psychostimulant treatment, we employed selective non-peptide neurokinin-1 (NK-1) and cholecystokinin-2 (CCK-2) receptor antagonists that readily cross the blood brain barrier. We infused the neurokinin-1 receptor (NK-1R) antagonist, L-733,060, into the striatum of freely moving rats via a microdialysis probe in order to assess the effects of SP on cocaine-induced DA overflow in the striatum. Infusion of the NK-1R antagonist prior to a systemic injection of cocaine (10 mg/kg i.p.) significantly attenuated DA overflow in the striatum.

Conversely, infusion of a CCK-2 receptor (CCK-2R) antagonist, L-369,293, through the microdialysis probe evoked DA overflow in the striatum in the absence of cocaine and potentiated DA overflow after a single injection of cocaine (10 mg/kg i.p.).

Exposure to METH (10 mg/kg 4x at two-hour intervals) produced deficits of dopamine transporters (DAT) in mice striatum that are detectable three days after the treatment and are long lasting. Pre-treatment (i.p. injections) with the NK-1R antagonist, WIN-51,708 30 minutes before the 1st and 4th injections of METH prevented the loss of DAT in the striatum.

Moreover, pre-treatment with the NK-1R antagonist prevents METH-induced cell death.

Taken together, these results demonstrate that the

NK-1R and the CCK-2R are important modulators

of the actions of the psychostimulants cocaine and METH.

Neuropeptide receptors represent

an important control point mediating the effects

of the neurotransmitter DA in the striatum of the rodent brain.


Angulo, Angulo & Yu 2004

Abstract – Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021, USA. angulo@genectr.hunter.cuny.edu

Antagonists of the neurokinin-1 or dopamine D1 receptors confer protection from methamphetamine on dopamine terminals of the mouse striatum.

Methamphetamine (METH) is a highly addictive compound that induces toxicity of the dopamine (DA) terminals of the neostriatum.

Exposure to METH induces long-term deficits in dopamine transporter (DAT) and tyrosine hydroxylase (TH) levels

as well as induction of glial fibrillary acidic protein (GFAP) in the caudate putamen (CPu) and the nucleus accumbens (NAc).

The primary effect of exposure to METH is elevation of the level of extracellular DA;

therefore, we assessed the role of the DA D1 receptor (D1R) and neurokinin-1 receptor (NK-1R) on the expression of toxicity.

METH was injected intraperitoneally (10 mg/kg) four times at 2-h intervals (an acute toxic dose), and the mice were sacrificed three days after the treatment.

Exposure to METH resulted in marked reduction of DAT sites (reduced to 30 and 21% relative to control in medial and lateral aspects of the CPu) assessed by binding of [125I]RTI-121 by autoradiography or Western blot analysis.

Pretreatment with the nonpeptide NK-1R antagonist WIN-51,708 (10 mg/kg) 30 min prior to the first and fourth injections of METH prevented the loss of DAT sites of the CPu.

Moreover, pretreatment with WIN-51,708 also prevented the reduction of TH levels induced by METH as well as the induction of GFAP in astrocytes. Pretreatment with the D1R antagonist SCH-23390 (0.25 mg/kg) 30 min before the first and fourth injections of METH conferred partial protection on DAT sites of the CPu. These results demonstrate that receptors postsynaptic to the DA terminals of the CPu are needed in order to express the neurotoxic effects of METH on integral components of the DA terminals of the nigrostriatal projection.


Yu, Cadet & Angulo 2002


Lacka & Czyzyk 2008

Abstract – (didn’t print) – article in Polish

[Hormones and the cardiovascular system.]

Hormones have an influence on many tissues and organs, including the cardio-vascular system (CVS).

Depending on their activity on CVS, they can be divided into 4 groups: having hypertensive or hypotensive influence and chronotropic positive or negative action.

Endocrine regulation in CVS may occur in many ways. Apart from hormones usually connected with CVS regulation, other more recently, discovered ones can act on it. A few of these act directly through specific receptors in heart or vessel wall cells, whereas some act indirectly – stimulating other neuroendocrine factors.

Additionally, novel mechanisms of signal transduction have been discovered for steroid and thyroid hormones, which are independent of gene transcription regulation and are – known as “nongenomic”.

Hormones which increase blood pressure include: urotensin II, endothelins, angiotensin II, catecholamines, aldosterone, antidiuretic hormone, glucocorticosteroids, thyroid hormones, growth hormone and leptin.

On the other hand, blood pressure can be decreased by: natriuretic peptides, the calcitonin gene-related peptide (CGRP) family, angiotensin 1-7, substance P, neurokinin A, ghrelin, Parathyroid hormone-related protein (PTHrP), oxytocin, and, sex hormones.

Hormones which when appearing in excess increase the heart rate are: catecholamines, endothelins, glucocorticosteroids, thyroid hormones, leptin and PTHrP.

Those which decrease the heart rate include: natriuretic peptides, substance P, neurokinin A, oxytocin, angiotensin 1-7.


Darmani et al 2008

Abstract (didn’t print) – Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA.

A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: Evidence from the least shrew.

Although the neurotransmitter basis of chemotherapy-induced vomiting (CIV) is thought to be multifactorial,

it is generally accepted that acute (immediate) CIV is mainly due to the release of serotonin (5-HT) within the gastrointestinal tract,

while the delayed phase occurs

following substance P (SP) release in the brainstem.

The aim of the current study was to test this dogma in the least shrew model of vomiting.

Thus, we initially investigated the temporal development of cisplatin’s immediate and delayed emetic effects in the least shrew and subsequently determined the concomitant changes in the turnover of major emetic neurotransmitters both in the central and peripheral loci associated with CIV. Cisplatin (0, 5, 10 and 20 mg/kg, i.p.) caused dose- and time-dependent emetic effects. A 10 mg/kg dose of cisplatin produced both phases of emesis with corresponding peak mean frequencies occurring at 2-3 and 33 h post-treatment, at 5 mg/kg it failed to cause significant emesis in either phase, while its 20 mg/kg dose induced both phases earlier but toxicity restricted the full 47 hour observation. Cisplatin (10 mg/kg, i.p.)-induced peak immediate and delayed phases were associated with concomitant increases in the turnover of 5-HT, dopamine and SP in both the shrew brainstem and jejunum [The upper portion of the small intestine].

The discussed increases during both phases appear to be site specific since neurotransmitter release was not persistently altered in the shrew frontal cortex or duodenum [The first part of the small intestine], although occasionally increases or decreases did occur. Our findings suggest that the least shrew appears to be a sensitive and rapid emesis model for both phases of CIV, and both emetic phases are associated with specific increases in the release of all of the cited neurotransmitters in both the brainstem and jejunum. Thus, the generally accepted neurotransmitter dogma needs to be updated since more recent neurochemical studies in humans as well as other clinical findings support the current basic results obtained in the least shrew.


Viola & Luster 2008

Abstract (didn’t print) – Istituto Clinico Humanitas IRCCS, 20089 Rozzano, Milan, Italy. antonella.viola@humanitas.it

Chemokines and their receptors: drug targets in immunity and inflammation.

The chemokine system

coordinates leukocyte migration in immunity and inflammation and is implicated in the pathogenesis of many human diseases.

Although several successful strategies have been identified to develop drugs targeting chemokines and their receptors, this has not yet resulted in many new therapeutics. This is likely due to a complexity of the chemokine system, which was not initially appreciated, that is characterized by redundancy, pleiotropy, and differences among species.

Allegretti et al 2008

Abstract (didn’t print) – Research Center, Dompé pha.r.ma s.p.a., I-67100 L’Aquila, Italy.

Allosteric inhibitors of chemoattractant receptors: opportunities and pitfalls.

Given the central role of chemokines in infection, inflammation and immunity, chemokine receptors are a prime target for pharmacological intervention, and more so after the recent approval of chemokine receptor inhibitors for HIV.

Allosteric inhibitors offer a largely unexploited opportunity to interfere with and modulate chemokine receptor activation and signaling.


In enzymology, inhibition or activation of an enzyme by a small regulatory molecule that interacts at a site (allosteric site) other than the active site (at which catalytic activity occurs).]

In addition to characterizing binding mode as a first step to understanding the specific mechanism underlying drug action, allosteric inhibitors pose new questions concerning different phases in drug discovery and pharmacological characterization, including the identification of appropriate screening tests, the evaluation of inhibitory effects on different signaling pathways and the implications of agonist- and signaling pathway-dependent inhibition for overall in vivo efficacy.


Holloway, Rao & Shannon 2002

Abstract – Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.

Regulation of cytokine gene transcription in the immune system.

The controlled expression of

cytokine genes

is an essential component of an immune response.

The specific types of cytokines as well as the time and place of their production is important in generating an appropriate immune response to an infectious agent.

Aberrant expression is associated with pathological conditions of the immune system such as autoimmunity, atopy and chronic inflammation.

Are they always aberrant, or sometimes just adaptive to extreme threatening conditions?

Cytokine gene transcription

is generally induced in a cell-specific manner.

[re Haddad, Saade & Safieh-Garabedian 2002, p 2, “Cytokines are mediators of inter- and intracellular communications” and they reference this article]

Over the last 15 years, a large amount of information has been generated describing the transcriptional controls that are exerted on cytokine genes. Recently, efforts have been directed at understanding how these genes are transcribed in a chromatin context. This review will discuss

the mechanisms by which cytokine genes become available for transcription

in a cell-restricted manner

as well as the mechanisms by which these genes sense their environment

and activate high level transcription in a transient manner.

Particular attention will be paid to the role of chromatin in allowing transcription factor access to appropriate genes.


Nikolajczyk 2006

Abstract – Department of Microbiology, Boston University School of Medicine, 715 Albany Street L-516, Boston, MA 02118, USA. bnikol@bu.edu

Regulation of cytokine transcription in the context of chromatin.

Understanding the transcriptional regulation

of an important class

of innate and adaptive immune system effector molecules,

the cytokines,

is increasingly important given the promise cytokine regulation holds for treating various autoimmune and inflammatory diseases.

Studies defining the mechanisms regulating cytokine transcription initially focused on identifying the cis-acting elements and trans-acting factors that activate cytokine promoters and enhancers. In the past, these studies were largely completed in the absence of

constraints instituted by cellular chromatin.

Over the past decade it has become obvious that changes in chromatin accessibility critically control, rather than simply correlate with, the transcriptional activation of most genes, including cytokines.

Hence candidate transcriptional activators are being re-evaluated for potency in the context of cellular chromatin.

Several distinct mechanisms for manipulating the generally repressive context of chromatin have been identified for cytokine genes.

Most recently, single nucleotide polymorphisms in cytokine transcriptional regulatory elements have been shown to play measurable roles in regulating cytokine levels in the context of naturally selected haplotypes.

Overall, subtle differences in DNA sequence

and nucleoprotein complex composition,

including protein post-translational modification,

come together in cell type-specific combinations to explain

the normal variation in cytokine transcription

throughout the human populace.


Shannon et al 2001

Abstract – Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, South Australia. frances.shannon@anu.edu.au

The role of architectural transcription factors in cytokine gene transcription.

The strict control of cytokine gene transcription

is required for the correct regulation of an immune response.

Cytokine gene transcription is generally inducible and can also be cell-type specific.

Promoter and enhancer regions

that control the expression of these genes

assemble complex arrays of transcription factors

known as enhanceosomes.

One important aspect of the organization of these multi-protein complexes is the presence of proteins known as architectural transcription factors.

Architectural proteins

influence structural aspects of enhanceosomes

through protein: DNA as well as protein: protein interactions.

The high mobility group I(Y) and the cold shock domain families of architectural proteins have been shown to play roles in cytokine gene transcription and will be discussed here.

These families of proteins interact with specific structural features of DNA, modulate transcription factor binding to DNA, and interact directly with other transcription factors.

The mechanisms by which they affect inducible cytokine gene transcription will be discussed.


Lomvardas & Thanos 2002

Abstract – Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, NY 10032, USA.

Modifying gene expression programs by altering core promoter chromatin architecture.

Transcriptional activation of the IFN-beta gene

in response to virus infection requires the assembly of an

enhanceosome, which

instructs a recruitment program

of chromatin modifiers/remodelers

and general transcription factors

to the promoter.

This program culminates

with sliding of a nucleosome blocking the core promoter

to a downstream position,

a prerequisite for transcriptional activation.

We show that delivery of this nucleosome

to the same downstream position

to create an accessible IFN-beta core promoter

prior to enhanceosome assembly

results in major changes in the gene expression program

with regard to the

temporal pattern and the signal specificity of the transcriptional response.

Thus, the identity of a gene expression program

is achieved and maintained by the dynamic interplay

between specific enhanceosomes

and specific local chromatin structure.


Merika & Thanos 2001

Abstract – Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.


Gene-specific transcriptional regulation in higher eukaryotes

[a single-celled or multicellular organism whose cells contain a distinct membrane-bound nucleus]

is mediated by complex cis-acting

[regulatory genes

in place along a strand of DNA

that encodes a genetic instruction]

control elements

that specify the location, timing and magnitude of the response.

During the past five years, an argument has been made that in several cases specificity in gene transcription is achieved by the assembly of higher-order three-dimensional transcription factor/enhancer DNA complexes, termed enhanceosomes.

The inherent co-operativity in enhanceosome assembly

and the embedded synergy in transcription

ensure that a specific gene would be selected for activation only if all the enhanceosome components are present in the same nucleus.

Enhanceosomes activate transcription

by recruiting chromatin-modifying activities

and basal transcription factors

to the nearby promoters.


de Laat & Grosveld 2003

abstract – Department of Cell Biology and Genetics, Faculty of Medicine, Erasmus University, Rotterdam, PO Box 1738, 3000DR Rotterdam, The Netherlands. w.delaat@erasmusmc.nl

Spatial organization of gene expression: the active chromatin hub.

Developmental and tissue-specific expression of higher eukaryotic genes involves activation of transcription at the appropriate time and place and keeping it silent otherwise.

Unlike housekeeping genes, tissue-specific genes generally do not cluster on the chromosomes.

They can be found in gene-dense regions of chromosomes as well as in regions of repressive chromatin.

Depending on the location, shielding against positive or negative regulatory effects from neighboring chromatin may be required and hence insulator and boundary models were proposed.

They postulate that chromosomes are partitioned into physically distinct expression domains, each containing a gene or gene cluster with its cis-regulatory elements.

Specialized elements at the borders of such domains

are proposed to prevent cross-talk between domains,

and thus to be crucial in establishing

independent expression domains.

However, genes and associated cis-acting sequences often do not occupy physically distinct domains on the chromosomes.

Rather, genes can overlap

and cis-acting sequences can be found

tens or hundreds of kilobases

away from the target gene,

sometimes with unrelated genes in between.

How cool is that!  A measure in terms of kilobases!

Therefore the ability of a gene

to communicate with positive cis-regulatory elements

rather than the presence of specialized boundary elements appears to be key to establishing

an independent expression profile.

Our recent finding that active beta-globin genes physically interact in the nuclear space with multiple cis-regulatory elements, with inactive genes looping out, has provided a potential mechanistic framework for this model.

We refer to such a spatial unit of regulatory DNA elements as an active chromatin hub (ACH).

We propose that productive active chromatin hub (ACH) formation underlies correct gene expression, requiring the presence of protein factors with the appropriate affinities for each other bound to their cognate DNA sequences.

Proximity and specificity determines which

cis-acting sequences and promoter(s)

form an active chromatin hub (ACH),

and thus which gene will be expressed.

Says which gene, but not how

Other regulatory sequences

can interfere with transcription

by blocking the appropriate physical interaction

between an enhancer and promoter

in the active chromatin hub (ACH).

Possible mechanisms by which

distal DNA elements encounter each other

in the 3D nuclear space

will be discussed.


Zhou et al 2006

Abstract – National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, People’s Republic of China.

Active chromatin hub of the mouse alpha-globin locus forms in a transcription factory of clustered housekeeping genes.

RNA polymerases

can be shared by a particular group of genes

in a transcription “factory” in nuclei,

where transcription may be coordinated in concert

with the distribution of coexpressed genes

in higher-eukaryote genomes.

Moreover, gene expression can be modulated

by regulatory elements

working over a long distance.

Here, we compared the conformation of a 130-kb chromatin region containing the mouse alpha-globin [globin – One of a group of genes which codes for a respiratory globin protein. These are found in many animals including humans] cluster and their flanking housekeeping genes in 14.5-day-postcoitum fetal liver and brain cells. The analysis of chromatin conformation showed that the active alpha1 and alpha2 globin genes and upstream regulatory elements are in close spatial proximity, indicating that looping may function in the transcriptional regulation of the mouse alpha-globin cluster. In fetal liver cells, the active alpha1 and alpha2 genes, but not the inactive zeta gene, colocalize with neighboring housekeeping genes C16orf33, C16orf8, MPG, and C16orf35. This is in sharp contrast with the mouse alpha-globin genes in nonexpressing cells, which are separated from the congregated housekeeping genes. A comparison of RNA polymerase II (Pol II) occupancies showed that active alpha1 and alpha2 gene promoters have a much higher RNA Pol II enrichment in liver than in brain. The RNA Pol II occupancy at the zeta gene promoter, which is specifically repressed during development, is much lower than that at the alpha1 and alpha2 promoters. Thus, the mouse alpha-globin gene cluster may be regulated through moving in or out active globin gene promoters and regulatory elements of a

preexisting transcription factory in the nucleus,

which is maintained by the flanking clustered

housekeeping genes,

[housekeeping genes – any of the genes that are constitutively expressed at a relatively constant level across many or all known conditions]

to activate or inactivate

alpha-globin gene expression.


Levings et al 2006

Abstract – Department of Biochemistry and Molecular Biology, University of Florida, Center for Mammalian Genetics, Shands Cancer Center, Powell Gene Therapy Center, Gainesville, Florida 32610, USA.

Recruitment of transcription complexes to the beta-globin locus control region and transcription of hypersensitive site 3 prior to erythroid differentiation of murine embryonic stem cells.

Eukaryotic chromosomal DNA

is densely packaged in the nucleus

and organized into discrete domains

of active and inactive chromatin.

Gene loci that are activated during the process of cell differentiation

undergo changes that result in modifications of specific histone tail residues

and in loosening of chromatin [mass of genetic material composed of DNA and proteins that condense to form chromosomes in eukaryotic cell division] structure.

The beta-globin genes are expressed exclusively in erythroid cells.

High-level expression of these genes is mediated by a locus control region (LCR), a powerful DNA regulatory element composed of several DNase I hypersensitive (HS) sites and located far upstream of the beta-globin genes.

Here we show that RNA polymerase II and specific histone modifications that mark transcriptionally active chromatin domains are associated with the LCR core elements HS2 and HS3 in murine embryonic stem cells prior to differentiation along the erythroid lineage. At this stage HS3 is abundantly transcribed. After in vitro differentiation, RNA Polymerase II can also be detected at the embryonic epsilon- and adult beta-globin genes. These results are consistent with the hypothesis that activation of the beta-globin gene locus is initiated by protein complexes recruited to the LCR.


Panne 2008

Abstract – EMBL, 6 Rue Jules Horowitz, BP181, 38042 Grenoble, France. panne@embl.fr

The enhanceosome.

The interferon-beta (IFN-beta) enhanceosome

is a paradigm for understanding the role of transcription factor complexes

in eukaryotic signal integration.

Recent structural studies provide a complete atomic model of the enhanceosome at the protein-DNA interface.

The composite model shows how binding of eight transcription factors to enhancer DNA creates a continuous recognition surface.

The extensive overlap of individual binding sites

creates a composite element

that ensures that the enhancer operates

as a single unit of regulation.

The absence of major protein-protein interfaces

between the transcription factors suggests that

cooperative binding occurs

through a combination of binding-induced conformational changes

in DNA structure and specific interactions

with coactivator proteins such as CBP/p300.

Contacts with virtually every nucleotide

explain why the enhancer is evolutionary conserved in mammalian genomes.


West & Fraser 2005

Abstract – Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Western Infirmary, Glasgow, UK. a.west@clinmed.gla.ac.uk

Remote control of gene transcription.

In this review, we look at the most recent studies of

DNA elements that function over long genomic distances

to regulate gene transcription and will discuss

the mechanisms genes employ

to overcome the positive and negative influences of their genomic neighborhood

in order to achieve accurate programs of expression.

Enhancer elements

activate high levels of transcription of linked genes

from distal locations.

Recent technological advances have demonstrated

chromatin loop interactions

between enhancers and their target promoters.

Moreover, there is increasing evidence that these dynamic interactions regulate the repositioning of genes to foci of active transcription within the nucleus.

Enhancers have the potential to activate a number of neighboring genes over a large chromosomal region,

hence, their action must be restricted in order to prevent activation of non-target genes.

This is achieved by specialized DNA sequences,

termed enhancer blockers (or insulators),

that interfere with an enhancer’s ability

to communicate with a target promoter when positioned between the two.

Here, we summarize current models of enhancer blocking activity and discuss recent findings of how it can be dynamically regulated.

It has become clear that enhancer blocking elements should not be considered only as structural elements on the periphery of gene loci, but as regulatory elements that are crucial to the outcome of gene expression.

The transcription potential of a gene can also be susceptible

to heterochromatic silencing

originating from its chromatin environment.

Insulator elements

can act as barriers to the spread of heterochromatin

[densely staining condensed chromosomal regions, believed for the most part to be genetically inert].

We discuss recent evidence supporting a number of non-exclusive mechanisms of barrier action, which mostly describe the modulation of chromatin structure or modification.


Gaszner & Felsenfeld 2006

Abstract – National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0540, USA.

Insulators: exploiting transcriptional and epigenetic mechanisms.

Insulators are DNA sequence elements

that prevent inappropriate interactions

between adjacent chromatin domains.

One type of insulator establishes domains that separate enhancers and promoters to block their interaction,

whereas a second type creates a barrier against the spread of heterochromatin.

Recent studies have provided important advances in our understanding of the modes of action of both types of insulator. These new insights also suggest that the mechanisms of action

of both enhancer blockers and barriers

might not be unique to these types of element,

but instead are

adaptations of other gene-regulatory mechanisms.


Engel & Bartolomei 2003

Abstract – Howard Hughes Medical Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Mechanisms of insulator function in gene regulation and genomic imprinting.

Correct temporal and spatial patterns of gene expression are required to establish unique cell types.

Several levels of genome organization are involved in achieving this intricate regulatory feat.

Insulators are elements that modulate interactions

between other cis-acting sequences

and separate chromatin domains with distinct condensation states.

Thus, they are proposed to play an important role in the partitioning of the genome into discrete realms of expression.

This review focuses on the roles that insulators have in vivo and reviews models of insulator mechanisms in the light of current understanding of gene regulation.


Zhao & Dean 2005

Abstract – Laboratory of Cellular and Developmental Biology, NIDDK, NIH, Bethesda, MD 20892, USA.

Organizing the genome: enhancers and insulators

Enhancers can activate their target genes over large linear distances.

Insulators can delimit the influence of an enhancer to an appropriate target.

There are a number of intertwined mechanisms by which the regulatory functions of enhancers and insulators might be carried out at the level of the chromatin fiber.

Recent evidence suggests that both enhancers and insulators participate in higher-order organization of chromatin in the nucleus and in localization of their regulated sequences

to both subnuclear

[of, relating to, or being a particle smaller than the atomic nucleus] structures and compartments.

Novel experimental approaches are helping to reveal the mechanisms underlying nuclear organization of developmentally regulated genes.


Geyer & Clark 2002

Abstract – Department of Biochemistry, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA. pamela-geyer@uiowa.edu

Protecting against promiscuity: the regulatory role of insulators

Eukaryotic genomes contain transcriptional regulatory elements that alter promoter activity through long-range interactions.

Many control elements show a broad range of promoter interactions, suggesting that these elements are capable of inappropriate transcription.

The identification of a novel class of directing regulatory elements, called insulators, has provided clues into mechanisms used in eukaryotic genomes to maintain transcription fidelity.


contribute to the organization of independent domains

of gene function by restricting enhancer and silencer function.

This review describes the properties of insulators and related elements that have been isolated from several eukaryotic genomes. Two classes of models of insulator function are considered. These models provide insights into possible mechanisms used by these diverse elements to provide regulatory autonomy.


Valenzuela & Kamakaka 2006

Abstract – Unit on Chromatin and Transcription, NICHD/NIH, Bethesda, Maryland 20892, USA.

Chromatin insulators.

Active and silenced chromatin domains

are often in close juxtaposition to one another,

and enhancer and silencer elements operate

over large distances to regulate the genes in these domains.

The lack of promiscuity in the function of these elements suggests that active mechanisms exist to restrict their activity.

Insulators are DNA elements that restrict the effects of long-range regulatory elements.

Studies on different insulators from different organisms have identified common themes in their mode of action. Numerous insulators map to promoters of genes or have binding sites for transcription factors and like active chromatin hubs and silenced loci, insulators also cluster in the nucleus.

These results bring into focus potential conserved mechanisms by which these elements might function in the nucleus.


Gerasimova & Corces 2001

Abstract – Department of Biology, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, UDA. tgerasimova@jhu.edu

Chromatin insulators and boundaries: effects on transcription and nuclear organization.

Chromatin boundaries and insulators

are transcriptional regulatory elements

that modulate interactions between enhancers and promoters and protect genes

from silencing effects

by the adjacent chromatin.

Originally discovered in Drosophila,

insulators have now been found in a variety of organisms, ranging from yeast to humans.

They have been found interspersed with regulatory sequences in complex genes and at the boundaries between active and inactive chromatin.

Insulators might modulate transcription

by organizing the chromatin fiber within the nucleus

through the establishment of higher-order domains

of chromatin structure.


Bushey, Dorman & Corces 2008 – get this article

Abstract – Department of Biology, Emory University, Atlanta, GA 30322, USA.

Chromatin insulators: regulatory mechanisms and epigenetic inheritance

Enhancer-blocking insulators

are DNA elements that disrupt the communication

between a regulatory sequence,

such as an enhancer or a silencer,

and a promoter.


participate in both

transcriptional regulation and global nuclear organization,

two features of chromatin that are thought to be maintained from one generation to the next through

epigenetic mechanisms.

Furthermore, there are many regulatory mechanisms in place that enhance or hinder insulator activity.

These modes of regulation could be used

to establish

cell-type-specific insulator activity

that is epigenetically inherited

along a cell and/or organismal lineage.

This review will discuss the evidence for epigenetic inheritance and regulation of insulator function.


Wallace & Felsenfeld 2007

Abstract – Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892-0540, United States.

We gather together: insulators and genome organization.

When placed between an enhancer and promoter,

certain DNA sequence elements inhibit

enhancer-stimulated gene expression.

The best characterized of these enhancer-blocking insulators,

gypsy in Drosophila and the

CTCF-binding element in vertebrates and flies,

stabilize contacts between distant genomic regulatory sites leading to the formation of

loop domains.

Current results show that CTCF mediates long-range contacts in the mouse beta-globin locus and at the Igf2/H19-imprinted locus.

Recently described

active chromatin hubs and transcription factories

also involve long-range interactions;

it is likely that CTCF interferes with their formation when acting as an insulator.

The properties of CTCF,

and its newly described genomic distribution,

suggest that it may play an important role

in large-scale nuclear architecture,

perhaps mediated by the co-factors with which it interacts in vivo.


Ishihara, Oshimura & Nakao 2006

Abstract – Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

CTCF-dependent chromatin insulator is linked to epigenetic remodeling.

Chromatin insulators

are boundary elements between

distinctly regulated, neighboring chromosomal domains,

and they function by blocking the effects of nearby enhancers

in a position-dependent manner.

Here, we show that the SNF2-like chromodomain helicase protein CHD8 interacts with the

insulator binding protein CTCF.

Chromatin immunoprecipitation analysis revealed that CHD8 was present at known CTCF target sites, such as the differentially methylated region (DMR) of H19, the locus control region of beta-globin, and the promoter region of BRCA1 and c-myc genes. RNA interference-mediated knockdown of CHD8 significantly abolished the H19 DMR insulator activity that depends highly on CTCF, leading to reactivation of imprinted IGF2 from chromosome of maternal origin. Further, the lack of CHD8 affected CpG methylation and histone acetylation around the CTCF binding sites, adjacent to heterochromatin, of BRCA1 and c-myc genes. These findings provide insight into the

role of CTCF-CHD8 complex

in insulation and epigenetic regulation

at active insulator sites.


Yang et al 2003

Abstract – Medical Service, VA Palo Alto Health Care System, and Division of Endocrinology, Department of Medicine, Stanford University, Palo Alto, California 94304, USA.

Epigenetic regulation of Igf2/H19 imprinting at CTCF insulator binding sites.

The mouse insulin-like growth factor II (Igf2) and H19 genes are located adjacent to each other on chromosome 7q11-13 and are reciprocally imprinted.

It is believed that the allelic expression of these two genes is regulated by the binding of CTCF insulators to four parent-specific DNA methylation sites in an imprinting control center (ICR) located between these two genes.

Although monoallelically expressed in peripheral tissues, Igf2 is biallelically transcribed in the CNS.

In this study, we examined the allelic DNA methylation and CTCF binding in the Igf2/H19 imprinting center in CNS, hypothesizing that the aberrant CTCF binding as one of the mechanisms leads to biallelic expression of Igf2 in CNS. Using hybrid F1 mice (M. spretus males x C57BL/6 females), we showed that in CNS, CTCF binding sites in the ICR were methylated exclusively on the paternal allele, and CTCF bound only to the unmethylated maternal allele, showing no differences from the imprinted peripheral tissues. Among three other epigenetic modifications examined, histone H3 lysine 9 methylation correlated well with Igf2 allelic expression in CNS. These results suggest that CTCF binding to the ICR alone is not sufficient to insulate the Igf2 maternal promoter and to regulate the allelic expression of the gene in the CNS, thus challenging the aberrant CTCF binding as a common mechanism for lack of Igf2 imprinting in CNS. Further studies should be focused on the identification of factors that are involved in histone methylation and CTCF-associated factors that may be needed to coordinate Igf2 imprinting.


IGF2 – insulin-like growth factor 2 (somatomedin A) – This gene encodes a member of the insulin family of polypeptide growth factors that is involved in development and growth. It is an imprinted gene and is expressed only from the paternally inherited allele. It is a candidate gene for eating disorders. There is a read-through, INS-IGF2, which aligns to this gene at the 3′ region and to the upstream INS gene at the 5′ region. Alternatively spliced transcript variants, encoding either the same or different isoform, have been found for this gene. [provided by RefSeq]


Kurukuti et al 2006

Abstract – Medical Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.

CTCF binding at the insulin-like growth factor-II (IGF2)/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues.

The adjacent IGF2 and H19 genes

are imprinted in most normal mouse and human tissues,

but imprinting is often lost in tumors.

Mouse models suggest that parental-allele specific CCCTC-binding factor (CTCF) binding at the IGF2/H19 imprinting control region (ICR) regulates the expression of these two genes. Using chromatin immunoprecipitation and PCR, we show that in several normal and neoplastic human tissues, CTCF consistently binds unmethylated ICR elements, but CTCF binding does not result in predictable gene expression.

In the fetal brain, CTCF binding is monoallelic and specific for the unmethylated ICR, yet IGF2/H19 expression is biallelic.

In osteosarcoma tumors, aberrant methylation of the IGF2/H19 ICR results in equally aberrant CTCF binding, yet expression of these genes does not correlate with CTCF binding.

This is the first description of

chromatin immunoprecipitation for CTCF binding

at the human IGF2/H19 ICR, and the results demonstrate that CTCF binding at the IGF2/H19 ICR is insufficient to regulate the expression of IGF2/H19 in many human tissues.




Chesnokova & Melmed 2002

Abstract – Cedars-Sinai Research Institute, University of California-Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.

The neuroendocrine and immune systems communicate bidirectionally.

The neuro-immune-endocrine interface is mediated by cytokines acting as auto/paracrine or endocrine factors regulating pituitary development, cell proliferation, hormone secretion, and feedback control of the hypothalamic-pituitary-adrenal (HPA) axis.

At birth or during neonatal ontogenesis,

cytokines produce permanent alterations of HPA axis function and the stress response.

Overexpressing IL-6 or leukemia inhibitory factor leads to significant changes in pituitary development and functions. Pituitary corticotroph POMC gene expression is regulated by CRH as well as several gp130 cytokines acting as neuro-immuno-endocrine modulators. Conversely, HPA axis functions modulate susceptibility or resistance to inflammatory disease. Cytokines (including IL-1, TNF, and members of the gp130 cytokine family)

participate as mediators of a complex HPA axis

response to stress and inflammation.

Prolonged exposure to proinflammatory cytokines increases levels of the dominant negative glucocorticoid receptor isoform.

Nonresponsiveness of the HPA axis to

glucocorticoid negative feedback control

provides a defense from destructive effects of cytokine excess.

At the same time, gp130 cytokines stimulate pituitary suppressor of cytokine signaling (SOCS)-3, which represses cytokine signaling and abrogates cytokine-induced corticotroph POMC gene transcription and ACTH secretion.


Silverman et al 2005

Abstract – Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, Georgia 30322, USA.

Compelling data has been amassed indicating that soluble factors, or cytokines, emanating from the immune system can have profound effects on the neuroendocrine system, in particular the hypothalamic- pituitary-adrenal (HPA) axis.

HPA activation by cytokines (via the release of glucocorticoids), in turn, has been found to play a critical role in restraining and shaping immune responses.

Thus, cytokine-HPA interactions represent a fundamental consideration regarding the maintenance of homeostasis and the development of disease during viral infection.

Although reviews exist that focus on the bi-directional communication between the immune system and the HPA axis during viral infection (188,235), others have focused on the immunomodulatory effects of glucocorticoids during viral infection (14,225). This review, however, concentrates on the

other side of the bi-directional loop of neuroendocrine-immune interactions, namely, the

characterization of HPA axis activity during viral infection

and the mechanisms employed

by cytokines to stimulate glucocorticoid release.


Webster & Sternberg 2004

Abstract – Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.

The hypothalamic-pituitary-adrenal (HPA) axis is activated during many bacterial and viral infections, resulting in an increase in circulating glucocorticoid levels.

This HPA axis activation and glucocorticoid response are critical for the survival of the host, as demonstrated by the fact that removal of the HPA axis (by adrenalectomy or hypophysectomy) or glucocorticoid receptor (GR) blockade enhances the severity of the infection and in some cases enhances the mortality rate. Replacement with a synthetic glucocorticoid reverses these effects by reducing the severity of the infection and provides protection against lethal effects. In addition, some bacteria and viral infections have been shown to affect the GR directly. These have been described and the implications of such an effect discussed.


Gupta et al 2007

Abstract – Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. shaktig@gmail.com

The body’s primary stress management system

is the hypothalamic pituitary adrenal (HPA) axis.

The HPA axis responds to physical and mental challenge

to maintain homeostasis

in part by controlling the body’s cortisol level.

Dysregulation of the HPA axis is implicated in

numerous stress-related diseases.

RESULTS: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary.

This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis.

In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state.

A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels.

Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state.

One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS).

CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism.

High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.


Pariante 2006

Abstract – Stress, Psychiatry and Immunology Laboratory, Section of Clinical Neuropharmacology, Division of Psychological Medicine, Institute of Psychiatry, King’s College London, London, UK. c.pariante.kcl.ac.uk

The glucocorticoid receptor: part of the solution or part of the problem?

Clinical studies have demonstrated hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and increased levels of cortisol in patients with major depression,

because of an impairment of glucocorticoid receptor (GR)-mediated negative feedback (glucocorticoid resistance).

Moreover, clinical and experimental studies have shown that antidepressants increase GR function, thus leading to resolution of glucocorticoid resistance. Interestingly, a number of studies have also demonstrated that manipulating GR function with both agonists and antagonists has an antidepressant effect, and indeed that other drugs targeting the HPA axis and cortisol secretion – even drugs with opposite effects on the HPA axis – have antidepressant effects. These studies do not support the notion that cortisol has ‘negative’ effects on the brain. On the contrary, this paper concludes that

a lack of the ‘positive’ effects of cortisol on the brain,

because of glucocorticoid resistance,

is likely to be involved in the pathogenesis of depression

Interesting point


Juruena, Cleare & Pariante 2004

Abstract – article in Portuguese – Division of Psychological Medicine, Section of Neurobiology of Mood Disorders, Institute of Psychiatry, University of London, London, UK. m.juruena@iop.kcl.ac.uk

OBJECTIVES: Changes in the hypothalamic-pituitary-adrenocortical (HPA) system are characteristic of depression. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), several studies have examined the number and/or function of GRs in depressed patients. METHODS: Review scientific evidences have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of CRF in various brain regions postulated to be involved in the causality of depression.

RESULTS: This article summarizes the literature on GR in depression and on the impact of antidepressants on the GR in clinical and preclinical studies, and supports the concept that impaired GR signaling is a key mechanism in the pathogenesis of depression, in the absence of clear evidence of decreased GR expression. The data also indicate that antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear.

We propose that antidepressants in humans could inhibit steroid transporters localised on the blood-brain barrier and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis.

CONCLUSION: Enhanced cortisol action in the brain might prove to be a successful approach to maximize therapeutic antidepressant effects. Hypotheses regarding the mechanism of these receptor changes involve non-steroid compounds that regulate GR function via second messenger pathways. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders


Pariante et al 2004

Abstract – Institute of Psychiatry, King’s College London, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK. spjucmp@iop.kcl.ac.uk

Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear. Studies in depressed patients, animals and cellular models have demonstrated that antidepressants increase glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression and function; this, in turn, is associated with enhanced negative feedback by endogenous glucocorticoids, and thus with reduced resting and stimulated hypothalamic-pituitary-adrenal (HPA) axis activity.

In a series of studies conducted over the last few years, we have shown that antidepressants modulate GR function in vitro by inhibiting membrane steroid transporters that regulate the intracellular concentration of glucocorticoids. In this paper, we will review the effects of membrane steroid transporters and antidepressants on corticosteroid receptors. We will then present our unpublished data on GR live microscopy in vitro, showing that

ligand-induced translocation of the GR starts within 30 seconds and is completed within minutes. Furthermore, we will present our new data using an in situ brain perfusion model in anaesthetized guinea-pigs, showing that entry of cortisol to the brain of these animals is limited at the blood-brain barrier (BBB).

Finally, we will present a comprehensive discussion of our published findings on the effects of chemically unrelated antidepressants on membrane steroid transporters, in mouse fibroblasts and rat cortical neurones. We propose that antidepressants in humans could inhibit steroid transporters localized on the BBB and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis. Enhanced cortisol action in the brain might prove to be a successful approach to maximize therapeutic antidepressant effects.


Weigent & Blalock 1995

Abstract – University of Alabama at Birmingham, Department of Physiology and Biophysics 35294-0005, USA.

Organisms respond to infection with complex adaptations involving bidirectional communication between the immune and neuroendocrine systems. The idea of intercellular communication between the neuroendocrine and immune systems via common signal molecules has provided a conceptual framework for such crosstalk. The studies to date show that cells of the immune system contain receptors for neuroendocrine hormones and can also be considered a source of pituitary and hypothalamic peptides. The structure and pattern of synthesis of these peptides by leukocytes appear similar to neuroendocrine hormones, although some differences exist. Once secreted, these peptide hormones may function as endogenous regulators of the immune system as well as conveyors of information from the immune to the neuroendocrine system. The plasma hormone concentrations contributed by lymphocytes usually do not reach the levels required when the pituitary gland is the source, but because immune cells are mobile, they have the potential to locally deposit the hormone at the target site. Likewise, other studies show that cells of the neuroendocrine system contain receptors for cytokines and can also be considered a source of cytokines, particularly interleukin-1 (IL-1) and IL-6. In the pituitary IL-1 beta coexists with thyroid stimulating hormone in a subpopulation of thyrotropes, suggesting it may have a role as a pituitary paracrine factor.

The cytokines, including IL-1, IL-2, IL-6, interferon-gamma, and tumor necrosis factor, exert profound effects on hypothalamic pituitary axes.

It is our hypothesis that the relay of information to the neuroendocrine system represents a sensory function for the immune system

wherein leukocytes recognize stimuli that are not recognizable by the central and peripheral nervous systems (i.e., bacteria, tumors, viruses, and antigens).

The recognition of such noncognitive stimuli

by immunocytes is then converted into information

and a physiological change occurs.


Chikanza & Grossman 2000

Abstract – Bone and Joint Research Unit, St Bartholomew’s and Royal London Hospital School of Medicine and Dentistry, London, United Kingdom. i.c.chikanza@mds.qmw.ac.uk

The neuroendocrine and immune responses to inflammatory stress represent important integrated physiologic circuits for the regulation of inflammation whose basis has been reviewed.

Proinflammatory cytokines such as IL-1 beta, TNF alpha, and IL-6 released from inflammatory foci initiate a local inflammatory response and travel by way of the blood-stream to the central nervous system, where they trigger a variety of neuroendocrine counterregulatory mechanisms.

There is an important

NEI loop.

Stimulatory signals are received by the neural systems from inflammatory foci and are transduced by the hypothalamus, thereby

initiating a complex hormonal and cytokine

cascade of reactions aimed at modulating inflammation

and returning the organism to normal physiologic homeostasis once the trigger has been neutralized.

Conversely, a number of mechanisms that modulate the anti-inflammatory activity of the neuroendocrine responses to inflammation are also activated. Defects in the neuroendocrine-immune interactions can profoundly affect the susceptibility to developing chronic inflammatory disease and influencing survival after bacterial infections.

The NEI loop

has important pathophysiologic implications for disease processes.


Morale et al 2001

Abstract – Department of Pharmacology, Medical School, University of Sassari, Sassari, Italy.

Bidirectional communication

between the neuroendocrine and immune systems

during ontogeny

plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life.

Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function.

Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity.

The neuroendocrine-immune system is very sensitive

to preperinatal experiences,

including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities.

We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level.

In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators.

Hence, neuron-glial signaling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers.

The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized.

The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.


Marchetti et al 2001

Abstract – Department of Pharmacology, Medical School, University of Sassari 07100, Sassari, Italy. bianca.marchetti@oasi.en.it

Current research evidence suggests that interactions between genetic and environmental factors contribute to modulate the susceptibility to degenerative disorders, including inflammatory and autoimmune diseases of the central nervous system (CNS).

In this context, bidirectional communication between the neuroendocrine and immune systems

during ontogeny

plays a pivotal role in programming the development

of neuroendocrine and immune responses in adult life,

thereby influencing the predisposition to several disease entities.

Glucocorticoids (GCs),

the end products of the hypothalamic-pituitary-adrenocortical (HPA) axis,

gender and signals generated by hypothalamic-pituitary-gonadal (HPG) axis are major players coordinating the development of immune system function and exerting powerful effects in the susceptibility to autoimmune disorders,

including experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS). In particular,

GCs exert their beneficial immunosuppressive and anti-inflammatory effects in inflammatory disorders of the CNS, after binding to their cytoplasmic receptors (GRs).

Here we review our work using transgenic (Tg) mice with a dysfunctional GR from early embryonic life on programming vulnerability to EAE. The GR-deficiency of these Tg mice confers resistance to active EAE induction. The interplay between GCs, proinflammatory mediators, gender and EAE is summarized. On the basis of our data, it does appear that exposure to a defective GR through development programs major changes in endogenous neuroendocrine and immune mechanisms controlling the vulnerability to EAE. These studies highlight the plasticity of the HPA-immune axis and its pharmacological manipulation in autoimmune diseases of the CNS.


Morale et al 2004

Abstract – OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, 94018 Troina, Italy.

Glucocorticoids (GCs)

exert via glucocorticoid receptors (GRs) potent anti-inflammatory and immunosuppressive effects.

Emerging evidence indicates that an inflammatory process is involved in dopaminergic nigro-striatal neuronal loss in Parkinson’s disease. We here report that the GR deficiency of transgenic (Tg) mice expressing GR antisense RNA from early embryonic life has a dramatic impact in “programming” the vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The GR deficiency of Tg mice exacerbates MPTP-induced toxicity to dopaminergic neurons, as revealed by both severe loss of tyrosine hydroxylase positive nigral neurons and sharp decreases in striatal levels of dopamine and its metabolites.

In addition, the late increase in dopamine oxidative metabolism and ascorbic acid oxidative status in GR-deficient mice was far greater than in wild-type (Wt) mice. Inducible nitric oxide synthase (iNOS) was sharply increased in activated astrocytes, macrophages/microglia of GR-deficient as compared with Wt mice. Moreover, GR-deficient microglia produced three- to fourfold higher nitrite levels than Wt mice; these increases preceded the loss of dopaminergic function and were resistant to GR the inhibitory effect of GC, pointing to peroxynitrites as candidate neurotoxic effectors. The iNOS inhibitor N6-(1-iminoethyl)-L-lysine normalized vulnerability of Tg mice, thus establishing a novel link between genetic impairment of GR function and vulnerability to MPTP.


Marchetti et al 2005

Abstract – OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN), Italy. bianca.marchetti@oasi.en.it

Alterations in developmental programming of neuroendocrine and immune system function may critically modulate vulnerability to various diseases.

In particular, genetic factors, including gender,

may interact with early life events such as

exposure to hormones, endotoxins, or neurotoxins, [including the toxins created in the body from severe abuse and neglect of infant and child] thereby influencing disease predisposition and/or severity,

but little is known about the role of the astroglial cell compartment and its mediators in this phenomenon.

Indeed, in the context of innate inflammatory mechanisms, a dysfunction of the astroglial cell compartment is believed to contribute to the selective degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta in Parkinson’s disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Hence,

in response to brain injury

the roles of astrocytes and microglia are

very dynamic and cell type-dependent,

do we put alterations in brain development due to abuse in the same compartment as brain injury?

in that they may exert the known proinflammatory (harmful) effects,

but in certain circumstances they can turn into highly protective cells and exert anti-inflammatory (beneficial) functions,

thereby facilitating neuronal recovery and repair.

Here, we summarize our work suggesting a chief role of hormonal programming of glial response to inflammation and oxidative stress in MPTP-induced loss of DA neuron functionality and demonstrate that endogenous glucocorticoids and the female hormone estrogen (E(2)) inhibit the aberrant neuroinflammatory cascade, protect astrocytes and microglia from programmed cell death, and stimulate recovery of DA neuron functionality, thereby triggering the repair process.

The overall results highlight glia as a final common pathway directing neuroprotection versus neurodegeneration.

Such recognition of endogenous glial protective pathways may provide a new insight and may contribute to the development of novel therapeutic treatment strategies for PD and possibly other neurodegenerative disorders.


Morale et al 2003

Abstract – Department of Neuropharmacology, OASI Institute for Research and Care (IRCCS) on Mental Retardation and Brain Aging, Via Conte Ruggero 73, 94018 Troina (EN), Italy.

Bidirectional communication between the neuroendocrine and immune systems plays a pivotal role in health and disease.

Signals generated by the hypothalamic-pituitary-gonadal (HPG) axis (i.e. luteinizing hormone-releasing hormone neuropeptide LHRH,

and sex steroids) are major players

coordinating the development immune system function.

Conversely, products generated by immune system activation

exert powerful and longlasting effects

on HPG axis activity.

In the central nervous system (CNS), one chief

neuroendocrine-immune (NEI) compartment

is represented by the astroglial cell population and its mediators.

Of special interest, the major supporting cells of the brain and the thymus,

astrocytes and thymic epithelial cells,

share a similar origin and a similar set of peptides, transmitters, hormones and cytokines functioning as paracrine/autocrine regulators.

This may explain some fundamental analogies in neuropeptide LHRH regulation of both cell types during ontogeny and in adult life.

Hence, the neuropeptide LHRH significantly modulates astrocyte and thymic cell development and function.

Here we focus this work on neuropeptide LHRH neuron-glial signaling cascades which dictate major changes during neuropeptide LHRH neuronal differentiation and growth as well as in response to hormonal manipulations and pro-inflammatory challenges.

The interplay between neuropeptide LHRH, growth factors, estrogens and pro-inflammatory mediators will be discussed, and the potential physiopathological implications of these findings summarized. The overall study highlights the plasticity of this intersystem cross-talk and emphasize neuron-glial interactions as a key regulatory level of neuroendocrine axes activity.


Avola et al 2000

Abstract – Department of Chemical Sciences, Medical School, University of Catania, Italy.

Recent evidence indicates that astroglial-derived growth factors (GFs) participate in the development of luteinizing hormone-releasing hormone (LHRH) neurons,

but it is still unknown whether LHRH neurons may exert a reciprocal modulation of glial cell function. Using immortalized hypothalamic LHRH (GT1-1) neurons in co-culture with glial cells, we have recently shown that basic fibroblast growth factor (bFGF) plays a prominent role in the glial-induced acquisition of the mature LHRH phenotype by GT1-1 cells. We have resorted to this model and combined biochemical and morphological approaches to study whether the response of glial cells to a number of GFs (including bFGF, insulin-like growth factor I, IGF-I, epidermal growth factor, EGF and insulin) expressed during LHRH neuron differentiation, is modulated by co-culture with pure LHRH neurons. Pre-treatment of hypothalamic astrocytes with an inactive (‘priming’) dose of bFGF for 12 h powerfully increased astroglia proliferative response to IGF-I (10 ng/ml), EGF (10 g/ml) and insulin (10 microg/ml), inducing a 65-100% increase in the [3H]thymidine incorporation compared to untreated cultures. When astroglial cells and developing GT1-1 neurons were co-cultured for 5 days in vitro (DIV), the [3H]thymidine incorporation was significantly higher than in astroglial cells cultured without neurons. Application of the different GFs to the co-culture for either 12 or 24 h further stimulated DNA synthesis to various extent according to the GF applied and the time of application. Localization of the proliferating cells by dual immunohistochemical staining, followed by cell counting and bromodeoxiuridine (BrdU) labeling index calculation, revealed that the incorporation of BrdU was restricted to the nuclei of LHRH-immunopositive neurons. Such changes were accompanied by extensive morphological alterations of astroglial and LHRH fiber networks, whereas neutralization of bFGF activity in GT1-1 neuron-glial co-cultures by a bFGF-antibody, dramatically counteracted the observed effects. The functional switch of astroglia proliferative response to GFs coupled to the potent morphological and functional modifications of developing glia and pure LHRH neurons observed in vitro, support a

bidirectional interaction between immortalized LHRH neurons and astroglial cells and

identify bFGF as a key player in this crosstalk.



Gallo et al 2000

Abstract – Department of Pharmacology, Medical School, University of Catania, 95125 Catania, Italy.

Luteinizing hormone-releasing hormone (LHRH) neurons

play a pivotal role in the neuroendocrine control of mammalian reproduction.

Astrocytes were shown to be involved in the regulation of LHRH neuronal function, but little is known about the contribution of astroglial-derived factors in the regulation of LHRH neuron development.

In order to gain insight into the mechanisms regulating the development of these cells, at morphological and biochemical levels we characterized the neurotrophic effects exerted by young astrocytes (maintained in culture for 8 days in vitro) and old astrocytes (maintained 26 days) on the

differentiation, proliferation, and phenotypic expression of

immortalized hypothalamic LHRH neurons

(GT(1-1)) neurons in vitro. Culturing GT(1-1) cells in the presence of young glia for different time intervals caused a marked acceleration in the acquisition of their neuronal phenotype. At all times examined, GT(1-1) cells cocultured with young glia exhibited a significantly greater extension of processes/cell, larger number of processes/cell and greater surface area of growth cones than GT(1-1) cells grown over nonglial adhesive substrates (polylysine). By contrast, when GT(1-1) neurons were cocultured with old glia, the length of neuronal processes and the growth cone surface area were significantly lower than in control GT(1-1) neurons cultured in the absence of glia. At 3 days in vitro (DIV), GT(1-1) neurons cocultured with young glia exhibited a 50% lower incorporation of [(3)H]thymidine than GT(1-1) neurons cultured without glia. By contrast, in the presence of old glia [(3)H]thymidine incorporation was significantly higher in cells cocultured with glia than in GT(1-1) neurons cultured alone. Localization of the proliferating cells by dual immunohistochemical staining revealed that the incorporation of bromodeoxiuridine (BrdU) was restricted to nuclei of GT(1-1) neurons when these were cocultured with young glia, but associated with both neurons and astrocytes in the presence of old glia. At the functional level, coculture of GT(1-1) neurons with young glia increased the spontaneous release of LHRH as compared to GT(1-1) neurons grown in the absence of glia. By contrast, in the presence of old glia LHRH release in the medium was significantly lower than in controls. Conditioned medium of young glia (ACM-Y) induced significant neurotrophic and functional effects on GT(1-1) cells, but these effects were 50% less potent than the coculture itself. Heat denaturation of ACM-Y totally abolished its neurotrophic and functional properties, indicating that they involved a peptide factor. Suppression of bFGF activity in ACM-Y reduced its neurotrophic activity by approximately 40%, but did not affect its LHRH release-promoting effects. By contrast, neutralization of endogenous bFGF activity in GT(1-1) neurons cocultured with young glia counteracted both neurotrophic and functional effects of young glia. Treatment of old glia with bFGF rescued its neurotrophic and functional effects on GT(1-1) cells. Moreover, the ACM of aged bFGF-treated old glia was the most powerful neurotrophic stimulus for GT(1-1) neurons.

These results suggest that:

1) soluble peptidic factors, including bFGF, and mechanism(s) requiring coculture are responsible for the highly potent neurotrophic and functional effects of young glia;

2) the inhibitory effects of old glia on neurite outgrowth and LHRH release are mediated in part by soluble inhibitory molecules and in part by factors requiring coculture with old glia;

3) old glia may revert to a growth-supporting state when treated with bFGF and this functional shift involves a diffusible molecule with potent neurotrophic and functional effects on immortalized LHRH neurons.


Marchetti 1996

Abstract – Department of Pharmacology, Medical School, University of Catania, Italy.

Neurons and astrocytes have a close anatomic and functional relationship that plays a crucial role during development and in the adult brain.

Astrocytes in the central nervous system (CNS) express receptors for a variety of growth factors (GFs), neurotransmitters and/or neuromodulators; in turn, neuronal cells can respond to astrocyte-derived GFs and control astrocyte function via a common set of signaling molecules and intracellular transducing pathways.

There is also increasing evidence that soluble factors from lymphoid/mononuclear cells are able to modulate the growth and function of cells found in the CNS, specifically macroglial and microglial cells.

Furthermore, glial cells can secrete immunoregulatory molecules that influence immune cells as well as the glial cells themselves.

As neuronal and immune cells share common signaling systems, the potential exists for bidirectional communication not only between lymphoid and glial cells, but also between neuronal cells and immune and glial cells.

In the present work, interactions of luteinizing-hormone-releasing hormone (LHRH) and the astroglial cell are proposed as a prototype for the study of neuroimmune communication within the CNS in the light of

(1) the commonality of signal molecules (hormones, neurotransmitters and cytokines) and transduction mechanisms shared by glia LHRH neurons and lymphoid cells;

(2) the central role of glia in the developmental organization and pattern of LHRH neuronal migration during embryogenesis, and

(3) the strong modulatory role played by sex steroids in mechanisms involved in synaptic and interneuronal organization, as well as in the sexual dimorphisms of neuroendocrine-immune functions.

During their maturation and differentiation in vitro, astroglial cells release factors able to accelerate markedly the LHRH neuronal phenotypic differentiation as well as the acquisition of mature LHRH secretory potential, with a potency depending on both the ‘age’ and the specific brain localization of the astroglia, as well as the degree of LHRH neuronal differentiation in vitro.

Regional differences in astroglial sensitivity to estrogens were also measured. Different experimental paradigms such as coculture and mixed-culture models between the immortalized LHRH (GT1-1) neuronal cell line and astroglial cells in primary culture, disclosed the presence of a bidirectional flow of informational molecules regulating both proliferative and secretory capacities of each cell type. The importance of adhesive mechanisms in such cross-talk is underscored by the complete abolition of GT1-1 LHRH production and cell proliferation following the counteraction of neuronal-neuronal/neuronal-glial interactions through addition of neural-cell adhesion molecule antiserum. Other information came from pharmacological experiments manipulating the astroglia-derived cytokines and/or nitric oxide, which revealed cross-talk between the neuronal and astroglial compartments. From the bulk of this information, it seems likely that interactions between astroglia and LHRH neurons play a major role in the integration of the multiplicity of brain signals converging on the LHRH neurons that govern reproduction.

Another important facet of neuronal-glial interactions is that concerning neuron-guided migration, and unraveling astroglial/LHRH-neuronal networks might then constitute an additional effort in the comprehension of defective LHRH-neuronal migration in Kallman’s syndrome.


Marchetti 1997

Abstract – Department of Pharmacology, Medical School, University of Catania, 95125 Catania, Italy. marc@ictuniv.unict.it

Neuron-astrocyte interactions play a crucial role during development and in the adult brain.

During development,

glial cells are involved in the guidance of neuronal precursors and in extending neuronal fiber projections.

Astrocytes can promote neurite outgrowth,

both “in vitro” and “in vivo”.

In the central nervous system (CNS), they express receptors for a variety of growth factors (GFs), neurotransmitters and/or neuromodulators.

In turn, neuronal cells can respond to astrocyte-derived growth factors and control astrocyte function via a common set of signaling molecules and intracellular transducing pathways.

It is also well established that astrocytes are involved with regenerative failure within the CNS following injury.

Increasing evidence support the viewpoint that soluble factors from lymphoid/mononuclear cells modulate the growth and function of cells found in the CNS, specifically macroglia and microglia cells. Furthermore, glial cells can secrete immunoregulatory molecules that influence immune cells, as well as the glial cells themselves. In recent years, a bi-directional flow of informational molecules between LHRH neurons, subserving the neuroendocrine control of reproductive function, and astroglia cells has been disclosed.

During their maturation and differentiation in vitro, astroglial cells release peptide growth factors that markedly accelerate LHRH neuronal phenotypic differentiation . In addition, these peptides induce the acquisition of mature LHRH secretory potential, with a potency depending on both the “age” and the specific brain localization of the astroglia, as well as the degree of LHRH neuronal differentiation “in vitro”. Different experimental paradigms such as co-culture and mixed culture models between the GT1-1 neurons and astroglial cells in primary culture, disclosed the presence of a bi-directional flow of informational molecules regulating both proliferative and secretory capacities of each cell type. Growth factors are key players in LHRH neuron-astroglia crosstalk. In particular, basic fibroblast growth factor (bFGF) was identified as a major differentiation factor for the immortalized hypothalamic LHRH neuronal cell line.

A specific synergy/cooperation between bFGF and other growth factors was also revealed at specific stages of LHRH neuron differentiation, indicating that the sequential expression of specific growth factors may participate in the processes of LHRH neuron migration, differentiation and functional regulation. Since bFGF is expressed in GT1-1 neurons and glial cells a possible paracrine/autocrine regulatory loop is suggested. Indeed, neutralization experiments aimed at counteracting endogenous bFGF during neuron-glia interactions dramatically inhibited astroglia neurotrophic effects. On the other hand, the importance of adhesion molecules in cell-to-cell communication was underscored by the significant inhibition of GT1-1 LHRH production and cell proliferation following the counteraction of neuron-neuron/neuron-glia interactions through addition of neuronal cell adhesion molecule (N-CAM) antiserum. Other information came from pharmacological experiments manipulating the astroglial-derived cytokines and/or nitric oxide, which revealed a crosstalk between the neuronal and astroglial compartments. From the bulk of this information, it seems likely that

interactions between astroglia and LHRH neurons play a major role in the integration of the multiplicity of brain signals converging on the LHRH neurons that govern reproduction.


Marchetti et al 2000

Abstract – Department of Pharmacology and Gynecology, Medical School, University of Sassari, Viale S. Pietro 43/B, 07100 Sassari, Italy. bianca.marchetti@oasi.en.it

Signals generated by the

hypothalamic-pituitary-gonadal (HPG) axis

powerfully modulate immune system function.

This article summarizes some aspects of the impact of gender in neuroendocrine immunomodulation. Emphasis is given to the

astroglial cell compartment,

defined as a key actor in neuroendocrine immune communications.

In the brain, the principal hormones of the HPG axis

directly interact with astroglial cells.

Thus, luteinizing hormone releasing hormone, LHRH,

influences hypothalamic astrocyte development and growth,

and hypothalamic astrocytes direct LHRH neuron differentiation.

Hormonally induced changes in neuron-glial plasticity may dictate major changes in CNS output,

and thus actively participate in sex dimorphic immune responses.

The impact of gender in neuroimmunomodulation is further underlined by the sex dimorphism in the expression of genes encoding for neuroendocrine hormones and their receptors within the thymus, and by the potent modulation exerted by circulating sex steroids during development and immunization.

The central role of glucocorticoids in the

interactive communication between neuroendocrine

and immune systems, and the impact of gender on hypothalamic-pituitary-adrenocortical (HPA) axis modulation is underscored in transgenic mice expressing a glucocorticoid receptor antisense RNA.


Uchakin et al 2007

Abstract – article in Russian

Close interaction between the immune and nervous systems is well documented.

The ability of immunocompetent cells to express receptors to neuroendocrine mediators as well as secrete many of them is proved.

The current literature suggests that the hormones of the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonodal axes play the most significant role in the regulation of immune responsiveness. On the other hand, the immune system communicates with the CNS directly through the cytokines that are able to cross the blood-brain barrier, or directly via the nervus vagus, as well as via secondary messengers.

Receptors to a number of cytokines have been found in the nervous tissue.

Moreover, glial cells are able to secrete cytokines in the amount significant enough for at least autocrine action. In this article, the authors review the

role of the “major” stress hormones such as

cortisol, DHEA, growth hormone in the

regulation of immune response,

as well as neuro- and


properties of two major groups of cytokines that support cell-mediated (Type 1) and humoral (Type 2) immune reactions. This review emphasizes neuro-endocrine-immune interactions in response to infection both under laboratory and clinical conditions.


Voigt et al 1996

Abstract – Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton 97006, USA.

It is becoming increasingly evident that the secretory activity of LHRH neurons is regulated not only by transsynaptic inputs but also by trophic molecules of glial and neuronal origin.

The present experiments were undertaken to gain insights into the potential cell-cell mechanisms by which basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF alpha), two growth factors produced in the hypothalamus, may affect LHRH neuronal function.

Northern blot analysis showed that the LHRH-producing cell line GT1-7 contains the messenger RNA (mRNA) encoding the type 1 fibroblast growth factor receptor (FGFR-1) but not that encoding the epidermal growth factor (EGF) receptors,

which mediates the biological actions of both TGF alpha and EGF. Ligand-induced receptor phosphorylation experiments demonstrated that GT1-7 cells possess biologically active FGFR-1s but not EGF receptors.

Exposure of the cells to bFGF resulted not only in FGFR-1 tyrosine phosphorylation, but also in tyrosine phosphorylation of phospholipase C gamma, one of the initial enzymes in the intracellular signaling cascade initiated by FGFR activation.

GT1-7 cells proliferated in response to this activation. Despite the presence of biologically active receptors, bFGF did not significantly stimulate release of the mature LHRH decapeptide. Instead, bFGF increased the steady-state levels of the mRNA encoding the LHRH precursor processing endoprotease PC2, with a time course comparable to that of phorbol esters, suggesting that, as shown in the companion paper, the actions of the growth factor on LHRH neurons involve facilitation of the initial step in LHRH prohormone processing.

The increase in PC2 gene expression was not accompanied by changes in LHRH mRNA levels. Unlike these direct actions of bFGF on GT-1 cells, TGF alpha appears to act indirectly via astroglial intermediacy. Exposure of GT1-7 cells to TGF alpha or EGF failed to affect several parameters of cellular activity including LHRH release, LHRH and PC2 mRNA levels, and cell proliferation. In contrast, astrocyte culture medium conditioned by treatment with TGF alpha led to sustained stimulation of LHRH release with no changes in LHRH gene expression and a transient increase in PC2 mRNA levels. Although no definitive evidence for the presence of FGFR-1 in normal LHRH neurons could be obtained by either double immunohistochemistry or double in situ hybridization procedures, fetal LHRH neurons in primary culture responded to bFGF with neurite outgrowth. Thus, normal LHRH neurons may have an FGFR-1 content too low for detection by regular histochemical procedures, and/or detectable expression of the receptor may be confined to a much earlier developmental stage. The mitogenic effect of bFGF on GT1-7 cells supports this possibility and suggests a role for FGF in the cell proliferation events that precede acquisition of the LHRH neuronal phenotype. It appears that once this phenotype is established, bFGF may promote the differentiation of LHRH neurons. The results also suggest that the secretory capacity of LHRH neurons develops under a dual trophic influence, one on peptide processing exerted directly by bFGF on early neurons, and another on LHRH release, exerted by TGF alpha via the intermediacy of astroglial cells.


Marchetti et al 1998

Abstract – Department of Pharmacology, Medical School, University of Catania, Italy. marc@mbox.unict.it

The brain-pituitary-reproductive axis

and the brain thymus-lymphoid axis

are linked by an array of internal mechanisms of communication

that use similar signals

(neurotransmitters, peptides, growth factors, hormones)

acting on similar recognition targets.

such communication networks

form the basis and control each step and every level

of reproductive physiology.

Cannabinoids must fit in here

endocrine, neural, glial, or immunologically competent cells

may achieve their specific functions using common mechanisms,

but employing them to different degrees.

Luteinizing hormone-releasing hormone (LHRH),

the chief hormone orchestrating reproductive events.

Within the thymus LHRH plays a unique role of immunomodulator, contributing to the sex-dependent changes in immune responsiveness during the estrous-menstrual cycle as well as pregnancy.

From the recent cloning and sequencing of lymphocyte LHRH, the expression of LHRH receptor mRNA in lymphocyte, the transduction mechanisms involved, and the steroidogenic sensitivity of the intralymphocyte LHRH system. It would appear that this peptide may act as an immunological response modifier in the brain-pituitary-lymphoid-gonadal axis.

The interplay between neuronal, endocrine, and immune compartments is further emphasized in the study of LHRH-astroglial interactions.

Astrocytesare able to manufacture a wide variety of signaling agents and can secrete immunoregulatory molecules that influence immune cells, as well as the glial cells themselves.

Astroglia and the

immortalized hypothalamic LHRH (GT1-1) neurons

communicate with an array of mechanisms, via soluble mediators as well as cell-to-cell contacts.

Manipulation of astroglial-derived cytokines and nitric oxide (NO) in GT1-1 neuron-astroglia cocultures, underscores a potential cross-talk between different intra/inter-cellular mediators in the dynamic control of LHRH release. Further studies aimed to disclose at a biochemical and a molecular level such bidirectional, informative network will give us new insights into more general issues concerned with the malfunction of the neuroendocrine-immune axis.  1998 article

I know there’s a link here with the cannabinoid system – I guess I have to put it here


Navarrete & Araque 2008

Abstract – Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.

Endocannabinoids mediate neuron-astrocyte communication.

Endocannabinoids mediate neuron-astrocyte communication.

Cannabinoid receptorsplay key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the

existence of endocannabinoid-mediated neuron-astrocyte communication,

revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.


Bindukumar et al 2008

Abstract – Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Buffalo General Hospital, University at Buffalo, State University of NY, Kaleida Health, 100 High Street, Buffalo, NY 14203, USA.

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes.

Delta-9-tetrahydrocannabinol (Delta(9)-THC), the main psychoactive component of marijuana, is known to dysregulate various immune responses.

Cannabinoid (CB)-1 and -2 receptors are expressed mainly on cells of the central nervous system (CNS) and the immune system.

The CNS is the primary target of cannabinoids and astrocytes are known to play a role in various immune responses. Thus we undertook this investigation to determine the global molecular effects of cannabinoids on normal human astrocytes (NHA) using genomic and proteomic analyses. NHA were treated with Delta(9)-THC and assayed using gene microarrays and two-dimensional (2D) difference gel electrophoresis (DIGE) coupled with mass spectrometry (MS) to elucidate their genomic and proteomic profiles respectively. Our results show that the expression of more than 20 translated protein gene products from NHA was differentially dysregulated by treatment with Delta(9)-THC compared to untreated, control NHA.


Kreutz et al 2008

Abstract – Dr. Senckenbergische Anatomie, Institut für Anatomie II, J. W. Goethe-Universität, Frankfurt am Main, Germany.

Endocannabinoids like 2-arachidonoylglycerol (2-AG) exert neuroprotective effects after brain injuries.

According to current concepts, these neuroprotective effects are due to interactions between 2-AG and cannabinoid (CB)1 receptors on neurons.

Moreover, 2-AG modulates migration and proliferation of microglial cells which are rapidly activated after brain lesion. This effect is mediated via CB2- and abnormal-cannabidiol (abn-CBD)-sensitive receptors.

In the present study, we investigated whether the abn-CBD-sensitive receptor on microglial cells contributes to 2-AG-mediated neuroprotection in organotypic hippocampal slice cultures (OHSCs) after excitotoxic lesion induced by NMDA (50 muM) application for 4 h. This lesion caused neuronal damage and accumulation of microglial cells within the granule cell layer. To analyze the role of abn-CBD-sensitive receptors for neuroprotection and microglial cell accumulation, two agonists of the abn-CBD-sensitive receptor, abn-CBD or 2-AG, two antagonists, 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen1-yl]-benzene (O-1918) or cannabidiol (CBD), and the CB1 receptor antagonist AM251, were applied to NMDA-lesioned OHSC. Propidium iodide (PI) labeling was used as a marker of degenerating neurons and isolectin B(4) (IB(4)) as a marker of microglial cells. Application of both, abn-CBD or 2-AG to lesioned OHSC significantly decreased the number of IB(4) (+) microglial cells and PI(+) neurons in the dentate gyrus. In contrast to AM251, application of O-1918 or CBD antagonized these effects. When microglial cells were depleted by preincubation of OHSC with the bisphosphonate clodronate (100 mug/mL) for 5 days before excitotoxic lesion, 2-AG and abn-CBD lost their neuroprotective effects. We therefore propose that the

endocannabinoid 2-AG exerts its neuroprotective effects

via activation of abn-CBD-sensitive receptors on

microglial cells.


Fernandez-Ruiz et al 2007

Abstract – Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain. jjfr@med.ucm.es

Two types of cannabinoid receptor have been cloned and characterized. Whereas CB1 receptors are ubiquitously expressed in neurons of the CNS, CB2 receptors have been thought to be absent from the CNS. Recent data now question this notion and support the expression of CB2 receptors in microglial cells, astrocytes and even some neuron subpopulations. This discrete distribution makes CB2 receptors interesting targets for treating neurological disorders because CB2-selective agonists lack psychoactivity. Here, we review evidence supporting the idea that CB2 receptors are implicated in the control of fundamental neural cell processes, such as proliferation and survival, and that their pharmacological manipulation might be useful for both delaying the progression of neurodegenerative disorders and inhibiting the growth of glial tumors.



McCarty 2006

Abstract – Natural Alternatives International, 1185 Linda Vista Dr., San Marcos, CA 92078, USA. mccarty@pantox.com

Chronic neurodegenerative disorders are characterized by activation of microglia in the affected neural pathways.

Peroxynitrite, prostanoids, and cytokines generated

by these microglia can potentiate the excitotoxicity

that contributes to neuronal death and dysfunction

in these disorders–both by direct effects on neurons,

and by impairing the capacity of astrocytes to sequester and metabolize glutamate.

This suggests a vicious cycle in which the

death of neurons leads to microglial activation,

which in turn potentiates neuronal damage.

If this model is correct, measures which down-regulate microglial activation may have a favorable effect on the induction and progression of neurodegenerative disease, independent of the particular trigger or target involved in a given disorder. Consistent with this possibility, the antibiotic minocycline, which inhibits microglial activation, shows broad utility in rodent models of neurodegeneration. Other agents which may have potential in this regard include PPARgamma agonists, genistein, vitamin D, COX-2 inhibitors, statins (and possibly policosanol), caffeine, cannabinoids, and sesamin; some of these agents could also be expected to be directly protective to neurons threatened with excitotoxicity. To achieve optimal clinical outcomes, regimens which down-regulate microglial activation could be used in conjunction with complementary measures which address other aspects of excitotoxicity.


Shelton & McCarthy 1999

Abstract – Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA.

Astrocytes closely contact neurons where they respond to neuronally released glutamate in immature brain slices. In previous studies, neither metabotropic nor ionotropic glutamate receptor-mediated responses were detected by imaging Ca2+ in astrocytes from mature (P21-P42) animals, suggesting astrocyte glutamate receptors only contribute to hippocampus physiology during development. In contrast to Ca2+ imaging, published electrophysiological experiments suggest P30-P35 astrocytes have alpha-amino-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. For this study, we imaged astrocytes in P31-P38 hippocampal slices to determine if metabotropic and ionotropic glutamate receptor activation elevates intracellular calcium in mature astrocytes. Drugs were perfused while [Ca2+]i was monitored (confocal imaging) in cells loaded with Calcium Green 1-AM. Imaged cells were subsequently identified as astrocytes by GFAP/S-100 immunostaining. Astrocytic Ca2+ increased after glutamate application in the presence of a glutamate uptake inhibitor. An agonist at group I/II metabotropic glutamate receptors, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), elicited Ca2+ increases as did group I agonist 3,5-dihydroxyphenylglycine (DHPG), suggesting that mature astrocytes respond to glutamate via metabotropic glutamate receptors. AMPA also elicited Ca2+ elevations that were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and occurred after treatment with omega-conotoxin MVIIC to block neurotransmitter release. These results demonstrate that astrocytes in mature hippocampus have functional ionotropic and metabotropic glutamate receptors that regulate astrocytic calcium levels. Glutamatergic regulation of astrocytic [Ca2+]i may be involved in synapse modeling, long-term potentiation, excitotoxicity and other events dependent on glutamatergic transmission in adult hippocampus.

Dheen, Jaur & Ling

Abstract – Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore 117597.

An inflammatory process in the central nervous system (CNS) is believed to play an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, prion diseases, multiple sclerosis and HIV-dementia.

The inflammatory response is mediated by the activated microglia, the resident immune cells of the CNS,

which normally respond to neuronal damage and remove the damaged cells by phagocytosis.

Activation of microglia is a hallmark of brain pathology.

However, it remains controversial whether microglial cells have beneficial or detrimental functions in various neuropathological conditions. The chronic activation of microglia may in turn cause neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins.

Therefore, suppression of microglia-mediated inflammation has been considered as an important strategy in neurodegenerative disease therapy. Several anti-inflammatory drugs of various chemical ingredients have been shown to repress the microglial activation and to exert neuroprotective effects in the CNS following different types of injuries. However, the molecular mechanisms by which these effects occur remain unclear. In recent years, several research groups including ours have attempted to explain the potential mechanisms and signaling pathways for the repressive effect of various drugs, on activation of microglial cells in CNS injury. We provide here a comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases. This review article further summarizes the role of microglial cells in neurodegenerative diseases and various forms of potential therapeutic options to inhibit the microglial activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases.


Marchalant et al 2008

Abstract – Department of Psychology, Psychology Building, Ohio State University, Columbus, OH 43210, USA.

The number of activated microglia increase during normal aging. Stimulation of endocannabinoid receptors can reduce the number of activated microglia, particularly in the hippocampus, of young rats infused chronically with lipopolysaccharide (LPS). In the current study we demonstrate that endocannabinoid receptor stimulation by administration of WIN-55212-2 (2mg/kgday) can reduce the number of activated microglia in hippocampus of aged rats and attenuate the spatial memory impairment in the water pool task. Our results suggest that the action of WIN-55212-2 does not depend upon a direct effect upon microglia or astrocytes but is dependent upon stimulation of neuronal cannabinoid receptors.

Aging significantly reduced cannabinoid type 1 receptor binding but had no effect on cannabinoid receptor protein levels. Stimulation of cannabinoid receptors may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer’s disease.


Ortega-Gutierrez, Molina-Holgado & Guaza 2005

Abstract – Neural Plasticity Department, Neuroimmunology Group, Cajal Institute, CSIC, Madrid, Spain.

Astrocytes play a key role regulating aspects of inflammation in the central nervous system (CNS). Several enzymes, such as the inducible nitric oxide synthase (iNOS) or the cyclooxygenase-2 (COX-2), along with different inflammatory mediators such as the free radical nitric oxide (NO) or proinflammatory cytokines, have been proposed to be involved in the cell damage associated with neuroinflammation.

Recent studies suggest that the endogenous cannabinoid system (ECS) may be involved in the regulation of neuroinflammation.

Cannabinoid agonists decrease neurotoxicity and release of proinflammatory factors from activated glial cells and anandamide itself is able to promote antiinflammatory responses in astrocytes via CB1 cannabinoid receptors.

The present study is aimed at studying whether UCM707, a potent and selective anandamide uptake inhibitor, is able to inhibit the production of proinflammatory mediators by LPS-stimulated astrocytes. Our findings indicate that UCM707 is able to reduce NO release, iNOS expression, and the production of the proinflammatory cytokines tumoral necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in a significant manner, while producing a slight increase in IL-6 levels. These effects can be reproduced by administration of the synthetic agonist HU210 and partially or totally blocked by administration of CB1 or CB2 selective antagonists, further supporting the involvement of the ECS. These results confirm the ability of UCM707 to reinforce the beneficial effects induced by anandamide and make it an attractive candidate for the management of those pathologies with neuroinflammation as one of their hallmarks.


Gaillard 2003

Abstract – article in French – Division d’Endocrinologie, Diabétologie et Métabolisme, Centre Hospitalier Universitaire Vaudois-CHUV, CH-1011 Lausanne, Suisse.

The endocrine and immune systems are interrelated via a bidirectional network in which hormones affect immune function and, in turn, immune responses are reflected in neuroendocrine changes.

This bidirectional communication is possible because both systems share a common “chemical language” that results from a sharing of common ligands (hormones and cytokines) and their specific receptors.

Cytokines are important partners in this crosstalk.

They play a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis responses at

all three levels: the hypothalamus, the pituitary gland and the adrenals.

Acute effects of cytokines are

produced at the central nervous system level,

particularly the hypothalamus,

whereas pituitary and adrenal actions are slower

and are probably involved during prolonged exposure

to cytokines

such as during chronic inflammation or infection. Or chronic psychological stress?

Several mechanisms have been proposed by which peripheral cytokines may gain access to the brain. They include an

active transport through the blood-brain barrier, a

passage at the circumventricular organ level, as well as a

neuronal pathway through the vagal nerve.

The immune-neuroendocrine interactions

are involved in numerous physiological and pathophysiological conditions

and the interactions with the HPA axis may represent a mechanism through which the immune system, by stimulating the production of glucocorticoids,

avoids an overshoot of inflammatory response.

They may also be involved in the state of hypogonadism, of hypothyroidism and growth inhibition which can occur during inflammatory and infectious diseases. The crosstalk between the immune and endocrine systems

is important to homeostasis,

since the interactions can produce various appropriate adaptative responses

when homeostasis is threatened.



Cizza & Sternberg 1994

Abstract – Clinical Neuroendocrinology Branch, National Institute of Mental Health, NIH, Bethesda, Maryland 20892.

The central nervous system (CNS) affects the immune system through endocrine, paracrine, and neuronal mechanisms.

The immune system in turn communicates with the CNS through many of the same mechanisms.

Evidence that this bidirectional communication plays a vital role in susceptibility to inflammatory and infectious disease

is derived largely from animal models in which the communication has been interrupted or reconstituted surgically, pharmacologically, or on a preexisting genetic basis.

The advantage of animal models for studying the pathophysiologic relevance of such connections is that the systems can be manipulated at several levels and at different times in relation to development of the inflammatory disease and the outcome of the manipulation can be quantified. While in vitro studies may be used to further define the subcellular and molecular mechanisms of these interactions,

only an intact organism, in which the central nervous system is connected to the immune system, can be used to fully define the nature of these interconnections. We have to keep this wholeness intact in our thinking, as well

This review describes approaches to studying CNS-immune system interactions, using relatively inflammatory-susceptible and inflammatory-resistant [doves and hawks] Lewis and Fischer rats as models for evaluating the role of the HPA axis in susceptibility to inflammatory disease.


Marques-Deak, Cizza & Sternberg 2005

Abstract – Section on Neuroendocrine Immunology and Behavior, Integrative Neural Immune Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.

Many studies have established the routes by which the immune and central nervous (CNS) systems communicate. This

network of connections permits the CNS

to regulate the immune system

through both neuroendocrine and neuronal pathways.

How do they know it’s not the other way around?

Or is it such a circle that there is no beginning or end?

In turn, the immune system signals the CNS

through neuronal and humoral routes,

via immune mediators and cytokines.

This regulatory system between the immune system and CNS plays an important role in susceptibility and resistance to autoimmune, inflammatory, infectious and allergic diseases.

This review focuses on the

regulation of the immune system

via the neuroendocrine system, and

underlines the link between

neuroendocrine dysregulation

and development of

major depressive disorders,

autoimmune diseases and


Link here with osteoporosis with

cannabinoid bone regulation


Eskandari, Webster & Sternberg 2003

Abstract – Section on Neuroendocrine Immunology and Behavior, NIMH/NIH, Bethesda, MD, USA. ems@codon.nih.gov

Inflammation and inflammatory responses

are modulated by a

bidirectional communication

between the neuroendocrine and immune system.

Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate.

The CNS signals the immune system

through hormonal pathways,

including the hypothalamic-pituitary-adrenal HPA axis

and the hormones of the neuroendocrine stress response,

and through neuronal pathways,

including the autonomic nervous system.

The hypothalamic-pituitary-gonadal HPG axis

and sex hormones also

have an important immunoregulatory role.

The immune system signals the CNS

through immune mediators and cytokines

that can cross the blood-brain barrier,

or signal indirectly through the vagus nerve

or second messengers.

Neuroendocrine regulation of immune function

is essential for survival during stress or infection

and to modulate immune responses in inflammatory disease.

This review discusses neuroimmune interactions and

evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis.


Tetel 2000

Abstract – Center for Neuroendocrine Studies and, Neuroscience and Behavior Program, University of Massachusetts, Amherst 01003, USA. tetel@cns.umass.edu

Steroid hormones influence a variety of neuroendocrine events, including brain development, sexual differentiation and reproduction. Hormones elicit many of these effects by binding to neuronal steroid receptors, which are members of a nuclear receptor superfamily of transcriptional activators. However, the mechanisms by which activated steroid receptors regulate gene expression in brain are not well understood. Recently, a new class of proteins, known as nuclear receptor coactivators, have been found to dramatically enhance steroid receptor mediated transactivation of genes in vitro. Here, the proposed molecular mechanisms of how these coactivators enhance the transcriptional activity of steroid receptors are summarized. While much is known about the mechanisms of these coactivators in vitro, it is unclear how these cofactors function in hormone action in vivo or in the brain. This paper discusses some of the initial and enticing investigations into the role of these important coregulatory proteins in neuroendocrine events. Finally, some of the critical issues and future directions in nuclear receptor coactivator function in neuroendocrinology are highlighted.


Charlier & Balthazart 2005

Abstract – University of Liège, Center for Cellular and Molecular Neurobiology, Research Group in Behavioral Neuroendocrinology, Belgium. thierry.charlier@student.ulg.ac.be

Nuclear receptors,

such as estrogen, glucocorticoid or thyroid hormone receptors, have been shown to play a critical role in brain development and physiology.

The activity of these receptors is modulated by the interaction with several proteins and, in particular, coactivators are required to enhance their transcriptional activity. The steroid receptor coactivators (SRC-1, -2 and -3) are currently the best characterized coactivators and we review here the current knowledge on the distribution and function of these proteins in the brain. Knock-out models and antisense techniques have demonstrated the requirement for SRC-1 and -2 in the brain, focusing mainly on steroid and thyroid hormone-dependent development and behavior.

The precise function of SRC-3 in the brain is currently unknown but its presence throughout the brain suggests an important function.

Although the molecular biology of SRCs is relatively well known, the in vivo control of their expression, post-translational modifications and time- and cell-specific interactions with the different nuclear receptors remain elusive.

A complete understanding of hormone action on brain and behavior will not be attained until a better knowledge of coactivator physiology is achieved.


Jara et al 2006

Abstract – Research Division, Clinical and Epidemiology Research Unit, Internal Medicine Department, Hospital de Especialidades Contro Médico La Raza, IMSS, Mexico City, Mexico. luis_jara_quezada@hotmail.com

The relationship between immune-neuroendocrine system is firmly established. The messengers of this connection are



neurotransmitters and


The immune-neuroendocrine system has the capacity to synthesize and release these molecules, which, in turn, can stimulate or suppress the activity of immune or neuroendocrine cells by binding to receptors.

In fact, hormones, neuropeptides and neurotransmitters participate in innate and adaptive immune response.

Autoimmune rheumatic diseases (ARD) are characterized by

aberrant production of

pro-inflammatory cytokines,

which are a potent activator of the HPA axis.

In consequence, high levels of pro-inflammatory hormones

such as estrogens and prolactin, and

low levels of glucocorticoids, an anti-inflammatory hormone,

have been described in the active phase of ARD. In addition, high levels of pro-inflammatory hormones and cytokines have also been frequently detected in organ involvement of patients with ARD, suggesting an abnormal local neuroendocrine immune interaction. There is evidence that hormonal changes may appear before the symptomatic phase of the disease. Therefore, it is possible that

a pro-inflammatory hormone favors the

rupture of tolerance,

which is a key feature of autoimmune diseases.

The interactions between the immune-neuroendocrine system have a major impact on our understanding of the pathogenic mechanisms, diagnosis and therapy of ARD.


Niess et al 2002

Abstract – Biomedizinisches Forschungszentrum, Campus Virchow-Klinikum, Berlin, Germany.

Stress has long been postulated to influence the progression of inflammatory bowel disease (IBD). Our current understanding of the relationship between stress and IBD is still limited, and hence explanation for the occurrence of relapses has remained largely speculative. Stress affects the immune system, the neuroendocrine system and the intestinal epithelia.

Stress induces the release of pro-inflammatory Th1 cytokines and neuropeptides, such as tachykinins.

Thereby, stress may induce alterations of the intestinal epithelium via the interaction of the neuroendocrine and immune system and may induce relapses of IBD. The present review focuses on this network and highlights the role of distinct mediators and mechanisms, i.e. neurotransmitters, hormones and immune cells, which are involved in the response to stress on the one hand, and contribute to the onset, progression or relapses of IBD on the other.

Petrovsky 2001

Abstract – Autoimmunity Research Unit, Canberra Clinical School, University of Sydney and Division of Science and Design, University of Canberra, Canberra, Australian Capital Territory, Australia. nikolai.petrovsky@anu.edu.au

Although the neuroendocrine system has immunomodulating potential, studies examining the relationship between stress, immunity and infection have, until recently, largely been the preserve of behavioral psychologists. Over the last decade, however, immunologists have begun to increasingly appreciate that neuroendocrine-immune interactions hold the key to understanding the complex behavior of the immune system in vivo.

The nervous, endocrine and immune systems

communicate bidirectionally

via shared messenger molecules

variously called neurotransmitters, cytokines or hormones.

Their classification as neurotransmitters, cytokines or hormones is more serendipity than a true reflection of their sphere of influence.

Rather than these systems being discrete entities we would propose that they constitute, in reality,

a single higher-order entity.

This paper reviews current knowledge of neuroendocrine-immune interaction and uses the example of T-cell subset differentiation to show the previously under-appreciated importance of neuroendocrine influences in the regulation of immune function and, in particular,

Th1/Th2 balance and

diurnal variation there of.


Spangelo & Gorospe 1995

Abstract – Department of Chemistry, University of Nevada Las Vegas 89154, USA.

A rapidly growing body of evidence reveals that complex networks of communication exist between the neuroendocrine and the immune systems.

Essential to the maintenance and function of the immune-endocrine circuitry are an array of chemical mediators produced by cells of the immune and endocrine systems. Cytokines are glycoproteins (molecular masses of 15,000-20,000) that are elaborated by antigen-activated immune cells and responsible for orchestrating immune cellular activities. These inflammatory mediators also affect the functioning of the neuroendocrine system.

Thus, interleukin-1 (IL-1), IL-2, IL-4, IL-6, tumor necrosis factor-alpha and interferon-gamma affect the secretion of hypothalamic and anterior pituitary hormones in vitro and in vivo, and specific high-affinity receptors for IL-1, IL-2, and IL-6 have been identified in neuroendocrine tissues. A paracrine role for these factors in the regulation of neuroendocrine function may be advanced because certain of these mediators (e.g., IL-1, IL-6) are present in the hypothalamus as well as the anterior and neurointermediate lobes of the pituitary.

The production of these cytokines in neuroendocrine cells is enhanced by neuropeptides, endotoxin, and other cytokines.

We propose that the local neuroendocrine cytokinergic tone may act in a facilitative manner to enhance the secretion of hypothalamic-pituitary hormones.


Ferencík & Stvrtinová 1997

Abstract – article in Slovak – Immunologický ústav Lekárskej fakulty Univerzity Komenského v Bratislave, Slovakia. ferencik@fmed.uniba.sk

[Is the immune system our sixth sense? Relation between the immune and neuroendocrine systems]  title of this article

There is an overwhelming evidence that cytokines, peptide hormones and neurotransmitters, as well as their receptors, are present in the brain, endocrine and immune systems. The structure and pattern of synthesis of these peptides by leukocytes appear similar to those synthesized in the neuroendocrine system, although some differences exist. Once secreted, these peptide hormones may function as endogenous regulators inside of the each system and also in bidirectional communication between the immune and neuroendocrine systems.

Such communication suggests

an immunoregulatory role for the brain

and a sensory function for the immune system

which may sense stimuli that are not recognized

by the central and peripheral nervous systems (noncognitive stimuli).

Well, I’ll be darned!  I found it – this is what I suspected!  In 1997 writing from Slovakia!

The plasma hormone concentrations contributed by lymphocytes usually do not reach the levels required when the pituitary gland is the source, but because immune cells are mobile, they have the potential to deposit the hormone locally at the target site.

Several immunoregulatory cytokines, including IL-1, IL-2, IL-6, IFN-gama and TNF are produced not only in the immune system but in the neuroendocrine system as well. They have profound effects on neuroendocrine functions especially on hypothalamic pituitary axes.

Neuroendocrine influences that modulate the immune function mainly include mental and physical stress.

It can reduce the resistance of organism

to infectious diseases and malignancies

by compromising the immune system directly or indirectly.

The brain is not an immunologically privileged site and therefore may become the target of immunologic attacks resulting in neuroimmunological diseases with an autoimmune component.

The impact of psychological and psychosocial factors on the immune system is studied by psychoneuroimmunology

whereas neuroendocrine immunology is generally interested in the interactions between the immune and neuroendocrine systems under physiological and pathological conditions. Well, they can draw the line where they want to, but for those of us in suffering bodies, the line is imaginary

The recognition of the identity of ligands and receptors

in the immune, nervous, and endocrine systems

suggest a radically altered view of the immune systems impact on other tissues and organ systems, and vice versa. This will undoubtedly change our understanding of physiology, and consequently should profoundly impact the practice of medicine. (Tab. 5, Fig. 4, Ref. 85.)


Kumsta et al 2007

Abstract – Department of Psychobiology, University of Trier, Trier, Germany.

Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders.

Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease.

METHODS: We investigated 206 healthy subjects and assessed associations

between four common GR gene (NR3C1) polymorphisms

(ER22/23EK, N363S, BclI, 9beta)

and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress

(Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS:

Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses ….whereas

male BclI GG carriers showed diminished responses.

Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction ….

Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03).

CONCLUSIONS: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity.

These findings support the relevance of

GR gene polymorphisms in HPA axis regulation.

Genetic variations of the GR might constitute a risk factor

in development of HPA axis related disorders.


Wust et al 2004

Abstract – Department of Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany. wuest@uni-trier.de

Find elsewhere in text



3a chapter 3 emotions

to be included in chapter 3 symptoms and detections


Etkin et al, 2006

Nonemotional (cognitive) conflict resolution – studied and info already exists


“…we find that activity in the amygdala and dorsomedial and dorsolateral prefrontal cortices reflects the amount of emotional conflict.  By contrast, the resolution of emotional conflict is associated with activation of the rostral anterior cingulate cortex.  Activation of the rostral cingulate is predicted b the amount of previous-trail conflict-related neural activity and is accompanied by a simultaneous and correlated reduction of amygdalar activity.  These data suggest that emotional conflict is resolved through top-down inhibition of amygdalar activity by the rostral cingulate cortex.”  Etkin et al, 2006, 1

Which of a large number of sensory stimuli do we dedicate processing resources to?

Attentional mechanisms are engaged to prioritize processing, diminish distraction by stimuli that is irrelevant to a task at hand.

“To ensure optimal performance, the brain is thought to resolve “conflict” by monitoring continuously for distracters that produce responses that are incompatible with the current task (Botvinick et al., 2001).  Emotionally salient stimuli, such as those that signal potential danger, are particularly effective in interfering with ongoing cognitive processes (LeDoux, 2000; Mathews, 1990; Tipples and Sharma, 2000).”  Etkin et al, 2006, 1

[they are using a task related to fear and happy faces with words congruent or incongruent written across them – I hope they relate the information about face processing brain regions which are very specific —-]

anterior cingulate cortex – thought to play critical role in executive attention

some authors divide the ACC into a dorsal “cognitive” division and a ventral “affective division


“The dorsal cingulate and adjacent dorsomedial prefrontal cortex are connected with “cognitive” regions such as the lateral prefrontal and motor/premotor cortices….”  Etkin et al, 2006, 2

“The ventral division, composed of rostral (pregenual) and subgenual components, is connected with “affective” regions such as the amygdala.”  Etkin et al, 2006, 2

“The dorsal and ventral divisions of the anterior cingulate are also interconnected with each other….”  Etkin et al, 2006, 2

“…activity in the dorsal cingulate and the [adjacent] dorsomedial prefrontal cortex associated with the monitoring of conflict…”  Etkin et al, 2006, 2

have additional roles in general outcome evaluation, volitional processes, attentional selection, and autonomic control

“…activity in the lateral prefrontal cortices was associated with the resolution of conflict….”  Etkin et al, 2006, 2


activate the rostral anterior cingulate, part of the ventral “affective” division

….tasks involving emotional processing in general, processing of emotional distracters, particularly processing of negatively valenced stimuli

“By extrapolation from the involvement of the dorsal cingulate in the processing of cognitive conflict, the rostral and subgenual cingulate have been thought to play a role in processing emotional conflict.”  Etkin et al, 2006, 3

“These studies, however, presented emotional stimuli in blocks…and therefore could not distinguish the mechanisms associated with the monitoring of conflict from those associated with the resolution of conflict….The exact function of the rostral cingulate in emotional conflict, therefore, remains unclear.”  Etkin et al, 2006, 3

which regions track emotional conflict and which regions are involved in emotional conflict resolution….functional interconnectivity….whether neural conflict resolution would be recruited in a flexible manner on the current trial, to the degree appropriate for the amount of conflict signaled by conflict-tracking regions on the previous trial….for conflict resolution to be successful, the regions underlying conflict resolution must in turn regulate the source of the emotional conflict….examine whether increased activity in regions involved in conflict resolution was associated with decreased activity in upstream regions involved in conflict processing


amygdalae revealed a cluster in the right amygdala where activity was greater in low than high conflict resolution trials

………..suggesting that activity in the amygdala reflects the amount of emotional conflict

……..none in amygdala more active in high than low conflict

…..the effect of emotional conflict in the amygdala did not differ between fearful and happy face targets or fearful and happy words

………….”These results therefore show that emotional conflict itself leads to activation of the amygdala, independently of stimulus valence.”  Etkin et al, 2006, 4

medial and lateral prefrontal cortices, including the anterior cingulate, as these frontal regions have been previously implicated in cognitive conflict monitoring and resolution

……activity within prefrontal cortex tracking the amount of emotional conflict was observed in three areas:  midline dorsomedial prefrontal and bilateral dorsolateral prefrontal cortices

………activity corresponding to the resolution of conflict was observed in only one area:  the rostral anterior cingulate

“These data suggest that the rostral cingulate is engaged during emotional conflict resolution and not for the monitoring or generation of such conflict.”  Etkin et al, 2006, 4

“A critical prediction of a sequential conflict monitoring and resolution model is that the amount of previous-trial conflict determines the amount of conflict resolution on the current trial and, thus, that conflict resolution acts in an anticipatory fashion.  We evaluated activity in regions tracking the amount of emotional conflict (amygdala and dorsomedial and dorsolateral prefrontal cortices) on incongruent trials and correlated it with rostral cingulate activity on the following trial (i.e. postincongruent trials)….We found that incongruent trial activity in the dorsomedial prefrontal cortex…the right dorsolateral prefrontal cortex…and the amygdala…all predicted rostral cingulate activity on the following trial….”  Etkin et al, 2006, 5

The rostral cingulate projects to the amygdala, and the amygdala in turn regulates various sites, including the hypothalamus and through it the sympathetic nervous system….”  Etkin et al, 2006, 5

“…inverse relationship between conflict resolution-related activity (high versus low conflict resolution trials) in the rostral cingulate and simultaneous activity in the right amygdala…the region of the amygdala that responds to emotional conflict overlaps substantially with the region negatively coupled to the rostral cingulate.”  Etkin et al, 2006, 5

next examined activity in this overlapping region to understand the relationship between the amygdala and the rostral cingulate on each trial type….during high conflict resolution trials, greater activity in the rostral cingulate predicted reduced activity in the amygdala…..by contrast, during low conflict resolution trials, activity in the rostral cingulate did no significantly predict activity in the amygdala….explored whether regulation of activity in the amygdala may arise from a cortical site apart from the rostral cingulate….inverse relationship between activation in the amygdala and activation in the dorsal cingulate (5) and dorsomedial prefrontal cortex….no coupling showed within either the left or right amygdala with the dorsomedial prefrontal cortex….These data support the idea that the rostral cingulate may resolve emotional conflict in part by decreasing engagement of the amygdala by incongruent emotional distracters.”  Etkin et al, 2006, 6

“One important function of the amygdala is to recruit autonomic responses to emotionally salient stimuli by activation of the sympathetic nervous system through the amygdala’s hypothalamic projections.”  Etkin et al, 2006, 6

tested whether suppression of autonomic responsivity  was related to the success of conflict resolution….found that greater blunting of the SCR on high conflict resolution trials relative to low conflict resolution trials predicted better emotional conflict resolution….supporting the idea that the rostral cingulate resolves emotional conflict by suppressing amygdalar activity and output, which leads to a blunting of the sympathetic autonomic response to incongruent emotional distracters  Etkin et al, 2006, 6

“In dynamic causal modeling, a significant positive modulatory effect implies directional “activation” of the target by the source region, while a significant negative modulation implies “inhibition” of the target by the source region….”  Etkin et al, 2006, 6

“…the triggering of increased current-trial conflict resolution by previous-trial incongruency is associated with a specific enhancement of a top-down inhibitory pathway from the rostral cingulate to the amygdala….”  Etkin et al, 2006, 7


response conflict arising from emotional incongruence leads to robust behavioral interference

this interference can be reduced through an anticipatory conflict-resolution mechanism that is recruited in response to conflict on current trial

activity in amygdala and dorsomedial and dorsolateral prefrontal cortices tracked the amount of emotional conflict created by emotionally incompatible stimuli

while activity in the rostral anterior cingulate cortex was associated with the resolution of this conflict

activity in the amygdala and dorsomedial and dorsolateral prefrontal cortices on conflict trials directly predicted resolution-related activity in the rostral cingulate on the following trial, consistent with the sequential, anticipatory nature of conflict monitoring and resolution processes

activation of the rostral cingulate during high conflict resolution trials was accompanied by a concomitant reduction in amygdalar activity

the degree to which rostral cingulate activation predicted reduced amygdalar activity, as well as the reduction in autonomic responsivity, a function regulated by the amygdala, was related to subjects’ behavioural success at emotional conflict resolution

by analyzing effective connectivity between the amygdala and rostral cingulate we found that previous-trial incongruency, which leads to greater current-trial conflict resolution, was associated specifically with activation of an “inhibitory” top-down pathway from the rostral cingulate to the amygdala

these findings advance our understanding of the mechanisms by which amygdala activity is regulated for the purpose of resolving emotional conflict and, in particular, the function of the rostral cingulate during emotional conflict.


“In our task, unintended processing of the distracter word and its emotional significance in an incongruent stimulus led to activation of an emotional representation incompatible with that of the intended face target [word happy presented on a fearful face, fear written on a happy face].

“Activation  of incompatible emotional representations leads to a competition for some of the same neural resources in the processing of the face and word

“This conflict for processing resources is represented in the brain both as emotional conflict and consequently as response conflict.

“Our data indicate that activity tracking of the amount of conflict (either because regions generate or monitor conflict) can be seen in the amygdala and dorsomedial and dorsolateral prefrontal cortices.

“Because the amygdala is associated with affective processes and the dorsomedial and dorsolateral prefrontal cortices have been associated with nonemotional attentional processes, it is tempting to suggest that emotional conflict is generated in the amygdala, while the resultant response conflict involves the dorsomedial and dorsolateral prefrontal cortices, a hypothesis that can be tested in future work.”  Etkin et al, 2006, 7

“The role of the amygdala in the generation of emotional conflict is also supported by the fact that the amygdala is sensitive to both emotionally valenced words…and facial expressions…indicating that both task processes (facial affect identification) and the task-irrelevant word distracters engage the amygdala.

“Moreover, previous studies have also found that the amygdala is particularly sensitive to ambiguity (a type of conflict), both in the context of interpreting facial expressions (Kim et al., 2003, 2004) and in the context of uncertainty during decision making (Hsu et al., 3005).” Etkin et al, 2006, 7


This “…amygdala regulation model…posits further that the rostral cingulate is not the emotional analog to the dorsal cingulate…but rather is associated with the resolution of emotional conflict.

Recent study tied rostral/subgenual cingulate activation to fear extinction (Phelps et al, 2004), a process that may be similar to emotional conflict resolution

Another study (Petrovic et al., 2005) rostral cingulate activation recruited in anxiety reduction involving control over an emotional stimulus to diminish the effect

Authors propose top-down [inhibitory] directionality of the rostral cingulate-amygdala interaction –

“In contrast to the conflict resolution function of the rostral cingulate we found that emotional conflict monitoring was instead associated with a dorsomedial prefrontal region.  Thus, we suggest that the dorsal cingulate/dorsomedial prefrontal cortex may have a conserved role in response conflict monitoring, regardless of whether the source of response conflict is cognitive or emotional.  These data argue against a strict functional division of the cingulate/dorsomedial prefrontal cortex into a ventral affective and a dorsal cognitive component (Bush et al., 2000).”  Etkin et al, 2006, 8

“…recent meta-analyses report that the dorsolateral prefrontal cortex is activated by effortful attentional processing associated with incongruent stimuli…[task difficulty]….”  Etkin et al, 2006, 8

“…previously reported that individual differences in trait anxiety predicted reaction times and activation of the amygdala only when fearful faces were processed unconsciously, not when they were processed consciously (Etkin et al., 2004).  This suggested that the unconscious biases in activation of the amygdala may be subject to secondary regulation by conscious processes (Etkin et al., 2004).”  Etkin et al, 2006, 8

Here we provide initial evidence that the rostral cingulate may be a key regulator of amygdalar activity and autonomic responsivity and that this regulation is related to the behavioral success of emotional conflict resolution.

Taken together, these studies suggest the response to threat in healthy subjects involves two distinct stages – an initial unconscious, anxiety-related bias reflected in amygdala activation (and with it enhanced vigilance), followed by a secondary context-responsive suppression of amygdalar responsiveness by the rostral cingulate.”  Etkin et al, 2006, 8

As terrible as my childhood was, I am not sure that I suffered much from emotional conflict.  Everything just was the way it was.  I was hurt physically, but I was not angry about that.  I was more resigned than anything else because I had never known a contrast.  [Part of the rule-breaking problems I suspect with betrayal trauma at later ages is due to the inconsistency – or perhaps the incongruity – between what the child has known and what then happens to them later]  I didn’t need to regulate emotions that I didn’t have.  Not like the counter balances inside the window frames of the old windows – down and up – my emotions just WERE, like they belonged to an animal.  I had no awareness separate from ongoing experience.  “Living is something you do until you are dead.”



“Our experiments on healthy subjects were carried out in order to understand what role the rostral cingulate (8) normally plays in nonpathological emotional conflict.

“But the data also allow us to better understand a variety of psychiatric disorders in which patients experience exaggerated interference from emotional distracters (Williams et al., 1996).

Patients with post-traumatic stress disorder (PTSD), for example, consistently show a

…..hypoactive rostral cingulate during trauma recall (Hull, 2002)

…..and in tasks involving emotional processing or distraction.

…..In PTSD, the severity of the symptoms also correlates with the degree of rostral cingulate hypoactivation (Shin et al., 2005).

“In depression, resistance to treatment is associated with hypoactivity of the rostral cingulate (Kumari et al., 2003).  Indeed, lower rostral cingulate activity prior to treatment actually predicts a poor response to antidepressant therapy (reviewed in Etkin et al., 2005).

“As would be predicted by our results, in both depression and PTSD, hyperactivation of the amygdala occurs to both conscious and unconscious threat (Davidson et al, 2002, Hull, 2002; Rauch et al., 2000; Sheline et al., 2001).

“Taken together, these findings suggest that elevated amygdalar activity and exaggerated behavioral interference may be due to deficient amygdalar inhibition by the rostral cingulate, which leads to an inability to deal with emotional conflict.  The capacity for recruitment of the rostral cingulate may thus determine how well an individual can cope with the intrusion of negative emotional stimuli or mental content.”  Etkin et al, 2006, 9


Dieguez, Assal & Bogousslavsky 2007

In Bogousslavsky & Hennerici 2007, eds

Article “Visconti and Fellini:  From Left Social Neorealism to Right-Hemisphere Stroke” pages 44-74

“…there are many things that we ignore with respect to how the brain works….There has been theorizing about the psychological bases of political beliefs.  Conservatism has been associated with a fear of death, a denial of self-inconsistencies and fear of change [Jost et al., 2003].  At the same time, right-hemispheric syndromes have been seen as the display of defensive mechanisms linked to denial of negative consequences and a quest to preserve one’s threatened self-integrity in the face of harm and risk of death.”  Page 72


van Gaalen et al 2006

abstract – The Netherlands

BACKGROUND: Impulsive decision making, apparent as intolerance for reinforcement delay, is prominent in attention-deficit/hyperactivity disorder. Commonly prescribed for this condition, amphetamine (Adderall), reduces impulsive decision making; however, the neuropharmacologic mechanism of this effect of amphetamine is unclear. METHODS: We

…….investigated the involvement of dopaminergic and noradrenergic neurotransmission in impulsive decision making in rats, using a delayed reward task.

RESULTS: Amphetamine and methylphenidate decreased impulsive decision making, which was mimicked by the selective dopamine reuptake inhibitor GBR 12909 but not by the noradrenaline reuptake inhibitor desipramine. Impulsive choice was increased by the dopamine D1 receptor antagonist SCH-23390 but not the dopamine D2 receptor antagonist eticlopride. The effect of amphetamine on impulsive choice was attenuated by pretreatment with eticlopride, whereas amphetamine retained its effect on impulsivity in the presence of SCH-23390. The alpha2 adrenoceptor agonist clonidine increased impulsivity, but the alpha1 adrenoceptor agonist phenylephrine did not affect impulsive decision making. CONCLUSIONS: These data demonstrate

an important role for dopaminergic neurotransmission in impulsive decision making, whereby tolerance to delay of reinforcement depends on dopamine D1 receptor activation.

Activation of dopamine D2 receptors appears to mediate the beneficial effects of amphetamine on impulsive behavior. Noradrenergic neurotransmission may play a minor role in impulsive choice.


Massat et al 2002

Abstract – Department of Psychiatry, University Clinics of Brussels, Erasme Hospital, Free University of Brussels, Brussels, Belgium. imassat@ulb.ac.be


Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls.

No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.


Pattij & Vanderschuren 2008

Abstract – The Netherlands

Impulsivity is a heterogenous phenomenon encompassing several behavioural phenomena that can be dissociated neuroanatomically as well as pharmacologically.

Impulsivity is pathological in several psychiatric disorders including …attention-deficit/hyperactivity disorder (ADHD),

…drug addiction and

…personality disorders.

…how about in PTSD and anger management issues?

Historically, deficits in central serotonin neurotransmission are thought to underlie impulsivity. Accumulating evidence also points towards an important role of brain dopamine and noradrenaline systems in impulsive behaviour, consistent with the therapeutic efficacy of amphetamine, methylphenidate and atomoxetine in ADHD.

However, recent findings also implicate

glutamate and

cannabinoid neurotransmission in impulsivity.

In this review, we will discuss some of the recent developments in the neuropharmacological manipulation of impulsive behaviour.


van gaalen et al 2006b

abstract – The Netherlands

Behavioral disinhibition can be investigated by measuring premature responding in the 5-choice serial reaction time task (5-CSRTT) in which attentional parameters can be measured as well. OBJECTIVE: The objective of the study was to investigate the involvement of dopamine neurotransmission in behavioral disinhibition using the 5-CSRTT in rats.

METHODS: The effects of amphetamine, cocaine, nicotine, the dopamine reuptake inhibitor GBR 12909, the noradrenaline reuptake inhibitor desipramine, the dopamine D1 receptor antagonist SCH 23390, and the dopamine D2 receptor antagonist eticlopride were studied in rats that were well-trained in the 5-CSRTT. Subsequently, the effects of amphetamine, cocaine, and nicotine were tested after pretreatment with SCH 23390 or eticlopride. RESULTS: What amphetamine, cocaine, and nicotine had in common is that they increased premature responding. However, these drugs had distinct effects on attentional parameters. GBR 12909 also enhanced premature responding, whereas desipramine reduced it. Eticlopride by itself had no effect on premature responding but it attenuated the increases in this parameter evoked by amphetamine, cocaine, or nicotine. SCH 23390 reduced premature responding on its own and also reduced its drug-induced enhancement. CONCLUSIONS: The present data show that behavioral disinhibition, i.e., the inability to withhold a premature response, is a common effect of drugs of abuse and that this effect is the result of enhanced dopaminergic neurotransmission.

……….In addition, dopamine D1 and D2 receptors play important, but perhaps distinct roles, in inhibitory control of behavior.

Well, I suppose that not even depressed people can inhibit their depressive – “
night seeking” “sickness” behavior, either.


Pattij et al 2007

Abstract – The Netherlands

RATIONALE: Impaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an

important role for

…dopamine D(1) and D(2) receptors and the

….nucleus accumbens (Acb)

in this respect. OBJECTIVE: The present experiments were designed to study the role of dopamine D(1) and D(2) receptors in the Acb in inhibitory response control. METHODS: Rats were trained in a five-choice serial reaction time task and received bilateral infusions into the Acb core or shell of either SCH 23390 or eticlopride (representing selective dopamine D(1) and D(2) receptor antagonists, respectively). Subsequently, the effects of systemic amphetamine on inhibitory response control were examined. ….. CONCLUSION: Our data provide evidence for the

involvement of dopamine D(1) and D(2) receptors in the Acb core and shell in inhibitory response control and attentional performance.


Winstanley et al 2005

Abstract – Cambridge, UK

Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems.

Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown.

These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity,

……….and in the mechanism by which amphetamine decreases impulsive choice


Pezze, Dalley & Robbins 2007

Abstract – Cambridge, UK

Nucleus accumbens (NAC)

………..dopamine may play a role in attentional and executive processes, as it modulates cortico-limbic inputs, including afferents from the prefrontal cortex.

The present study examined the role of NAC dopamine D1 and D2 receptors

………. in visual attentional processes and

. Optimal performance on the 5CSRT depends on both D1 and D2 receptors in the NAC,

………but they modulate different aspects of performance.

………D1 receptor agents had more selective effects on attentional accuracy while

………..D2 receptor stimulation did not affect accuracy or premature responses, but

enhanced perseverative responding.

This certainly makes me think of perseverance against all odds when the going gets tough.  When they talk about how genes interact with environment, I guess it doesn’t pay them so much to publish research about the protective and resiliency factors – the money is in finding what’s wrong so they can make drugs to sell to make things better.  Necessary – but not the whole picture or the whole answer.  Of course this research is talking about “sustained visual attention” but the next article implicates prefrontal involvement – like I say, they aren’t looking for what I am looking for – what helps us to survive insurmountably horrible childhoods, in spite of what else might go wrong in the process of manifesting genes – that assist us, even if they don’t make us as “perfect” as the next person – the body kept us alive.

D2 receptor – something here that doesn’t make sure you make the right choice, but perhaps that you keep on keeping on…if I had access to the article, I would like to know what they say about the processing of information from different cortico-limbic inputs!

The data are discussed in terms of the different functions of

………..NAC dopamine receptors in the processing of information

……..from its different cortico-limbic inputs.


Fletcher et al 2007

Abstract – Toronto

Exposure to repeated, intermittent, escalating doses of amphetamine [behavioral stimulant] in rats disrupts information processing in several tasks. Some of these deficits,

….notably impaired attentional set shifting,

….may reflect altered prefrontal cortex function.

This study examined the effects of repeated treatment with amphetamine on performance in the 5-choice serial reaction time test. This test measures

sustained visual attention, a behavior that is known to require the prefrontal cortex.

Rats were trained to respond to a brief light stimulus presented randomly in one of five spatial locations, with 100 trials per session. Once performance had stabilized rats were treated with escalating doses of amphetamine (three injections per week for 5 weeks at 1-5 mg/kg per week); testing was continued on nondrug days, and for several weeks of withdrawal. During the amphetamine-treatment and withdrawal phases accuracy of responding was unaffected, but errors of omission increased. Lengthening the stimulus duration abolished this effect. Reducing the stimulus duration also reduced response accuracy and this effect was more marked in amphetamine-treated rats. Both reduced accuracy, and increased omissions, seen in amphetamine-treated rats were reversed by injecting the D1 receptor agonist SKF38393 into the medial prefrontal cortex. This treatment also prevented the decline in accuracy in control animals that resulted from reducing the stimulus duration.

These results, indicating that exposure to amphetamine induces a long-lasting deficit in visual attention, add to a growing list of deficits suggesting that amphetamine-sensitized state may model the cognitive deficit state in schizophrenia.

The reversal of these deficits by a D1 receptor agonist provides further evidence that

……prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia.


Fletcher et al 2005

Abstract – Toronto

RATIONALE: Repeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse.

………. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function.

CONCLUSIONS: Results show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting.

……. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that

activating D(1) receptors in the mPFC improves aspects of cognition.


Dalley et al 2002

Abstract – Cambridge, UK

RATIONALE: Rats reared in social isolation exhibit hyperactivity and specific attentional disturbances in later adult life.

………These behavioural abnormalities may be relevant to impulsivity and other neuropsychiatric syndromes such as attention-deficit hyperactivity disorder and schizophrenia where

….disturbances in circuitry involving the prefrontal cortex have been identified.

OBJECTIVE: To establish whether isolation-reared rats show a differential susceptibility to cognitive processes that depend on the prefrontal cortex and its monoaminergic innervation. METHODS: Rats were reared in isolation from postnatal day 28 or in social groups of four and trained on the five-choice serial reaction time task, which assesses spatially divided visual attention. Following a range of manipulations designed to tax visual attention and response control, in vivo microdialysis was used in conjunction with behavioural testing to assess dopamine (DA) and serotonin (5-HT) release in the prefrontal cortex, either under baseline conditions prior to task initiation, or during task performance. Subjects were challenged with amphetamine (0.125 mg/kg intravenously) every 15 min, commencing 15 min after the start of the task.

RESULTS: Apart from being consistently slower to collect food rewards and …..showing more perseverative responses to an auditory distractor,  [is this any kind of an anxiety – hypervigilance response?]

……..isolates were unimpaired on accuracy, impulsivity and correct latency measures on the five-choice task. Basal levels of DA and 5-HT in the prefrontal cortex were also unaffected by isolation rearing. Amphetamine increased the speed of responding in control and isolation-reared animals and increased premature (impulsive) responding, but only in socially-reared animals. Cortical DA release increased to a similar extent in both groups following amphetamine challenge. By contrast, 5-HT release was attenuated in isolates under these conditions.

CONCLUSIONS: These findings highlight a rather specific deficit in 5-HT release in the prefrontal cortex of isolation-reared rats,

…….. although this appears not to affect visual attentional function. Rather, these data may be relevant to

……reduced impulsiveness of isolation-reared rats on the five-choice task. These findings are important in the context of animal models of attentional disturbances in schizophrenia.

It makes me wonder if this reduced impulsiveness is related to fear, or to an inhibition regarding seeking novelty – as in fear, depression, anxiety?


Carli et al 2006

Abstract – Italy

Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia.

……Several lines of evidence suggest a pathophysiological role for

glutamate NMDA receptors in the prefrontal cortex

in schizophrenia and associated disorders in attention and executive functioning.

We investigated how the interactions between

…….5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC)

……….contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT(1A) receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats.

The data show that 5-HT1A and 5-HT2A receptors in the mPFC ……exert opposing actions on attentional functioning and demonstrate a

……..dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as …..impulsivity and

….compulsive perseveration.

I am going to look at this idea of compulsive preservation – how was my mother’s lifelong obsession with me being the devil’s child not related to this?  She had a psychotic idea that obliterated my childhood – I would say it persevered!  How is chronic displacement of inner psychic realities, through projection, onto other people, not a preserving “quality?”  They might just be preserving life in the only adaptive way that the person, as a physical organism, has available to it.


Ou et al 2001

Abstract – Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario K1H-8M5, Canada.

MR and GR – serotonin interaction

Negative regulation of neuronal serotonin (5-HT1A) receptor levels by glucocorticoids …

may contribute to depression.

Both types I (mineralocorticoid) and II (glucocorticoid) receptors (MR and GR, respectively) participate in corticosteroid-induced transcriptional repression of the 5-HT1A gene; however, the precise mechanism is unclear.

A direct repeat 6-base pair glucocorticoid response element (GRE) half-site 5′-TGTCCT separated by 6 nucleotides was conserved in human, mouse, and rat 5-HT1A receptor promoters. In SN-48 neuronal cells that express MR, GR, and 5-HT1A receptors, deletion or inactivation of the nGRE (negative GRE) eliminated negative regulation of the rat 5-HT1A or heterologous promoters by corticosteroids, whereas its inclusion conferred corticosteroid-induced inhibition to a heterologous promoter. Bacterially expressed recombinant MR and GR preferentially bound to the nGRE as a heterodimer, as identified in nuclear extracts of MR/GR-transfected COS-7 cells, and with higher affinity than MR or GR homodimers. In SN48 and COS-7 cells, concentration-dependent coactivation of MR and GR was required for maximal inhibitory action by corticosteroids and was abrogated in the L501P-GR mutant lacking DNA binding activity.

Corticosteroid-mediated transcriptional inhibition was greater for MR/GR in combination than for MR or GR alone. These data represent the first identification of an nMRE/GRE and indicate that

heterodimerization of MR and GR mediates direct corticosteroid-induced transrepression of the 5-HT1A receptor promoter.


Meijer et al 2000

Abstract – Department of Physiology, Division of Nephrology, University of California, San Francisco, CA, USA.

The diverse effects of the corticosteroid hormones

are mediated in large measure by the

mineralocorticoid and glucocorticoid receptors,

two closely related members of the

nuclear receptor superfamily.

In the brain,

corticosteroids regulate neuronal excitability and responses

to neurotransmitters in a cell type-specific manner.

The 5-HT1A receptor, for example, is highly expressed in the hippocampus and raphe but transcription is repressed by corticosterone (the principal glucocorticoid in rodents) only in hippocampus.

We have used transient transfection of cultured cells to study the transcriptional regulation of the 5-HT1A receptor promoter by activators and repression by glucocorticoids.

We find that transcription factors Sp1 and NF-kB subunit p65, both of which are coexpressed in hippocampus with the 5-HT1A receptor in vivo, synergistically activate a reporter driven by receptor 5′-flanking region. Primer extension data suggest that the multiple transcription initiation sites used in reporter gene transcription correlate with those used in transcription of the endogenous gene which has a TATA-less promoter.

Repression of transcription by corticosteroids

was found to be mediated by both

mineralocorticoid and glucocorticoid receptors,

but not identically.

While glucocorticoid receptors potently inhibited both p65- and p65/Sp1-stimulated transcription, repression via mineralocorticoid receptors (MR) depended on the transcriptional activators that were present: p65-stimulated reporter activity was not repressed via MR, whereas a similar level of transcription resulting from synergistic activation by p65/Sp1-stimulation was repressed via MR. The

context-dependence of these MR-mediated effects

provides a model for the cell-type and state-dependent actions of corticosterone in the brain.


Obradovic et al 2004

Abstract – Max Planck Institute of Psychiatry, Munich, Germany.

Mineralocorticoid (MR) and glucocorticoid (GR) receptors are two closely-related members of the steroid nuclear receptor family of transcription factors that bind common ligands in the brain (corticosterone and cortisol) and supposedly have identical hormone response elements.

This raises the important question of how they can elicit differential biological actions in neurons in which they are often colocalized.

One plausible explanation is that they differentially recruit proteins (coregulators or other receptor-interacting factors) through cell-specific interactions with regions that diverge between MR and GR to modulate target gene transcription in a receptor-specific manner.

We therefore performed a yeast-two-hybrid screening of a human brain cDNA library with an AF1-containing region of the human MR as bait. This screening revealed several potential MR-interacting partners; among them were several clones [I don’t know what they mean by clones here] bearing homology to DAXX, FLASH, and FAF-1, all previously implicated in apoptosis. Coexpression of candidate clones in a mouse hippocampal cell line confirmed these interactions in a mammalian neural cell environment as well. In transient transactivation assays, DAXX and FLASH influenced MR- and GR-driven transcription of the MMTV-Luc reporter similarly; in contrast, although FAF-1 did not transactivate GR, it did selectively stimulate MR-mediated transcription. Thus, the present findings, that

1) DAXX, FLASH, and FAF-1 modulate the transcriptional activities of MR and GR and that

2) FAF-1 selectively coactivates only MR, provide possible clues for how these closely related receptors might differentially influence neuronal function.


Tirard et al 2004

Abstract – Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich, Germany.

Corticosteroid actions in the brain are exerted via the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). These receptors share several structural and functional similarities but their activation in the brain triggers distinct biological actions, for instance on neuronal survival or the regulation of the hypothalamo-pituitary-adrenal axis.

Like other hormone-activated receptors, the transcriptional properties of the MR and GR depend on their ability to recruit a variety of co-regulators, which modulate their activity on target promoters, in a specific manner.

The N-terminal regions of the MR and GR share the smallest degree of sequence conservation, whereas they display opposite effects on the transactivation properties of these receptors; thus, they may provide surfaces suitable for receptorspecific interactions with co-regulatory proteins.

Here, we employed a yeast two-hybrid system to identify molecules interacting with the N-terminal part of the MR (amino acids 170-433). This approach resulted in the isolation of representative cDNAs from all members of the protein inhibitor of

activated STAT (PIAS) family of proteins

as potential MR-interacting partners. In neural cells, PIAS3 exhibited a strong and specific interaction with MR, but not GR, as indicated by mammalian two-hybrid assays and co-immunoprecipitation experiments in vivo. The interaction with MR was enhanced in the presence of aldosterone, an MR agonist, and was found to occur through a conserved, serine- and acidic amino acid residue-rich domain of PIAS3. To compare the modulatory properties of PIAS proteins on MR and GR transcriptional activity in a neural environment, MMTV reporter gene assays were performed in the human neuroblastoma cell line SK-N-MC. This analysis revealed that PIAS3 can inhibit MR, but not GR, transactivation in response to their corresponding ligands. Further, it showed that PIAS1 and PIASxbeta, but not PIASy, could also inhibit MR-mediated transcription despite the lack of detected physical interaction with MR. Interestingly, PIASxbeta and PIASy dose-dependently co-activated GR, whereas PIAS1 impaired GR-induced transcription. Taken together the results reveal

differential modulatory roles of the PIAS proteins

on the transcriptional properties of MR and GR,

thus providing new insights into the bifurcating actions

of these two receptors in neural cells

where they are frequently co-localized.


Baviera, Ivernizzi & Carli 2008

Abstract – Italy

RATIONALE: Cognitive impairment in schizophrenia is particularly evident in the domains of attention and executive functions.

……… Attentional performance was assessed using the five-choice serial reaction time task. The task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responding), decision time (measured by correct response latency), and omissions.

…….rat study

CONCLUSIONS: The effects on “impulsivity” and “compulsive perseveration” in a rat model of attentional and executive deficit of schizophrenia might differentiate conventional and atypical antipsychotics. Antagonistic activity at 5-HT(2A) receptors may best explain the facilitatory effects of clozapine on cognition.


Calcagno, Carli & Ivernizzi 2006

Abstract – Italy

We studied the role of 5-HT(1A) receptors in controlling the release of glutamate (GLU) in the medial prefrontal cortex (mPFC) of conscious rats with the in vivo microdialysis technique.

….The effect of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin infused in the prefrontal cortex was examined under basal conditions and on the rise of extracellular GLU (+106%) induced by co-infusion of the competitive N-methyl-d-aspartate (NMDA) receptor antagonist … (CPP). …had no effect on basal extracellular GLU, but the higher concentration completely abolished the rise of extracellular GLU induced by CPP. CPP also increased extracellular serotonin (5-HT) in the mPFC (+50%) and this effect was antagonized by 3 microm 8-OH-DPAT which, by itself, had no effect on basal 5-HT release. The effects of 8-OH-DPAT on extracellular GLU and 5-HT were reversed by the 5-HT(1A) receptor antagonist WAY100 635 (100 microm), indicating a selective involvement of 5-HT(1A) receptors. WAY100 635 had no effect by itself. These results show that the stimulation of cortical 5-HT(1A) receptors prevents the CPP-evoked rise of extracellular GLU and 5-HT and suggest that these effects may contribute to the ability of intracortical 8-OH-DPAT to counteract cognitive deficits caused by the blockade of NMDA receptors.

I am lost at this point with this article, but will keep it here in case it helps clarify something else


Ryff, Singer & Love 2004


health – presence of wellness

……”…focus on what it means to flourish, such as having a sense of purpose and direction in life, good-quality relationships with others, and opportunities to realize one’s potential (Ryff & Singer 1998).  Of critical importance in this view is mapping the physiological substrates of human flourishing.”  Ryff, Singer & Love 2004, 1383

…..psychological well-being protective of good health [and comes from it]

………sociodemographic correlates, multiple biomarkers (neuroendocrine, immune, cardiovascular) – LINKS – patterns

“The core hypothesis of positive health, in fact, is that the experience of well-being contributes to the effective functioning of multiple biological systems, which may help keep the organism from succumbing to disease, or, when illness or adversity occurs, may help promote rapid recovery.”  Ryff, Singer & Love 2004, 1383

two distinct types of well being:  eudaimonic and hedonic

…….these 2 types vary as a function of age, socio-economic status, race/ethnicity


Shades of Hillman here!  Only he got it from Aristotle!  Go figure!

Aristotle = first wrote about eudaimonia as realization of one’s true potential

…………”According to this view, each individual comes into life with unique capacities, known as one’s ‘daimon’.  The central task of life is to recognize and realize these talents.”  Ryff, Singer & Love 2004, 1383

Ryff 1989 – six key dimensions of well-being

Self-acceptance:  capacity to see and accept one’s strengths & weaknesses

Purpose in life: having goals, objectives that give life meaning and direction

Personal growth: feeling personal talents, potential are being realized over time

Positive relations with others:  having close, valued connections with significant others

Environmental mastery:  being able to manage demands of everyday life

Autonomy:  having strength to follow personal convictions, even if they go against conventional wisdom  – Ryff, Singer & Love 2004, 1384

These are parameters related to secure attachment – There have been times, periods, sections of my life where I thought I was making progress on these – I think the incoherent life story aspect of insecure attachment interferes with the continuity of these parameters over time and over the lifespan – at this point, I feel numb and certainly disconnected from my past pursuit of any of these

“…eudaimonic well-being is not trait-like, but rather is dynamic, sowing cross-time change as individuals negotiate particular life transitions (e.g Kwan et al. 2003).”  Ryff, Singer & Love 2004, 1384

“…socio-economic standing, eudaimonic well-being is positively correlated with both educational attainment and occupational status…variability in eudaimonic well-being increases as one moves down the educational hierarchy….varying distributions also show that substantial numbers of individuals with limited educational attainment nonetheless have high eudaimonic well-being (Markus et al. 2004).”  Ryff, Singer & Love 2004, 1384

Reflective of nonagrarian based cultures –

“…ethnic minority status is a positive predictor of well-being:  i.e. American minorities, on average, are more likely to have high eudaimonic well-being than their white majority counterparts (Ryff et al. 2003).”  Ryff, Singer & Love 2004, 1384

“A key question from the positive health perspective is whether high eudaimonic well-being in contexts of inequality, or discrimination, confers protection at biological levels.”  Ryff, Singer & Love 2004, 1384


Ancient Greeks elaborated hedonism- rooted in ideas of pleasure, happiness, satisfaction of human appetites

….modern day, asking what makes experiences and life pleasant and unpleasant – subjective well-being – three components:  life satisfaction, presence of positive affect and absence of negative affect

…..expectations, goals and comparison processes influence subjective well-being…also found that people who strongly desire money and wealth (extrinsic goals) are more unhappy than those who do not – effect replicated in less economically developed countries – “Progress toward intrinsic goals, such as positive relationships, personal growth and community generativity, has been shown to enhance well-being…”  Ryff, Singer & Love 2004, 1385

(E) eudaimonic and (H) hedonic well-being are distinct but related

“…although highly correlated, each c5onstruct retains its uniqueness as a separate component of overall well-being….it is the strongly existential aspects of eudaimonic well-being (i.e. purpose in life, personal growth) that are most sharply differentiated from the affective and life satisfaction assessments of hedonic well-being.”  Ryff, Singer & Love 2004, 1385

“The probability of optimal well-being, defined as being high on both E…and H…well-being, increased as age, education, extraversion and conscientiousness increased and as neuroticism decreased.  Alternatively, those with higher E…than H… well-being (ca. 23% of the sample) tended to be younger, have more education and have higher levels of openness to experience.  Those with higher H…than E… well-being (ca. 22% of the sample) had less education, were more likely to be midlife and older adults, and had lower levels of openness to experience.”  Ryff, Singer & Love 2004, 1385

E and H well-being: links to biology

The key hypothesis of positive health is that well-being will be accompanied by optimal functioning of multiple physiological systems.  Over the long term, this biopsychosocial interplay is proposed to comprise part of the mechanistic processes that delay the onset of morbidity, help the organism maintain functional capacities, and thereby extend periods of quality living”  Ryff, Singer & Love 2004, 1385

“…purposeful life engagement (Eudaimonic well-being) evokes an active, striving organism, sometimes in the face of adversity.  As such, eudaimonic well-being may prompt greater biological activation of the organism than states of happiness or contentment (hedonic well-being).  Such activation may not be of the kind that contributes to pathogenesis.”  Ryff, Singer & Love 2004, 1385

study:  rather than investigating how adversity elevates biological risk, the attempt is to find out if well-being is associated with reduced biological risk


Neuroendocrine correlates – “…most inquiry has focused on the negative, such as elevated levels of cortisol, adrenaline or noradrenaline among caregivers….”  Ryff, Singer & Love 2004, 1386

e.g. “Flatter slopes of daily salivary cortisol have also been associated with repression of emotion (Giese-Davis et al. 2000) and have predicted early death among breast cancer patients (Sephton et al. 2000).”  Ryff, Singer & Love 2004, 1386

in study – ‘…older women with higher levels of personal growth and purpose in life and flatter daily slopes of salivary cortisol.  That is, as values on well-being increased, average values on the sloe of salivary cortisol moved from negative to near zero.  Subsequent examination of means at the three diurnal points clarified that individuals with higher scores on purpose and growth started the day with lower levels of salivary cortisol and stayed lower through the day than individuals with lower scores on theses two dimensions of eudaimonic well-being.”  Ryff, Singer & Love 2004, 1387

“The only other significant outcome for neuroendocrine markers was the finding that women with higher scores on autonomy, which assessed the capacity to follow one’s own convictions (even if they go against conventional wisdom), had significantly higher levels of noradrenaline than women reporting lower levels of autonomy.”  Ryff, Singer & Love 2004, 1387

p 1390 this is a “mystery” finding – “Because stress has been previously linked with increased levels of adrenaline and noradrenaline (e.g. Cacioppo et al. 1998), our findings underscores the need for future research to clarify distinctions between elevated levels of catecholamines that signify dysregulation from those that may reflect normal healthy functioning…..to distinguish between healthy and unhealthy neuroendocrine activation.”

Is it possible that there positive stress that parallels an assertive, positive interaction with one’s life is reflected in this increased noradrenaline?

immune correlates

“Inflammatory response has increasingly been targeted as an integral part of the stress response (Black 2003)….The interplay between stress and hormonal signals (glucocorticoids) that terminate inflammation has also received attention….Our question was whether high well-being would be linked with lower levels of inflammatory cytokines.”  Ryff, Singer & Love 2004, 1387

no significances for hedonic measures

those with highest levels of life purpose and significantly lower levels of inflammatory cytokines—those with higher well-being had lower cardiovascular risk

value of sleep

provides numerous restorative functions….circadian regulation maybe an important prerequisite for maintenance of host defenses against cancer…plays a mediating role in link between socio-economic status and health….

Those with higher levels of environmental mastery age 65+ had longer periods of time in bed, longer sleep duration, longer REM sleep, earlier onset REM sleep than those with lower levels of environmental mastery

Among oldest women in study, those with higher levels of positive relations with others had longer REM sleep and lower duration of body moving during sleep  Ryff, Singer & Love 2004, 1388

“…higher allostatic load (which combines risk across multiple physiological systems) is a significant predictor of incident cardiovascular disease, decline in cognitive and physical function, and mortality….whether well-being might reduce the likelihood of these effects by helping keep diverse biomarkers in healthy zones is a key question for  future research.”  Ryff, Singer & Love 2004, 1389


“”…older women with higher levels of purpose in life and personal growth showed flatter diurnal slopes of daily salivary cortisol than those with lower levels of such well-being.  Specifically, those who were purposefully engaged in life and continued to experience self development started the day with lower cortisol levels and stayed lower throughout the day than those with lower profiles on purpose and growth.  Such findings converge with the work of Linfors & Lundberg (2002), who used the same measures of eudaimonic well-being in a mixed age sample of men and women and found that those with high well-being had significantly lower salivary cortisol output that those with low well-being.”  Ryff, Singer & Love 2004, 1390


“An important question is whether well-being is merely the flip side of distress, depression and maladjustment.  If so, probing the biological correlates of well-being may not be distinctive from large prior literature documenting how negative psychological factors contribute to elevated risk across numerous systems….Links to biomarkers will probably constitute critical evidence for establishing the independence or bipolarity of psychological well-being and ill-being.  Flourishing and its attendant biology may, however, require an enriched array of biomarkers (e.g. endorphins, dopamine, opioid peptides, oxytocin….”  Ryff, Singer & Love 2004, 1391

authors believe there is a functional separation of the two

I would tend to think they are the “flip sides” of one another – as ill-being improves, well-being improves and vice versa  – how could they imagine they are different?


“…resilience, which takes well-being into interesting territory where the focus is on those who maintain high well-being in the face of adversity.  Defining resilience and how it arises (i.e. identifying relevant protective factors) is of increasing interest in the study of children and adults….We have examined resilience in multiple life contexts:  those who have  maintained 9or regained) high eudaimonic well-being in the face of major life challenges (e.g. relocation, caregiving) as well as those who sustain high eudaimonic well-being despite socio-economic disadvantage…or ethnic/minority status….What remains untested as yet is whether such high well-being vis-à-vis adversity is consequential for health.  That is, does it confer protection against illness, disease and disability, and, if so, what are the intervening mechanisms.”  Ryff, Singer & Love 2004, 1391

“We anticipate that the protective effects of high levels of well-being should be reflected in longer active life expectancy and disability-free life years.”  Ryff, Singer & Love 2004, 1391


Ryff 1989


Interviews with 171 middle-aged and older men and women

“Responses indicated that both age groups and sexes emphasized an “others orientation” (being a caring, compassionate person, and having good relationships) in defining well-being.

.middle-aged: stressed self-confidence, self-acceptance, and self-knowledge

older: accepting change as an important quality of positive functioning

This reminds me of that author I have in the notes here who talked about what people SAY they believe and what they actually DO


Harrington & Loffredo 2001


Extroverts showing higher psychological well-being and life satisfaction and lower self-consciousness than introverts

Intuition types scored higher in psychological well-being and lower in self-consciousness than Sensing types

Judging types scored higher in psychological well-being than Perceiving types.

Most dimensions of psychological well-being were negatively related to self-consciousness – this would indicate an internalized sense of self-security to me—but being able to have self-consciousness in the first place is a gift – not sure how they are defining this, but somehow I suspect that self-consciousness in their context is not “as positive” as NOT having it – strange, academia!


Gruenewald et al 2006


“…there seem to be many different combinations of biomarkers associated with high risk of adverse health outcomes in older adults, a reflection of the multiple biological pathways to disease, disability, and mortality in elderly populations.”  Gruenewald et al 2006, 14158

Well, we do all die.  We are not immortal – so they can determine what the “destiny” of the patterns are, what will kill a person

This article – to identify potentially diverse biological pathways to mortality in a high-functioning older cohort (70-79 years of age)

…………value zones of biomarkers

………..linkages between biomarkers and more macro upstream factors, such as environmental, behavioral, psychosocial and sociodemographic factors

…”…values on these markers may represent the biological signature of individuals’ life experiences and may represent the key pathways through which such experiences are transduced into positive or negative states of health.”  Gruenewald et al 2006, 14161

………….protective factor – role of DHEA-S in down-regulating cortisol




…relates to timing of the MR and GR related to the HPA stress response



Eukaryotes –

animals, plants, fungi, and protests – organisms whose cells are organized into complex structures enclosed within membranes – have “true” nuclei containing their DNA

Prokaryotes –

group of organisms that lack a cell nucleus or any other membrane-bound organelles – most are unicellular but a few have multicellular stages in later life cycles, include bacteria – originally thought to live only in inhospitable conditions such as extremes of temperature, pH, and radiation but have since been found in all types of habitats –




The suprachiasmatic nucleus (SCN) is a region of the brain, located in the hypothalamus, that is responsible for controlling endogenous circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions over a 24-hour period.

The SCN contains several cell types and several different peptides (including vasopressin and vasoactive intestinal peptide) and neurotransmitters, and interacts with many other regions of the brain.


The SCN is situated in the hypothalamus immediately above the optic chiasm on either side of the third ventricle.

Circadian effects

The SCN receives inputs from specialized photoreceptive retinal ganglion cells, via the retinohypothalamic tract.

Destruction of the SCN leads to a complete loss of circadian rhythm. Rats with damage to the SCN have no circadian rhythms, i.e., they sleep the same total amount, but at random times, for random lengths at a time.

The SCN also controls ‘slave oscillators’ in the peripheral tissues, which exhibit their own ~24 hour rhythms, but are crucially synchronized by the SCN.

The importance of entraining our bodies to an exogenous cue, such as light is reflected by several circadian rhythm sleep disorders, where this process does not function normally.

Neurons in the ventrolateral SCN (vlSCN) have the ability for light-induced gene expression. If light is turned on at night, the vlSCN relays this information throughout the SCN, in a process called entrainment.

Neurons in the dorsomedial SCN (dmSCN) are believed to make an endogenous 24-hour rhythm that can persist under constant darkness (in humans averaging about 24h 11min). Melanopsin-containing ganglion cells in the retina have a direct connection to the SCN via the retino-hypothalamic tract.

The SCN sends information to other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin.


Girotti, Weinberg & Spencer 2007

Abstract – Department of Psychology, University of Colorado, Boulder, Colorado 80309, USA. girotti@colorado.edu

Genes and HPA axis modulation

The hypothalamus-pituitary-adrenal (HPA) axis diurnal cycle of activity is manifest in circadian rhythms of ACTH and corticosterone secretion, which in the rat peak around the onset of the dark period.

This cycle is thought to be driven by

daily fluctuations in activity of CRH neurons

within the paraventricular nucleus of the hypothalamus (PVN),

controlled by suprachiasmatic nucleus inputs.

In this study we examined whether the circadian drive that regulates ACTH and corticosterone basal secretion in the rat is reflected in PVN immediate early gene expression and, if so, whether different genes respond uniformly or uniquely to circadian stimulatory input. In addition, we examined

how circadian drive and acute stress,

two categories of stimuli that induce HPA axis activation

, comparatively affect gene expression within different components of the HPA axis (c-fos mRNA, CRH heteronuclear RNA, and zif268 mRNA in PVN; c-fos mRNA, proopiomelanocortin heteronuclear RNA, and zinc finger 268 mRNA in anterior pituitary; c-fos mRNA and nerve growth factor I-B mRNA in adrenal cortex). Finally, we examined whether circadian differences in gene expression depend on endogenous glucocorticoids and, if so, whether the dependence is on an acute or permissive influence of the hormone.

We found that a circadian drive that regulates HPA axis basal hormone secretion is also manifest on basal c-fos gene expression in the PVN. Moreover, we show that

different immediate early genes within the HPA axis

anatomical components

display different diurnal patterns of gene expression.

These differential patterns result, in part, from gene-specific responses to circadian signals and acute and/or permissive glucocorticoid actions.


Choi et al 2007

Abstract – Neuroscience Program and Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. choidc@ucmail.uc.edu

Limbic and cortical neurocircuits

profoundly influence hypothalamic-pituitary-adrenal (HPA) axis responses to stress

yet have little or no direct projections

to the hypothalamic paraventricular nucleus (PVN).

Numerous lines of evidence suggest that the bed nucleus of the stria terminalis (BST) is well positioned to relay limbic information to the PVN. The bed nucleus of the stria terminalis (BST) comprises multiple anatomically distinct nuclei, of which some are known to receive direct limbic and/or cortical input and to heavily innervate the PVN. Our studies test the

hypothesis that subregions of the bed nucleus of the stria terminalis (BST) differentially regulate HPA axis responses to acute stress.

Male Sprague Dawley rats received bilateral ibotenate lesions, targeting either the principal nucleus in the posterior BST or the dorsomedial/fusiform nuclei in the anteroventral BST. Posterior BST lesions elevated plasma ACTH and corticosterone in response to acute restraint stress, increased stress-induced PVN c-fos mRNA, and elevated PVN corticotropin-releasing hormone (CRH) and parvocellular arginine vasopressin (AVP) mRNA expression relative to sham-lesion animals. In contrast, anterior BST lesions attenuated the plasma corticosterone response and decreased c-fos mRNA induction in the PVN but did not affect CRH and parvocellular AVP mRNA expression in the PVN.

These data suggest that posterior

bed nucleus of the stria terminalis (BST) nuclei

are involved in inhibition of the HPA axis, whereas the

anteroventral bed nucleus of the stria terminalis (BST) nuclei

are involved in HPA axis excitation.

The results indicate that the bed nucleus of the stria terminalis (BST) contains functional subdomains that play different roles

in integrating and processing limbic information

in response to stress

and further suggest that excitatory as well as inhibitory

limbic information is funneled through these important cell groups.


de Kloet, Joels & Holsboer 2005

abstract – Department of Medical Pharmacology, Leiden Amsterdam Center for Drug Research and Leiden University Medical Center, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands. e.kloet@lacdr.leidenuniv.nl

In response to stress,

the brain activates several neuropeptide-secreting systems. This eventually leads to the

release of adrenal corticosteroid hormones,

which subsequently feed back on the brain and bind

to two types of nuclear receptor that act as transcriptional regulators.

By targeting many genes, corticosteroids function

in a binary fashion, and serve as a

master switch in the control of neuronal and network responses that underlie behavioural adaptation.

In genetically predisposed individuals,

an imbalance in this binary control mechanism

can introduce a bias towards stress-related brain disease

after adverse experiences.

New candidate susceptibility genes that

serve as markers for the prediction of vulnerable phenotypes

are now being identified.


De Kloet 2004

Abstract – Division of Medical Pharmacology, LACDR/LUMC, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands. e.kloet@lacdr.leidenuniv.nl

The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system.

Their action-in concert

is crucial for individual differences in coping with other individuals,

which in turn depend on genetic- and experience-related factors.

This relates to oxytocin and vasopressin

The actions exerted by cortisol and corticosterone have an enormous diversity. They include the

regulation of rapid molecular aggregations,

membrane processes, and

gene transcription. In the latter transcriptional regulation,

the corticosteroid hormones have two modes of operation.

One mode is mediated by high-affinity mineralocorticoid receptors (MRs), which control gene networks

underlying stabilization of neuronal activity

as determinant for the sensitivity to trigger immediate responses to stress organized by

corticotrophin-releasing hormone (CRH)-1 receptor.

Whereas disturbance of homeostasis is

prevented by MR-mediated processes,

its recovery is facilitated via the low-affinity glucocorticoid receptors (GRs) that require stress levels of cortisol.

GRs promote in coordination with CRH-2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events.

The balance in the two stress system modes

is thought to be essential for

cell homeostasis,

mental performance, and


Imbalance induced by genetic modification or stressors

changes specific neural signaling pathways underlying cognition and emotion.

This yin-yang concept in stress regulation

is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid-induced stress-related disorders such as severe forms of depression.


de Kloet et al 2005b – call in this article

abstract – Department of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, P.O. Box 9502, 2300 RA Leiden, The Netherlands. e.kloet@lacdr.leidenuniv.nl

Adverse conditions during early life

are a risk factor for stress-related diseases

such as depression and post-traumatic stress disorder (PTSD).

See this article in child maltreatment


Kavanau 1997

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

The origin of both sleep and memory

appears to be closely associated with the evolution of mechanisms

of enhancement and maintenance of synaptic efficacy.

After the origin of activity-dependent synaptic plasticity,

whereby single activations of synapses led to short-term efficacy enhancements, lengthy maintenance of the enhancements probably was achieved

by repetitive activations (“dynamic stabilization“).

These are thought to have occurred either in the course of frequent functional use, or to have been induced spontaneously within the brain to maintain synaptic efficacies in circuits that were in infrequent use.

……….The latter repetitive activations are referred to as ‘non-utilitarian’ dynamic stabilization.

With the evolution of increasing repertories and complexities of behavioral

and sensory capabilities-

with vision usually being the vastly preeminent

sense-brain complexity increased markedly.

Accompanying the greater complexity,

needs for storage and maintenance of

hereditary and experimental information (memories)

also increased greatly.

It is suggested that these increases led to conflicts between sensory input processing during restful waking and concomitant ‘non-utilitarian’ dynamic stabilization of infrequently used memory circuits.

…………The selective pressure for the origin of primitive sleep

may have been a need to achieve greater depression of central processing of sensory inputs-largely complex visual information-than occurs during restful waking.

……………The electrical activities of the brain during sleep (aside from those that subserve autonomic activities) may function largely to maintain sleep and to dynamically stabilize infrequently used circuitry

encoding memories.

PTSD – this is interrupted – perhaps the experiences that are supposed to be stored as “infrequently used circuitry”

Are kept active and engaged IN CASE THEY WILL BE NEEDED SOON – and they are hence not “dynamically” stabilized but

Kept on active duty – ready to deploy instantly

Sleep may not have been the only evolutionary adaptation to conflicts between dynamic stabilization and sensory input processing.

………..In some ectothermic vertebrates, sleep may have been postponed or rendered unnecessary by a more readily effected means of resolution of the conflicts, namely, extensive retinal processing of visual information during restful waking.

…………….. By this means, processing of visual information in central regions of the brain may have been maintained at a sufficiently low level to allow adequate concomitant dynamic stabilization.

As endothermy evolved, the skeletal muscle hypotonia of primitive sleep may have become insufficient to prevent sleep-disrupting skeletal muscle contractions during ‘non-utilitarian’ dynamic stabilization of motor circuitry at the accompanying higher body temperatures and metabolic rates.

Selection against such disruption during dynamic stabilization of motor circuitry may have led to the inhibition of skeletal muscle tone

during a portion of primitive sleep,

the portion designated as “rapid-eye-movement sleep.”

Many marine mammals that are active almost continuously engage only in unihemispheric non-rapid-eye-movement sleep.

………They apparently do not require rapid-eye-movement sleep and accompanying ‘non-utilitarian’ dynamic stabilization of motor circuitry because this circuitry is in virtually continuous use.

……..Studies of hibernation by arctic ground squirrels suggest that each hour of sleep stabilizes brain synapses for as long as four hours.


Kavanau 1997b

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

The origin of both sleep and memory appears to be closely associated with the evolution of mechanisms of enhancement and maintenance of synaptic efficacy. The development of activity-dependent synaptic plasticity apparently was the first evolutionary adaptation of nervous systems beyond a capacity to respond to environmental stimuli by mere reflexive actions.

……..After the origin of activity-dependent synaptic plasticity, whereby single activations of synapses led to short-term efficacy enhancement, lengthy maintenance of enhancements probably was achieved by repetitive activations (“dynamic stabilization”).

…….One source of selective pressure for the evolutionary origin of neurons and neural circuits with oscillatory firing capacities may have been a need for repetitive spontaneous activations to maintain synaptic efficacy in circuits that were in infrequent use.

…….This process is referred to as “non-utilitarian” dynamic stabilization. …….Dynamic stabilization of synapses in “simple” invertebrates occurs primarily through frequent use.

…..In complex, locomoting forms, it probably occurs through both frequent use and non-utilitarian activations during restful waking.

With the evolution of increasing repertories and complexities of behavioral and sensory capabilities–with vision usually being the vastly pre-eminent sense brain complexity increased markedly.

…..Accompanying the greater complexity, needs for storage and maintenance of hereditary and experiential information (memories) increased greatly.

……… It is suggested that these increases led to conflicts between sensory input processing during restful waking and concomitant non-utilitarian dynamic stabilization of infrequently used memory circuits.

………The selective pressure for the origin of primitive sleep may have been a resulting need to achieve greater depression of central processing of sensory inputs largely complex visual information than occurs during restful waking.

……….The electrical activities of the brain during sleep (aside from those that subserve autonomic activities) may function largely to maintain sleep and to dynamically stabilize infrequently used circuitry encoding memories.

Sleep may not have been the only evolutionary adaptation to conflicts between dynamic stabilization and sensory input processing. In some ectothermic vertebrates, sleep may have been postponed or rendered unnecessary by a more readily effected means of resolution of the conflicts, namely, extensive retinal processing of visual information during restful waking.

…….By this means, processing of visual information in central regions of the brain may have been maintained at a sufficiently low level to allow adequate concomitant dynamic stabilization.

As endothermy evolved, the skeletal muscle hypotonia of primitive sleep may have become insufficient to prevent sleep-disrupting skeletal muscle contractions during non-utilitarian dynamic stabilization of motor circuitry at the accompanying higher body temperatures and metabolic rates.

……….Selection against such disruption during dynamic stabilization of motor circuitry may have led to the inhibition of skeletal muscle tone during a portion of primitive sleep, the portion designated as rapid-eye-movement sleep.

……….Many marine mammals that are active almost continuously engage only in unihemispheric non-rapid-eye-movement sleep.

………They apparently do not require rapid-eye-movement sleep and accompanying non-utilitarian dynamic stabilization of motor circuitry, because this circuitry is in virtually continuous use.

Studies of hibernation by arctic ground squirrels suggest that each hour of sleep may stabilize brain synapses for as long as 4 h. Phasic irregularities in heart and respiratory rates during rapid-eye-movement sleep may be a consequence of superposition of dynamic stabilization of motor circuitry on the rhythmic autonomic control mechanisms. Some information encoded in circuitry being dynamically stabilized during sleep achieves unconscious awareness in authentic …[dreams] don’t have article to read rest of this – long abstract here


Kavanau 1998

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

A major activity of the brain of most vertebrates during waking behavior is the processing of sensory information, preponderantly visual.

This processing is not fully compatible with the brain’s spontaneous oscillatory activity that

…..maintains (refreshes) infrequently used circuits

….. that store inherited and experiential information (memories).

Great reduction in sensory input and processing

during sleep

permits the refreshment of memory circuits

to occur unimpededly.

Accordingly, sleep may have evolved as ever augmenting needs for processing visual information during waking behavior by brains of great complexity conflicted increasingly with needs to refresh memory circuits. ………..The lack of a need for sleep by genetically blind fishes that live in caves, ………and sighted fishes that swim continuously,

………is consistent with this thesis, as their needs for processing of sensory information, predominantly visual, are either greatly reduced or nil.

Reduced requirements for processing sensory information by continuously swimming fishes owe to the following aspects of their behavior and ecology:

(1) visual input is greatly reduced or absent during lengthy periods of nocturnal activity;

(2) schooling greatly reduces needs for sensory information, particularly visual; (3) being maintained through frequent use, circuitry for most

inherited memories

needs no refreshment; and

(4) inasmuch as they lead a comparatively routine existence in essentially featureless, open waters, pelagic species acquire, and have need to refresh, relatively few experiential memories.

Analogous circumstances could account for the ability of migrating birds to fly for days without rest or sleep.


Kavanau 1999

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

Brain circuits for infrequently employed memories

are reinforced largely during sleep

by self-induced, electrical slow-waves,

a process referred to as “dynamic stabilization” (DS).

The essence of waking brain function in the absence of volitional activity is sensory input processing, an enormous amount of which is visual.

…….These two functions: circuit reinforcement by DS and sensory information processing come into conflict when both occur at a high level,

a conflict that may have been the selective pressure for sleep’s origin.

As brain waves are absent at the low temperatures of deep torpor,

essential circuitry of hibernating small mammals would lose its competence

if the animals did not warm up periodically to temperatures

allowing sleep and circuit reinforcement.

Blind, cave-dwelling vertebrates require no sleep because their sensory processing does not interfere with “dynamic stabilization” (DS)..

Is this part of what contributes to the sleep difficulties of blind people?

Nor does such interference arise in continuously-swimming fishes, whose need to process visual information is reduced greatly by life in visually relatively featureless, pelagic habitats, and by schooling.

Dreams are believed to have their origin in “dynamic stabilization” (DS)

of memory circuits.

They are thought to have illusory content when the circuits are partially degraded (incompetent),

with synaptic efficacies weakened through infrequent use.

Here, again, with PTSD perhaps the “circuits are partially degraded

And therefore incompetent – “weakened through infrequent use”

Partially degraded circuits

arise normally in the course of synaptic efficacy decay,

or pathologically through abnormal regimens of “dynamic stabilization” (DS).

Organic delirium may result from breakdown of normal regimens of “dynamic stabilization” (DS).of circuitry during sleep, leaving many circuits incompetent.

Activation of incompetent circuits during wakefulness

apparently produces delirium and hallucinations.

Some epileptic seizures may be induced by abnormal regimens of “dynamic stabilization” (DS).of motor circuitry.

……..Regimens of remedial “dynamic stabilization” (DS) during seizures induced by electroconvulsive therapy (ECT) apparently produce temporary remission of delirium by restoring functional or ‘dedicated’ synaptic efficacies in incompetent circuitry.

………..Sparing of sensory circuitry in fatal familial insomnia seemingly owes to supernormal circuit use in the virtual absence of sleep. ECT shocks and cardioverter defibrillation may have analogous remedial influences.



Fatal familial insomnia (FFI) is a very rare autosomal dominant inherited prion disease of the brain. The dominant gene responsible has been found in just 28 families worldwide; if only one parent has the gene, the offspring have a 50% chance of inheriting it and developing the disease. The disease’s genesis and the patient’s progression into complete sleeplessness is untreatable, and ultimately fatal.


Kavanau 2000

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu


appear to be generated in the process of reinforcing memory circuits of the brain, as circuits are activated by self-generated electrical slow waves,

with dream contents reflecting

information stored in activated circuits.

Illusory dreams and other healthy delirious states

appear to occur when activated memory circuits are incompetent,

containing synapses whose efficacies deviate from their ‘dedicated’ values.

Well, that’s a strange way to consider dreams – which, to me, can provide amazing information

Organic delirium and some other mental disorders may have their basis in brain pathologies that alter reinforcing slow waves, causing synaptic efficacies to depart from dedicated values.

…………..Activation of these incompetent circuits leads to recall of faulty memories–a substrate for delirium.

In treatment of organic delirium by electroconvulsive therapy (ECT), the electric shock temporarily suppresses abnormal slow-wave regimes, allowing remedial reinforcement regimes to resume. These restore dedicated synaptic efficacies, temporarily alleviating the delirium. The action of ECT shocks appears to parallel closely that of cardiac defibrillating shocks. Greater than normal amounts of circuit reinforcement protect sensory circuitry in fatal familial insomnia, and cognitive circuitry in encephalitis lethargica.


Kavanau 2001

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

Dreams are widely believed to be produced as the brain’s memory circuits are reinforced during sleep by self-generated

[meaning that the memories generate them?]

brain waves.

Reinforcement maintains synaptic strengths in the ‘dedicated’ ranges

that support circuit functions.

Without these activations,

turnover of molecules essential for synaptic function

would lead to deleterious alterations in, and eventual loss of, memories.

The pathological processes underlying many mental disorders

appear to exert their deleterious influences

by inducing abnormalities in brain waves,

largely in slow waves of less than about 14 cycles/s.

The pathologically altered slow waves, in turn,

cause long-lasting weakening or dysfunction of synapses of affected circuits, frequently resulting in mental disorders and deviant sleep.

These abnormalities can be remediated for varying periods

by therapies that restore normal brain waves.

With many trillions of synapses between billions of neurons

in enormously complex circuits needing reinforcement during sleep,

the process is susceptible to failures.

As a result, some synapses ‘normally’ weaken or become dysfunctional, accumulating to the greatest extent in old memory circuits.

Activation of resulting incompetent circuits

during waking

may lead to hallucinations and delusions;

activation during sleep may lead to dreams with

bizarre, incoherent or impossible contents.


Kavanau 2002

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

Mentation [thinking] during sleep states

is thought to originate in an activation of brain circuits

that encode inherited and experiential memories.

Spontaneous degradation of the strengths of synapses occurs in all brain circuits because of “turnover” of molecules essential for synaptic function.

In circuits employed frequently during waking, synaptic strengths are refreshed and maintained in their dedicated or functional ranges largely through use, by virtue of activity-dependent synaptic plasticity.

In circuits employed infrequently during waking,

synaptic strengths are refreshed largely during sleep,

by circuit activations induced by spontaneous, self-generated, largely low-frequency brain waves,

also by virtue of activity-dependent synaptic plasticity.

The outputs of circuits

activated during sleep

do not necessarily rise to the level of ‘unconscious’ awareness.


Such an absence of awareness of the outputs of individual circuits, that is, an absence of dreaming,

is proposed to be the primitive condition in animals that sleep.

On the other hand, temporal binding of these outputs

is accompanied by the thoughts and perceptions of dreams,

which is proposed to be the advanced condition.

Linking or serial ordering of otherwise ‘static’ thoughts and perceptions gives rise to continuous, often narrative and veridical, dreams.

In all cases, dream contents are derived from the memories

–not necessarily veridical—[ coinciding with reality]

encoded in the reinforced circuitry.

Well, we must be able to tap into memories of “other” places and times

During sleep

In the absence of synaptic strength refreshments during sleep,

synaptic strengths in infrequently used circuits

would weaken and the circuits would become incompetent,

with their encoded memories degraded or lost.

So, in PTSD, are the synaptic strengths used TOO frequently

So that they remain too strong and are never lost?

Maintenance of synaptic strengths in infrequently used circuitry [what are these?] during sleep apparently does not always achieve perfection.

Weakened synapses begin to occur in circuits in appreciable numbers

in children after the age of about 5 years.

When these ‘incompetent’ circuits (with weakened synapses)

are activated during sleep, there are minimal influences on dream contents, namely, distortions that make some objects,

such as animals, faces, and scenes, unrecognizable.

As weakened synapses increase in numbers with age,

the numbers of distorted objects in dreams also increase.

In adults, people in as many as 80% of dreams may be unrecognizable.

Besides the normal weakening of synaptic strengths, some synapses

become defective, in consequence of deleterious, adventitious, exogenous influences, for example, radiation.

As these faulty synapses accumulate in old memories,

activation of circuits incorporating them during sleep

leads to dreams with incoherent, bizarre, or impossible contents.

The infrequent activation of such old, incompetent circuits

in some waking conditions leads to

false memories,

delusions, or


What about “flashbulb” memories?


Kavanau 2004

Abstract – University of California, Department of Biology, Los Angeles 90095-1606, USA. lkavanau@biology.ucla.edu

The development of neural multifunctionality

given brain regions carrying out more than one function –

conferred great efficiency on brain function at early stages of evolution.

This applied to animals that led relatively simple lives with few needs for long-term memories, such as many lower invertebrates – many molluscs, echinoderms, worms, etc.

…….As more complex lifestyles and detailed focal vision evolved,

needs for self-initiated and reflexive activities increased in frequency,

and recognition of many locales, conspecifics, and other forms of life became essential.

These developments were accompanied by greatly expanded needs for neural processing supporting sensory and motor activities, and establishing and storing long-term memories.

………..Since these categories of neural processing occur in largely overlapping brain regions,

………brain functioning would have become increasingly maladaptive,

……..had the evolution of these more complex lifestyles not been accompanied by compensating adaptations that obviated these potentially conflicting brain activities.

These adaptations consisted of:

first, restful waking;

second, primitive sleep; and finally,

fully developed sleep, with its specialized rapid-eye-movement and non-rapid-eye-movement states,

that contribute to the maintenance of great efficiency of brain function.

The only animals with detailed focal vision that can achieve highly efficient brain function without sleep, are those in which demands on memory processing are greatly reduced in consequence of routine, monotonous, almost purely reflexive lifestyles, with few needs for acquiring experiential long-term memories. The best known animals in this non-sleeping category are tunas and many sharks.


Kavanau 2006

Abstract –

Biotelemetry has revealed daily 15-h behavioral sleep periods in a cubomedusan jellyfish, Chironex fleckeri. Its sleep is expected to be phylogenetically most primitive, since jellyfish possess only two germ layers. They belong to the phylum Cnidaria, the ‘simplest’ multicellular organisms with an organized nervous system. Cubomedusae have a complex visual system with 24 eyes of four different types, each type specialized for a different task. Input to these eyes during visually guided fast-swimming predation requires enormous amounts of neural processing, possibly nearly saturating the capacity of their comparatively simple nervous system. These heavy neural demands may account for the need for fifteen hours of sleep. C. fleckeri is the only animal known for which sleep may be either present or absent, dependent on lifestyle. Limited knowledge of behavior of some other cubomedusae suggests that they also possess this faculty. The finding of sleep in C. fleckeri supports current proposals of sleep’s origin and basic function.

Evolutionary analyses link sleep to a conflict produced by excessive processing demands on multifunctional neural circuitry for detailed focal vision by complex lensed eyes.

The conflict arises between the enormous demands of complex visual analysis and needs for split-second control of actions, on the one hand, and non-urgent processing of memories of ongoing and stored events, on the other.

Conflict is resolved by deferring the non-urgent processing to periods of sleep.

Without sleep, selection would favor the evolution of circuitry ‘dedicated’ to single or but few tasks, with corresponding lesser efficiency.

……………Had complex lensed eyes of medusae originated as a consequence of selection for increased mating success of males pursuing females, it could have occurred before the evolution of fast-swimming bilateral (three-germ-layered) prey.

…………….But if it was a consequence of selection for increased prey-hunting success, the origin of such eyes probably awaited the coexistence of bilateral preyThis just makes me chuckle!!!


Lee Kavanau 2002

Abstract – Department of Organismic Biology, Ecology and Evolution, University of California at Los Angeles (UCLA), 4 90095-1606, USA. lkavanau@biology.ucla.edu

Divergence of primitive sleep into REM and NREM states

is thought to have occurred in the nocturnal Triassic ancestors of mammals

as a natural accompaniment of the evolution of warm-bloodedness.

As ambient temperatures during twilight portions of primitive sleep

traversed these evolving ancestors’ core temperature,

mechanisms of thermoregulatory control that employ muscle contractions became superfluous.

The resulting loss of need for such contractions during twilight sleep led to muscle atonia [atonicity: lack of normal muscular tension or tonus].

With muscle tone absent, selection favored the persistence of the fast waves

of nocturnal activity during twilight sleep.

Stimulations by these waves reinforce motor circuits

at the increasing temperatures of evolving warm-bloodedness

without leading to sleep-disturbing muscle contractions.

By these and related interlinked adaptations, twilight sleep [weird, that’s what the birthing dope was called] evolved into REM sleep.

The daytime period of sleep became NREM sleep.

The evolution of NREM and REM sleephas implications for sleep’s maintenance processes for long-term memories.

During NREM sleep, there is an unsynchronized, uncoordinated stimulation and reinforcement of individual distributed component circuits

of consolidated memories by slow wave potentials,

a process termed ‘uncoordinated reinforcement’.

What good does this do?

The corresponding process during REM sleep

is the coordinated stimulation and reinforcement

of these circuits by fast wave potentials.

This action temporally binds the individual component circuit outputs into fully formed memories, a process termed ‘coordinated reinforcement’. Sequential uncoordinated and coordinated reinforcement, that is, NREM followed by REM sleep,

emerges as the most effective mechanism of long-term memory maintenance in vertebrates.

With the evolution of this two-stage mechanism of long-term memory maintenance,

it became adaptive to partition sleep into several NREM-REM cycles,

thereby achieving a more lengthy application of the

cooperative sequential actions.


Lee Kavanau 2005

Abstract – Department of Organismic Biology, Ecology and Evolution, University of California at Los Angeles (UCLA), 4 90095-1606, USA. lkavanau@biology.ucla.edu

A major controversy over REM sleep’s role in memory processing may owe

to inadequate allowances

for the highly conservative nature of evolutionary adaptations.

The controversy hinges on whether NREM sleep, alone, retains primitive memory processing capabilities.

The selective pressure for primitive sleep,

is thought to have been the need to obviate conflicts

between enormous neural processing requirements of complex visual analysis and split-second control of movements, on the one hand,

and memory processing, on the other.

The most efficient memory processing during mammalian and avian sleep appears to be a two-step process:

synapses in individual component circuits of events

are reinforced primarily by slow brain waves during NREM sleep,

with the reinforced components temporally bound by fast waves,

and manifested as dreams, during REM sleep.

This dual action could account for partitioning of sleep periods into multiple NREM-REM cycles. It is proposed that in the absence of REM sleep, all needed memory processing can be accomplished by NREM sleep, alone, though less efficiently.

Many symptoms of fatal familial insomnia are attributed to subnormal nightly reinforcement of brain circuitry because of almost total loss of sleep, and compensatory responses thereto during waking. During this disorder, sensory circuitry seemingly is spared by virtue of its supernormal reinforcement during almost continuous waking. Contrariwise, sparing of an adult’s ‘higher faculties’ in encephalitis lethargica appears to owe to supernormal circuit reinforcement during almost continuous sleep.


Now I have to go over to the cannabinoid area – with more information on sleep


see also in dopamine system

Lavialle et al 2008


Ivanova & Iuvone 2003

abstract – GA

The key regulatory enzyme in melatonin synthesis is arylalkylamine N-acetyltransferase (AANAT). In vivo, AANAT activity in chicken retinal photoreceptor cells exhibits a circadian rhythm that peaks at night. The purpose of the present study was to investigate the temporal development of light/dark and circadian oscillations of AANAT activity in cultured retinal cells prepared from 6- and 8-day-old chicken embryos ….. In cells incubated in this manner, a 2-h light pulse in the middle of the subjective night suppressed AANAT activity, indicating that the enzyme activity in the cultured cells is acutely suppressed by light, as it is in vivo.

These results indicate that the ability to express circadian regulation of AANAT activity is an intrinsic property of retinal cells that can develop in vitro.

Development of light-dark regulation of AANAT activity appears to precede the circadian clock-control of enzyme activity.


Chaurasia et al 2006

Abstract – GA

PURPOSE: Circadian clocks in retinas regulate a variety of biochemical and physiological processes. Retinal neurons, particularly photoreceptor cells, are thought to contain autonomous circadian clocks that control iodopsin expression, cFos expression, cAMP levels, and melatonin synthesis. Photoreceptor-enriched cell cultures prepared from chick embryo retina and entrained to a daily light-dark (LD) cycle exhibit circadian rhythms of cAMP levels and the activity of arylalkylamine N-acetyltransferase (AANAT), a key regulatory enzyme in melatonin synthesis. The present study was conducted to investigate the

expression of circadian clockwork machinery comprised of clock genes; a clock-controlled gene, Aanat;

and a clock output, melatonin, in the photoreceptor-enriched cultured retinal cells.

RESULTS: Cultured neural retina cells exposed to a light-dark cycle showed rhythmic expression of clock genes. Bmal1 and Npas2 (also known as Mop4) peaked late in the day in LD and in DD. Clock mRNA was high at night in LD, but arrhythmic in DD. Cry1 and Per2 transcripts increased rapidly in the early morning and were low at night. The rhythm of Per2 was reduced in amplitude in constant darkness (DD). Levels of Cry1 and Per2 transcripts were stimulated by light exposure at night. Melatonin release and Aanat mRNA were low during the day and high at night. Rhythmic expression of clock genes and Aanat was not observed in cultures not exposed to a LD cycle but treated otherwise identically to cultures described above. CONCLUSIONS: Photoreceptor-enriched cell cultures derived from chick embryo neural retina contain a complete circadian clockwork system that is entrained by the light-dark cycle, and has a core timekeeping mechanism and circadian output in the form of melatonin synthesis.


Ribelayga & Mangel 2003

Abstract – GA

In fish and other vertebrate retinas, although dopamine release is regulated by both light and an endogenous circadian (24-hour) clock, light increases dopamine release to a greater extent than the clock. The clock increases dopamine release during the subjective day so that D2-like receptors are activated. It is not known, however, whether the retinal clock also activates D1 receptors, which display a much lower sensitivity to dopamine in intact tissue. …. These observations demonstrate that H1 cell gap junctional coupling and thus D1 receptor activity are not affected by endogenous dopamine under dark-adapted conditions. The results suggest that two different dopamine systems are present in the goldfish retina.

….One system is controlled by an endogenous clock that activates low threshold D2-like receptors in the day,

……whereas the second system is controlled by light and involves activation of higher threshold D1 receptors.


Ribelayga, Wang & Mangel 2004

Abstract – AL

Although many biochemical, morphological and physiological processes in the vertebrate retina are controlled by a circadian (24 h) clock, the location of the clock and how the clock alters retinal function are unclear. For instance, several observations have suggested that dopamine, a retinal neuromodulator, may play an important role in retinal rhythmicity but the link between dopamine and a clock located within or outside the retina remains to be established.

We found that endogenous dopamine release from isolated goldfish retinae cultured in continuous darkness for 56 h clearly exhibited a circadian rhythm with high values during the subjective day. The continuous presence of melatonin (1 nM) in the culture medium abolished the circadian rhythm of dopamine release and kept values constantly low and equal to the night-time values. The selective melatonin antagonist luzindole (1 microM) also abolished the dopamine rhythm but the values were high and equal to the daytime values. Melatonin application during the late subjective day introduced rod input and reduced cone input to fish cone horizontal cells, a state usually observed during the subjective night. In contrast, luzindole application during the subjective night decreased rod input and increased cone input. Prior application of dopamine or spiperone, a selective dopamine D(2)-like antagonist, blocked the above effects of melatonin and luzindole, respectively.

These findings indicate that a circadian clock in the vertebrate retina regulates dopamine release by the activation of melatonin receptors and that endogenous melatonin modulates rod and cone pathways through dopamine-mediated D(2)-like receptor activation.


Ribelayga & Mangel 2007

Abstract – GA

Horizontal cells are second order neurons that receive direct synaptic input from photoreceptors. In teleosts horizontal cells can be divided into two categories, cone-connected and rod-connected. Although the anatomy and physiology of fish cone horizontal cells have been extensively investigated, less is known about rod horizontal cells. …We conclude that similarly to cone horizontal cells, rod horizontal cells are extensively coupled to one another in darkness and that the extent of coupling is dramatically reduced by bright light stimulation or dopamine D1-receptor activation. However, in contrast to cone horizontal cells whose light responses are under the control of the retinal clock, the light responses of rod horizontal cells under dark-adapted conditions were similar during the day, night, subjective day, and subjective night thus demonstrating that they are not under the influence of the circadian clock.


Ribelayga, Cao & Mangel 2008

Abstract – GA

Although rod and cone photoreceptor cells in the vertebrate retina are anatomically connected or coupled by gap junctions, a type of electrical synapse, rod-cone electrical coupling is thought to be weak. …mouse retina, we show that …..the retinal circadian clock,

……and not the retinal response to the visual environment,

….controls the extent and strength of rod-cone coupling by activating dopamine D(2)-like receptors in the day, so that rod-cone coupling is weak during the day but remarkably robust at night. The results demonstrate that circadian control of rod-cone electrical coupling serves as a synaptic switch that allows cones to receive very dim light signals from rods at night, but not in the day. The increase in the strength and extent of rod-cone coupling at night may facilitate the detection of large dim objects.


Pandi-Perumal et al 2006

Abstract – Mt Sinai, NY

Authors also from Malaysia, Switzerland, Argentina and Germany

Melatonin – widely distributed in nature – functional activity in unicellular organisms, plants, fungi, animals –

….in most vertebrates including humans melatonin is synthesized primarily in the pineal glad

.melatonin implicated in broad range of effects with a significant regulatory influence over many of the body’s physiological functions

….is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus – secreted during the dark phase of the light/dark cycle – consequently is often called the ‘hormone of darkness’ – centrally involved in sleep regulation, as well as in other cyclical bodily activities

….”Melatonin is exclusively involved in signaling the ‘time of day’ and ‘time of year’ (hence considered to help both clock and calendar functions – to all tissues thus is considered to be the body’s chronological pacemaker or ‘Zieitgeber’

..synthesis also occurs in other in other areas of the body, including retina, gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling [signals target only cells in the vicinity of the emitting cell. Neurotransmitters represent an example.]

…………has also been extracted from seeds and leaves of many plants and in some is higher than the night-time plasma value in humans……

“In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes

antiapoptotic :  Something that prevents apoptosis – a type of cell death in which a series of molecular steps in a cell leads to its death

…”It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia

Ischemia: Inadequate blood supply (circulation) to a local area due to blockage of the blood vessels to the area.

…”Melatonin’s cytoprotective [protecting cells from noxious chemicals or other stimuli] properties have practical implications in the treatment of neurodegenerative diseases.

..also has immune-enhancing and oncostatic [cancer fighting] properties

…[both direct and indirect, the latter mediated by its effects on reproductive hormones]

…its ‘chronobiotic’ properties have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work

is an internal sleep facilitator, promotes sleep, recently introduced melatonin analog, agomelatine, also efficient for treatment of major depressive disorder and bipolar affective disorder

Melatonin’s role as a ‘photoperiodic molecule’ in seasonal reproduction has been established in photoperiodic species but its regulatory influence in humans remains under investigation


Wang, Du & Tong 2007

Abstract – China

This study was conducted to investigate the circadian rhythms and light responses of Clock and arylalkylamine N-acetyltransferase (NAT) gene expressions in the rat pineal gland under the environmental conditions of a 12 h light (05:00-17:00 h): 12 h-dark (17:00-05:00 h) cycle (LD) and constant darkness (DD). The pineal gland of Sprague-Dawley rats housed under a LD regime (n=42) for four weeks and of a regime (n=42) for eight weeks were sampled at six different times, every 4 h (n=7 animals per time point), during a 24 h period. Total RNA was extracted from each sample, and the semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was used to determine temporal changes in mRNA levels of Clock and NAT genes during different circadian or zeitgeber times.

In the DD or LD condition, both the Clock and NAT mRNA levels in the pineal gland showed robust circadian oscillation (p<0.05) with the peak at the subjective night or at nighttime. In comparison with the DD regime, the amplitudes and mRNA levels at the peaks of Clock and NAT expressions in LD in the pineal gland were significantly reduced (p<0.05). In the DD or LD condition, the circadian expressions of NAT were similar in pattern to those of Clock in the pineal gland (p>0.05).

These findings indicate that the transcriptions of Clock and NAT genes in the pineal gland not only show remarkably synchronous endogenous circadian rhythmic changes, but also respond to the ambient light signal in a reduced manner.


Bai et al 2008

Abstract – Germany

The photoreceptive retina and the non-photoreceptive pineal gland are components of the circadian and the melatonin forming system in mammals.

To contribute to our understanding of the functional integrity of the circadian system and the melatonin forming system we have compared the daily oscillation of the two tissues under various seasonal lighting conditions. For this purpose, the 24-h profiles of the expression of the genes coding for arylalkylamine N-acetyltransferase (AA-NAT), nerve growth factor inducible gene-A (NGFI-A), nerve growth factor inducible gene-B (NGFI-B), retinoic acid related orphan receptor beta (RORbeta), dopamine D4 receptor, and period2 (Per2) have been simultaneously recorded in the retina and the pineal gland of rats under short day (light/dark 8:16) and long day (light/dark 16:8) conditions.

We have found that the cyclical patterns of all genes are phase-advanced in the retina, often with a lengthened temporal interval under short day conditions.

In both tissues, the AA-NAT gene expression represents an indication of the output of the relevant pacemakers.

The temporal phasing in the AA-NAT transcript amount

….between the retina and the pineal gland

….is retained under constant darkness suggesting that

…. the intrinsic self-cycling clock of the retina oscillates in a phase-advanced manner with respect to the self-cycling clock in the suprachiasmatic nucleus, which controls the pineal gland.

We therefore conclude that daily rhythms in gene expression

……in the retina

……are phase-advanced with respect to the pineal gland,

……and that the same temporal relationship appears to be valid for the self-cycling clocks influencing the tissues.


Deurveilher & Semba 2005

Abstract – Nova Scotia

The circadian clock housed in the suprachiasmatic nucleus (SCN) controls various circadian rhythms including daily sleep-wake cycles.

Using dual tract-tracing, we recently showed that the medial preoptic area (MPA), subparaventricular zone (SPVZ) and dorsomedial hypothalamic nucleus (DMH) are well positioned to relay SCN output to two key sleep-promoting nuclei, namely, the ventrolateral and median preoptic nuclei.

The present study examined the possibility that these three nuclei may link the SCN with wake-regulatory neuronal groups. … These results suggest that the MPA, SPVZ and DMH are possible relay nuclei for indirect SCN projections not only to sleep-promoting preoptic nuclei as previously shown, but also to wake-regulatory cell groups throughout the brain.

…………. In the absence of major direct SCN projections to most of these sleep/wake-regulatory regions, indirect neuronal pathways probably play an important role in the circadian control of sleep-wake cycles and other physiological functions.


Chou et al 2003

Abstract – Harvard

The suprachiasmatic nucleus (SCN) contains the brain’s circadian pacemaker, but mechanisms by which it controls circadian rhythms of sleep and related behaviors are poorly understood.

………Previous anatomic evidence has implicated the

dorsomedial hypothalamic nucleus (DMH) in circadian control of sleep,

but this hypothesis remains untested. We now show that excitotoxic lesions of the DMH reduce circadian rhythms of wakefulness, feeding, locomotor activity, and

serum corticosteroid levels

by 78-89% while also reducing their overall daily levels.

……….We also show that the DMH

….receives both direct and indirect SCN inputs

….and sends a mainly GABAergic projection to the sleep-promoting ventrolateral preoptic nucleus,

……and a mainly glutamate-thyrotropin-releasing hormone projection to the

wake-promoting lateral hypothalamic area,

………including orexin (hypocretin) neurons.

Through these pathways, the DMH may influence a wide range of behavioral circadian rhythms.


Abrahamson & Moore 2006

Abstract – PA

The suprachiasmatic nucleus (SCN) of the hypothalamus

………controls circadian rhythms in


…neuroendocrine and

…physiological functions.

In this study, we test the hypothesis that caudal SCN efferents to the subparaventricular zone (SPVZ) control the rhythm in rest-activity (R-A) through projections on posterior hypothalamic area arousal systems (PHA). Small electrolytic lesions of the ventral SPVZ cause a selective loss of the circadian R-A rhythm, sparing the core body temperature rhythm. In contrast, large excitotoxic lesions of the posterior hypothalamic area (PHA) that effectively ablate populations of hypocretin and melanin concentrating hormone neurons projecting to cortex and subcortical arousal areas decrease R-A rhythm amplitude but do not disrupt circadian regulation. Since dorsomedial hypothalamic nucleus lesions have effects similar to PHA lesions…

these data support the view that the SPVZ is the principal relay nucleus for SCN signals to the multiple posterior hypothalamic arousal systems involved in generation of the R-A rhythm.


Coon et al 2002

Abstract – MD

Arylalkylamine N-acetyltransferase (AANAT; serotonin N-acetyltransferase, EC plays a unique transduction role in vertebrate physiology as the key interface between melatonin production and regulatory mechanisms.

Circulating melatonin is elevated at night in all vertebrates, because AANAT activity increases in the pineal gland in response to signals from the circadian clock.

Circadian regulation of melatonin synthesis is implicated in a variety of human problems, including jet lag, shift work, insomnia, and abnormal activity rhythms in blind persons.

In this report AANAT was studied in the rhesus macaque to better understand human melatonin regulation. AANAT mRNA is abundant in the pineal gland and retina, but not elsewhere;

………AANAT mRNA is uniformly distributed in the pineal gland, but is limited primarily to the photoreceptor outer segments in the retina.

Day and night levels of pineal and retinal AANAT mRNA are similar. In contrast, AANAT activity and protein increase more than 4-fold at night in both tissues. ………..The activity of hydroxyindole-O-methyltransferase, the last enzyme in melatonin synthesis, is tonically high in the pineal gland, but is nearly undetectable in the retina; hydroxyindole O-methyltransferase mRNA levels exhibited a similar pattern.

……….. This supports the view that the source of circulating melatonin in primates is the pineal gland.

………….The discovery in this study that rhesus pineal AANAT mRNA is high at all times is of special importance because it shows that posttranscriptional control of this enzyme plays a dominant role in regulating melatonin synthesis.


Ganguly, Coon & Klein 2002

Abstract – MD

Control of melatonin synthesis in the mammalian pineal gland: the critical role of serotonin acetylation.

The large daily rhythm in circulating melatonin levels is a highly conserved feature of vertebrate physiology: high values always occur at night.

The dynamics of the rhythm are controlled by the next-to-last enzyme in melatonin synthesis (serotonin –> N-acetylserotonin –> melatonin), arylalkylamine N-acetyltransferase (AANAT), the “melatonin rhythm enzyme“.

In vertebrate biology, AANAT plays a unique time-keeping role as the molecular interface between the environment and the hormonal signal of time, melatonin.

This chapter describes the mammalian AANAT regulatory system, which includes the retina, neural structures, transsynaptic processes, and molecular events.

……. In addition, special attention is paid to the functional characteristics of the systems which insure that the nocturnal increase in

melatonin is an accurate and reliable indicator of the duration of the night, and why the

melatonin rhythm is the most reliable output signal of the Mind’s Clock.


Coon & Klein 2006

Abstract – MD

The melatonin rhythm-generating enzyme, arylalkylamine N-acetyltransferase (AANAT) is

……….known to have recognizable ancient homologs in bacteria and fungi, but not in other eukaryotes.

Analysis of new cDNA and genomic sequences has identified several additional homologs in other groupings. First, an AANAT homolog has been found in the genome of the cephalochordate amphioxus, representing the oldest homolog in chordates. Second, two AANAT homologs have been identified in unicellular green algae. The homologs in amphioxus, unicellular green algae, fungi and bacteria are similarly primitive in that they lack sequences found in vertebrate AANATs that are involved in regulation and that facilitate binding and catalysis.

……… In addition, all these sequences are intronless. These features are consistent with horizontal transfer of the AANAT ancestor from bacteria to green algae, fungi and chordates.

………. Lastly, a third AANAT gene has been found in teleost fish, suggesting that AANAT genes serve multiple functions in addition to melatonin synthesis.


Blomeke et al 2008

Abstract – Germany

The melatonin rhythm is arguably the best marker for the phase of the endogenous “biological clock.”

………..Arylalkylamine N-acetyltransferase (AANAT) is known to catalyze the acetylation [the addition of an acetyl group (-COCH3) group to a molecule] of serotonin, a rate-limiting process in melatonin synthesis.

Different single-nucleotide polymorphisms (SNPs) in the AANAT gene were identified recently in the Japanese population, and one of the genes was significantly associated with the

………delayed sleep phase syndrome.  – [a daily sleep/wake rhythm in which the onset of sleep and wake times are later than desired; the person tends to go to bed later and get up later]

Thus, 54 healthy Caucasian males were genotyped to investigate whether these SNPs in the AANAT gene affected melatonin levels. The endogenous melatonin levels were analyzed in saliva under standardized experimental conditions (“constant routines”) by radioimmunoassay. Despite the broad temporal variation of the human nocturnal melatonin profiles, none of the investigated SNPs were found in the AANAT gene in this study.

These findings point to ethnic differences with respect to these SNPs, rather than time of day termed “morningness.” In summary, SNPs in the AANAT gene identified thus far cannot explain the observed interindividual differences for nocturnal melatonin profiles in the subjects investigated.


Kim et al 2007

Abstract – Republic of Korea

The circadian rhythm of pineal melatonin requires the nocturnal increment of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase [AANAT]) protein.

……..To date, only limited information is available in the critical issue of how AANAT protein expression is up-regulated exclusively at night regardless of its species-specific mRNA profiles.

……….Here we show that the circadian timing of AANAT protein expression is regulated by rhythmic translation of AANAT mRNA.

………….This rhythmic control is mediated by both a highly conserved IRES (internal ribosome entry site) element within the AANAT 5′ untranslated region and its partner hnRNP Q (heterogeneous nuclear ribonucleoprotein Q) with a peak in the middle of the night.

Consistent with the enhancing role of hnRNP Q in AANAT IRES activities, knockdown of the hnRNP Q level elicited a dramatic decrease of peak amplitude in the AANAT protein profile parallel to reduced melatonin production in pinealocytes. This translational regulation of AANAT mRNA provides a novel aspect for achieving the circadian rhythmicity of vertebrate melatonin.


Macchi & Bruce 2004

Abstract – Columbia, NY

Pineal gland – functions in humans still poorly understood

…main product in diurnal and nocturnal vertebrates is hormone melatonin

……synthesized and released in rhythmic fashion, during dark portion of the day-night cycle

………”Melatonin production is controlled by an endogenous circadian timing system and is also suppressed by light.”

“In mammals, including humans, the gland has lost direct photosensitivity, but responds to light via a multisynaptic pathway that includes a subset of the retinal ganglion cells containing the newly discovered photopigment, [protein?] melanopsin.”

“Although humans are not considered photoperiodic, the occurrence of seasonal affective disorder (SAD) and its successful treatment with light suggest that they have retained some photoperiodic responsiveness.”

Melatonin levels are associated with onset of puberty, as well as elevated levels in both men and women with hypogonadism and/or infertility – perhaps some remnants of its role in human reproduction?

Involvement with immune function with high levels promoting and low levels suppressing a number of immune system parameters

Detection of melatonin receptors in various lymphoid organs and in lymphocytes suggest multiple mechanisms of action

Has been shown to be a powerful antioxidant

“…there are reports of abnormal daily melatonin profiles in a number of psychiatric and neurological disorders, but the significance of such abnormalities is far from clear.”


Levitan 2007

Abstract – Toronto —-get

This review summarizes research on the chronobiology and neurobiology of winter seasonal affective disorder (SAD),

……….a recurrent subtype of depression characterized by a predictable onset in the fall/winter months and spontaneous remission in the spring/summer period. Chronobiological mechanisms related to circadian rhythms, melatonin, and photoperiodism play a significant role in many cases of SAD,

………. and treatment of SAD can be optimized by considering individual differences in key chronobiological markers.

,,,,,,,,,,,,,,Converging evidence also points to a role for the

……..major monoamine neurotransmitters


..norepinephrine, and

..dopamine in one or more aspects of SAD.

Ultimately, as with other psychiatric illnesses, SAD is best considered as a complex disorder resulting from the interaction of several vulnerability factors acting at different levels, the various genetic mechanisms that underlie them, and the physical environment.

………..Models of SAD that emphasize its potential role in human evolution will also be discussed.


San & Arranz 2008

Abstract – Spain

The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms

…………has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential.

Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist.

………..Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex).

…………..The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placebo-controlled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25mg/day, with the possibility of increasing doses to 50mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatine’s efficacy over a longer treatment period.


Eser, Baghai & Moller 2007

Abstract – Germany

Depressive disorders are of the highest socioeconomic and health-economic importance, as they are the psychiatric disorders that most frequently cause psychosocial disability. Despite the progress that has been made, currently available pharmacotherapies for depression still have a limited antidepressant efficacy with a delayed onset of several weeks, and still cause side effects; these unmet needs represent important reasons to continue to search for novel treatment options. A disorganization of circadian rhythms has been suggested to play an important role in the pathophysiology of major depression, and complaints regarding disturbed sleep are frequent in depressed patients. As endogenous melatonin secretion underlies the regulation of circadian rhythms, compounds with activity at melatonergic receptors have been proposed as potential novel therapeutics. Agomelatine (S-20098), a compound with agonistic properties at MT1 and MT2 receptors and antagonistic properties at the 5-HT2C receptor, has been shown preclinically to exhibit robust antidepressant effects in several experimental paradigms. Clinical trials, including phase III studies, have now demonstrated the superior efficacy of agomelatine in comparison with placebo, and a similar efficacy in comparison with active comparators, for the treatment of major depression. Agomelatine was even effective in severely depressed patients. In all studies published so far, agomelatine was found to be safe and its overall tolerability profile was superior to that of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors.


Hattar et al 2003

Abstract – Johns Hopkins University School of Medicine

Besides the conventional rod-cone system in mammals, a melanopsin-associated photoreceptive system conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment

This makes me think about the empathy research Harrison et al 2007[in empathy – attachment chapter] – how does that work, when one person who is empathisizing with another will change their pupil size to match the other they are empathisizing with – only happens with people who have high empathic abilities – works only with sadness, no other feeling – is this further related to my guesses about sadness and the HPA – that all alterations from normal are in reality about something the body is perceiving as PAINFUL! If return to normal does not occur in the HPA axis – return to normal after a stressor means competence exists, coping is adequate, or something new can be and IS learned  – but pupil size must be connected through this specific melanopsin-associated photoreceptive system?

.on removal “…of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive.  Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired.”

…..study found that the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions

.pupil reflex, entrainment to light/dark cycles, etc


Guler et al 2008

abstract – Johns Hopkins

circadian photoentrainment and pupillary light reflex (PLR) is considered a non-image-forming function that receives light from the rod and cone photoreceptors via a multisynaptic pathway to the brain by means of retinal ganglion cells

Retinal ganglion cells: collectively transmit visual information from the retina to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain. Retinal ganglion cells vary significantly in terms of their size, connections, and responses to visual stimulation but they all share the defining property of having a long axon that extends into the brain. These axons form the optic nerve, optic chiasm, and optic tract.


Hatori et al 2008

abstract – Salk Institute, CA

“Rod/cone photoreceptors of the outer retina and the melanopsin-expressing retinal ganglion cells (mRGCs) of the inner retina mediate non-image forming visual responses including entrainment of the circadian clock to the ambient light, the pupillary light reflex (PLR), and light modulation of activity.  Targeted deletion of the melanopsin gene attenuates [lessens] these adaptive responses with no apparent change in the development and morphology of the mRGCs.  Comprehensive identification of mRGCs and knowledge of their specific roles in image-forming and non-image forming photoresponses are currently lacking.”

How could our empathic abilities evolve and NOT be connected in their origins to sight?  Blindness is not the norm, yet social interaction as members of a social species IS normal.  How do the visual components of our brain systems interact with the limbic brain?  I cannot think about this because I don’t have the information I need about the brain regions and operations…..but, if strong social support is an essential factor in preventing PTSD or depression in response to stress, starting all the way back in childhood and continuing through the lifespan, and if it is primarily the pain of trauma that can be recognized empathically through a cooperation effect of pupil size – and if the HPA is stressed and repair cannot be made because its timing is off – the stop does not happen, or the go does not happen correctly – and cortisol and melatonin being both circadian hormones – the rhythm of rupture and repair being broken – nobody there to pay attention to one’s sadness which is the only emotion responded to in terms of pupil size – what is the connection with all of this?  Or am I looking for….what?  And how connected to the immune system?

Study – genetically labeled the mRGCs in mice, revealed “…that only a subset of mRGCs express enough immunocytochemically detectable levels of melanopsin.”

These results point to the mRGCs as the site of functional integration of the rod/cone and melanopsin phototransduction pathways and as the primary anatomical site for the divergence of image-forming and non-image forming photoresponses in mammals.”


Lechner et al 2000

Abstract – Austria

Immune system interacts with the HPA axis via so-called glucocorticoid increasing factors, produced by immune system during immune reactions, causing elevation of systemic glucocorticoid levels that contribute to preservation of immune reactions specificities

…altered immmuno-neuroendocrine dialogue via the hypothalamo-pituitary-adrenal axis in autoimmune disease-prone chicken and mouse strains

study results “…show that lupus-prone …mice do not react appropriately to changes of the light/dark cycle, circadian melatonin rhythms seem to uncouple from the light/dark cycle, and plasma corticosterone levels are elevated during the resting phase.”

The mice “…not only show an altered glucocorticoid response mediated via the hypothalamo pituitary adrenal axis to IL-1 [interleukin-1], but are also affected by disturbances of corticosterone and melatonin circadian rhythms.  Our findings may have implications for intrathymic T cell development and the emergence of autoimmune disease.”


Monteleone et al 2007

Abstract – Italy

The circadian profiles of melatonin and prolactin (PRL) were altered in obsessive-compulsive disorder patients; the circadian rhythm of cortisol was preserved, although at a higher level compared with controls – conditions were significantly related to severity of the OCD symptoms


Barriga et al

Abstract – UK and Canada

Studied:  relationship between stress and the circadian rhythm of blood levels of melatonin and corticosterone in ring dove [used constraint as stressor]

…….results show changes in the circadian rhythm of melatonin, with increased daytime levels in situations of stress accompanied by increased corticosterone levels – highest levels of melatonin were obtained when animals were treated with dexamethasone and then subjected to stress.

“There is much speculation about the relationship between the major product of the pineal gland, melatonin, on the activity of the …(HPA) system and adrenocortical glucocorticoid secretion.  Findings have been contradictory.”  Barriga et al 2002, p 232

……..some have found no evidence for coupling between melatonin and glucocorticoids

….others suggest that melatonin may act as a major regulator of adrenal function and that release of melatonin by pineal gland could influence glucocorticoids

……….must look at the data on pineal-HPA connection must take into consideration the concentrations of melatonin and corticosterone concentrations used in trials and time of day –

..since high concentrations of corticosterone inhibit melatonin production, lower concentrations of steroids have no effect

……..in addition, dexamethasone appears to affect nocturnal, but not diurnal, production of melatonin

both melatonin and the glucocorticoids exhibit a circadian rhythm

Given the antioxidant role of melatonin, our results support the idea of melatonin-corticosterone coupling with the possibility that melatonin released in situations of stress counteracts the adverse effects of glucocorticoids on the organism.”

Refer to the article on the “night behaviors” of melatonin – at all like depression?


Birketvedt, Sundsfjord & Florholmen 2002

Abstract – Norway

“The typical neuroendocrine characteristics of the night eating syndrome have previously been described as changes in the circadian rhythm by an attenuation in the nocturnal rise of the plasma concentrations of melatonin and leptin and an increased circadian secretion of cortisol….have an overexpressed…[HPA] axis with an attenuated response to stress…..results showed that, in night eaters compared with controls, the CRH-induced ACTH and cortisol response was significantly decreased to 47 and 71% respectively.  In conclusion, disturbances in the …{HAP} axis with an attenuated ACTH and cortisol response to CRH were found in subjects with night-eating syndrome.”


Benedict et al 2008

abstract – Switzerland

Background: Secretory activity of the hypothalamo-pituitary–adrenal (HPA) axis typically increases during the second half of nocturnal sleep. Assuming that this rise in ACTH and cortisol levels occurs in response to the negative energy balance induced by nocturnal fasting and concomitant increases in cerebral glucose consumption during REM sleep, we examined the effects of glucose infusion on nocturnal HPA axis activity during wake and sleep periods.

Methods and findings: According to a 2×2 design, healthy men were infused with glucose (4.5 mg/kg×min) and saline, respectively, during sleep (n=9) or total sleep deprivation (n=11). Circulating concentrations of ACTH, cortisol, glucose, insulin, and leptin were measured and food consumption from a breakfast buffet presented on the subsequent morning was assessed. Independent of sleep, nocturnal secretion of ACTH and cortisol was suppressed by glucose infusion (glucose vs saline: ACTH, 11.93±0.77 vs 13.60±1.08 pg/ml; cortisol, 5.21±0.92 vs 7.20±0.79 μg/dl; each P<0.05). In the sleep group, glucose infusion enhanced REM sleep while reducing the time spent in sleep stage 2 (each P<0.05). Sleep deprivation per se was associated with a reduction in leptin levels compared to sleep (P<0.05). Following nocturnal glucose infusion, food intake was reduced in comparison to placebo in the wake but not in the sleep group (P<0.05 and P>0.82, respectively).

Conclusions: Our findings indicate that nocturnal HPA axis activity is blunted by increased plasma glucose concentrations, suggesting that the brain regulates nocturnal ACTH and cortisol release in response to the level of energy available in the form of blood glucose. Sleep does not appear to be critically involved in this glucose/glucocorticoid feedback loop.




Night eating syndrome

There are at least two problems that involve disordered eating primarily at night: night eating syndrome, which is discussed here, and nocturnal sleep-related eating disorder, which is described on another page on our site. We suggest you read the material on both so you will have a better understanding of these perplexing and distressing problems.

Signs and symptoms

  • The person has little or no appetite for breakfast. Delays first meal for several hours after waking up. Is not hungry or is upset about how much was eaten the night before.
  • Eats more food after dinner than during that meal.
  • Eats more than half of daily food intake during and after dinner but before breakfast. May wake up and leave the bed to snack at night. May not be aware at the time of what they are doing.
  • This pattern has persisted for at least two months.
  • Person feels tense, anxious, upset, or guilty while eating.
  • NES is thought to be stress related and is often accompanied by depression. Especially at night the person may be moody, tense, anxious, nervous, agitated, etc.
  • Has trouble falling asleep or staying asleep. Wakes frequently and then often eats.
  • Foods ingested are often carbohydrates: sugary and starchy.
  • Behavior is not like binge eating which is done in relatively short episodes. Night-eating syndrome involves continual eating throughout evening hours.
  • This eating produces guilt and shame, not enjoyment.

How many people have night-eating syndrome?

Perhaps only one to two percent (1-2%) of adults in the general population have this problem, but research at the University of Pennsylvania School of Medicine suggests that about six percent of people who seek treatment for obesity have NES. Another study suggests that more than a quarter (27%) of people who are overweight by at least 100 pounds have the problem.


Night-eating syndrome has not yet been formally defined as an eating disorder. Underlying causes are being identified, and treatment plans are still being developed. It seems likely that a combination of biological, genetic, and emotional factors contribute to the problem.

One theory postulates that people with this condition are under stress, either recognized or hidden. Their bodies are flooded with cortisol, a stress hormone. Eating may be the body’s attempt to neutralize cortisol or slow down its production..  more onsite



Nocturnal sleep-related eating disorder

There are at least two problems that involve disordered eating primarily at night: nocturnal sleep-related eating disorder, which is discussed here, and night eating syndrome, which is described on another page on our site. We suggest you read the material on both so you will have a better understanding of these perplexing and distressing problems.

When I woke up this morning, there were candy bar wrappers all over the kitchen, and I had a stomach ache. I had chocolate on my face and hands. My husband says I was up eating last night, but I have no memories of doing so. Could he be playing a joke on me?

Maybe not. You might have nocturnal sleep-related eating disorder, a relatively unknown condition currently being investigated.

What is nocturnal sleep-related eating disorder (NS-RED)?

In spite of its name, NS-RED is not, strictly speaking, an eating disorder. It is thought to be a type of sleep disorder in which people eat while seeming to be sound asleep. They may eat in bed or roam through the house and prowl the kitchen.

These people are not conscious during episodes of NS-RED, which may be related to sleep-walking. They are not aware that they are eating. They have no memories of having done so when they wake, or they have only fragmentary memories. Episodes seem to occur in a state somewhere between wakefulness and sleep.

When people with NS-RED awake and discover the evidence of their nighttime forays, they are embarrassed, ashamed, and afraid they may be losing their minds. Some, when confronted with the evidence by family members, deny that they were the perpetrators. They truly do not believe they could have done such a thing and cannot admit to such dramatic loss of control.

Food consumed during NS-RED episodes tends to be high-fat, high-sugar comfort food that people deny themselves while awake. Sometimes these folks eat bizarre combinations of food (hotdogs dipped in peanut butter, raw bacon smeared with mayonnaise, etc.) or non-food items like soap that they have sliced like cheese. –more onsite


Grivas & Savvidou 2007

Abstract – Greece

Melatonin has been used as a therapeutic chemical – tumors

May play role in biologic regulation of mood, affective disorders, cardiovascular system, reproduction and aging

Melatonin may play a role in the pathogenesis of scoliosis (neuroendocrine hypothesis) but data cannot clearly support this hypothesis


Zhdanova  2005

Abstract – Boston

diurnal species – melatonin secretion coincides with usual hours of sleep

.in contrast nocturnal animals are at the peak of their activity while producing melatonin

effects of melatonin on sleep are mediated via specific melatonin receptors

……aging reduces responsiveness to melatonin treatment and this correlates with reduced functional potency of melatonin receptors


van den Heuvel et al 2005

abstract – Australia

“Elevated melatonin levels from either endogenous nocturnal production or exogenous daytime administration are associated in humans with effects including increased sleepiness, reduced core temperature, increased heat loss and other generally anabolic physiological changes.  This supports the idea that endogenous melatonin increases nocturnal sleep propensity, either directly or indirectly via physiological processes associated with sleep….melatonin is primarily a neuroendocrine transducer promoting an increased propensity for ‘dark appropriate’ behavior.  Thus, it is our view that exogenous melatonin is only hypnotic in those species or individuals for which endogenous melatonin increases sleep propensity and is consequently a dark appropriate outcome…..melatonin can exert hypnotic-like effects but only under limited circumstances.”

Is this an interaction within the HPA axis, then?  Is “dark appropriate” behavior related to depression?


Au-Yong & Firth 2008

Internet case report

24 year old student, blind since birth – two years ago a passenger in father’s car involved in a road accident – father received back and shoulder injuries

has been experiencing flashbacks persisting through two years – nightmares same content as flashbacks – fulfils diagnostic criteria for PTSD

……unusual case, only one other case report in the literature – perceptions of sounds predominate his flashbacks – disturbed attention has profound effects on patient

“Sleep disturbance was a dominant feature of our patient’s illness.  A recent study showed that patients with visual impairment (not affected by PTSD) are at particular risk of sleep disturbance….because there is limited input of light to the suprachiasmatic nucleus, the central hypothalamic circadian clock via the optic nerves and retinohypothalamic tracts.  The suprachiasmatic nucleus in turn controls the pineal gland’s melatonin rhythm, which mediates the circadian sleep cycle.  The sleep-wake cycle is affected by other cues other than light (non-photic cues) and these include mealtimes, daily routine and emotional disturbances, such as those experienced by our patient.  The disturbance of daily routine by PTSD symptoms no doubt contributes to the patient’s sleep disturbance.”


Tabandeh et al 1998


388 blind subjects – (originally was 403 but depression assessment led to dismissal of 15 people) – comparison of 44 normally sighted controls


48.7% had sleep disturbance

.prevalence higher and sleep disturbance was more severe in those with no perception of light

in comparison group 9.1% had mild sleep disturbance only

.difference between groups was highly significant

.most common sleep-related problem among the blind subjects was interrupted sleep, followed by increased sleep latency, short sleep duration, and daytime naps


no author – article 1999-04-09

Sleep and Circadian Rhythms


circadian is Latin for “around a day”

.the suprachiasmatic nucleus or SCN is the body’s biological clock, pair of pinhead-sized brain structures that together contain about 20,000 neurons, rests in hypothalamus, just above the point where the optic nerves cross – photoreceptors in the retina tissue at back of eye create signals that travel along the optic nerve to SCN

……signals from SCN travel to several brain regions, including the pineal gland which responds to light-induced signals by switching off production of the hormone melatonin

……SCN also governs functions synchronized with sleep/wake cycle including body temperature, hormone secretion, urine production, changes in blood pressure

……how could this are not be connected to HPA?  Cortisol is on a circadian rhythm

Our innate biological clock is set to 25 hours [I’ve read 24 hours 11 minutes] but our biological cycles usually follow the 24 hour cycle of the sun

…..can be affected to some degree by noises in our environment and routines

……..light therapy used to help jet lag

…….lights many times brighter than ordinary household light – near the time the subjects want to wake, helps reset their biological clocks to adjust to new time zones

……………..shift workers have increased risk of heart problems, digestive disturbances, and emotional and mental problems, all of which may be related to their sleeping problems

….”Major industrial accidents including the Exxon Valdez oil spill and the Three Mile Island and Chernobyl nuclear power plant accidents happened by fatigued night-shift workers

.study found night shift interns are twice as likely to misinterpret hospital test records which can endanger patients

many blind people have a kind of permanent jet lag and periodic insomnia because their circadian rhythms follow their innate cycle rather than a 24-hour one

.high doses of most supplements for melatonin can create new problems because it builds up in the body – potential side effects are still largely unknown


Catani et al  2003

Article – UK

White matter – nature of occipital and temporal connections – detailed virtual dissection of the living brain using DT-MRI –

Inferior longitudinal fasciculus (ILF) – [A bundle of long association fibers running the length of the occipital and temporal lobes of the cerebrum]

“Our results suggest that in addition to the indirect connections of the occipito-temporal projection system:  (i) a major associative connection between the occipital and anterior temporal lobe is provided by a fibre bundle whose origin, course and termination are consistent with classical descriptions of the ILF in man and with monkey visual anatomy; (ii) the tractography-defined ILF is structurally distinct from fibres of the optic radiation and from U-shaped fibres connecting adjacent gyri; (iii) it arises in extrastriate visual ‘association’ areas; and (iv) it projects to lateral and medial anterior temporal regions.  While the function of the direct ILF pathway is unclear, it appears to mediate the fast transfer of visual signals to anterior temporal regions and neuromodulatory back-projections from the amygdale to early visual areas.”  Abstract Cantani et al 2003, p 2093

The tractography results show occipital branches related to areas V2 and V4 and anterior temporal branches related to the lateral temporal cortex, parahippocampal gyrus and amygdale.  The connections allow direct, fast access of visual information to anterior temporal structures and from anterior temporal structures to the occipital lobe.”  Cantani et al 2003, p 2094

[parahippocampal gyrus (or hippocampal gyrus) is a grey matter cortical region of the brain that surrounds the hippocampus

Semantic knowledge (e.g., long-established knowledge about objects, facts, and word meanings) is known to be severely impaired by damage to the anterolateral temporal lobe

[Occipital lobe:  part of the brain, located at the rear of the cerebrum, where vision is processed]


Eriksson et al 2003

Abstract – Finland

“… case of severe visual agnosia in a child with an electrophysiological pattern of continuous spike-wave discharges in slow sleep (CSWS) in the occipito-temporal regions. … Published paediatric reports associate visual agnosia (i.e. an inability to recognize objects without impairment of visual acuity) mainly with symptomatic occipito-temporal aetiology (e.g. cortical dysplasia, vascular insults) and other neurological symptoms (e.g. autism). We describe a detailed 2 year electrophysiological and neuropsychological follow-up of an 8-year-old boy with sporadic seizures, occipito-temporal CSWS and visual agnosia. The growth and neurological development of the child had been considered as normal, neurological examination did not reveal any focal signs, visual acuity was intact and MRI was normal. First EEG and six consecutive 24 h video EEG recordings during the follow-up of 22 months showed continuous spike-and-wave activity covering over 85% of the non-REM sleep… This case adds a new facet to the spectrum of neuropsychological deficits in children with CSWS. Sleep EEG should be included in the etiological studies of children with specific neuropsychological problems and detailed neuropsychological assessment is needed for diagnostic and rehabilitation purposes.


Harrison et al 2007


Article is with empathy


Ferreira et al 1998

Abstract – France

“Recognition of different kinds of visual stimuli was studied in a patient who acquired apperceptive visual agnosia after a bilateral occipitotemporal lesion which partially spared the primary visual cortex. Impairment in recognising static objects perceived visually sharply contrasts with the relatively well preserved ability to recognise objects from gestures illustrating their use, and to recognise actions shown in line drawings. It is suggested that the occipitoparieto-frontal pathway is involved in the recognition of actions, and in the recognition of objects when sensorimotor experience is evoked.”




Lewy et al 2006

Article – Portland, OR

Winter depression – seasonal affective disorder (SAD)

Use of melatonin administration in morning or afternoon/evening to induce phase delays or phase advances, respectively without causing drowsiness

“SAD may be the first psychiatric disorder in which a physiological marker correlates with symptom severity before, and in the course of, treatment in the same patients.  The findings support the phase-shift hypothesis for SAD, as well as suggest a way to assess the circadian component of other psychiatric, sleep, and chronobiologic disorders.”  Lewy et al 2006, abstract, p. 7414

two phase-resetting agents for treating circadian rhythm disorders are bright light and melatonin – “…latter being only option for totally blind people who cannot synchronize to day/night cycle or do so at abnormal time.”  Lewy et al 2006, p. 7414

“In females of childbearing age, SAD is perhaps the most common mood disturbance unremittingly experienced year after year during the 6 months between the autumnal and vernal equinoxes at temperate latitudes, such as the northern United States and lower provinces of Canada…where there are marked season changes in natural day length (photoperiod).” Lewy et al 2006, p. 7414

“The [circadian phase-shift hypothesis] PSH is based on the seminal concept that some affective disorders might be at least partly due to a mismatch in circadian rhythms…specifically, between those rhythms related to the sleep/wake cycle and those that are more tightly coupled to the endogenous circadian pacemaker (located in the suprachiasmatic nuclei of the hypothalamus).”  Lewy et al 2006, p. 7414

“Induction of phase shifts by some agent other than light is a critical test of the PSH.  Melatonin is ideal for this purpose, because this “chemical signal of darkness” is thought to be opposite of light….melatonin must be taken at the opposite half of the photoperiod than when bright light is scheduled….”  Lewy et al 2006, p. 7414

“…the clinical benefit [for melatonin treatment]appears to be substantial, although not as robust as light treatment….”  Lewy et al 2006, p. 7418

“…most SAD patients might benefit from an appropriate low-dose formulation of melatonin taken in the afternoon.”  Lewy et al 2006, p. 7418





Goto & Grace 2008

abstract – Montreal

The nucleus accumbens

……….regulates goal-directed behaviors by integrating information from limbic structures and the prefrontal cortex.

Here, we review recent studies in an attempt to provide an integrated view of the control of information processing in the nucleus accumbens

……. in terms of the regulation of goal-directed behaviors

………….and how disruption of these functions might underlie the pathological states in drug addiction and other psychiatric disorders.

We propose a model that could account for the results of several studies investigating limbic-system interactions in the nucleus accumbens

……….and their modulation by dopamine and provide testable hypotheses for how these might relate to the pathophysiology of major psychiatric disorders.


Grace et al 2007

Abstract – U of Pittsburgh

There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders.

These systems include the

……ventral hippocampus, which is involved in context and focus on tasks,

…..the amygdala, which mediates emotional behavior, and

…..the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility.

Each of these systems has overlapping projections to the

………nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine.

Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions

……… and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.


Beninger & Banasikowski 2008

Abstract – Ontario

Dopamine D(3) receptors (Drd3) have been

……….implicated in the control

……….of responding by

………..drug-related conditioned incentive stimuli.

We review recent studies of the effects of Drd3 antagonists or partial agonists on the control of self-administration of intravenous (IV) cocaine, IV morphine and oral ethanol

……….on reward-rich and lean schedules, in reinstatement tests, on second-order schedules and on the acquisition and expression of conditioned place preference (CPP) and conditioned motor activity.

For comparison, related studies where conditioned stimuli are based on nutritional reward also are considered.

When self-administration depends more heavily on conditioned cues for its maintenance, for example on second-order schedules or lean ratio schedules, Drd3 antagonists or partial agonists reduce responding.

………..Although data are limited, similar effects may be seen for responding for cues based on drugs or nutritional rewards.

Drd3 agents also block the ability of conditioned cues to reinstate responding

………for cocaine or food.

Published results suggest that Drd3 plays a more important role

………in the expression

………..than in the acquisition of a CPP or conditioned motor activity.

The mechanism mediating the role of Drd3 in the control of responding by conditioned incentive stimuli remains unknown but

………. it has been found that Drd3 receptors increase in number in the nucleus accumbens during conditioning.

……….Perhaps Drd3 participates in the molecular mechanisms underlying the role of dopamine and of dopamine receptor subtypes in reward-related incentive learning.


Passos et al 2008

Abstract –  Brazil

Prolactin (PRL) secretion and its gene expression are

………..inhibited by dopamine.

………Prolactinomas are the most common secreting pituitary adenomas, and dopamine agonists (DA) are the first choice for their treatment. However, a subset of patients is resistant to DA. As the mechanisms involved in DA resistance are not fully understood, the aim of this study was to obtain new insights regarding the molecular differences between the prolactinomas that are responsive to DA and those that are resistant.

Methods: Tumor tissue samples were collected from 17 patients who harbored prolactinomas, which were classified as responsive or resistant according to their clinical and laboratorial reaction to DA.

………The expression of 6 genes was evaluated

……..dopamine receptor type 2 (DRD(2)),

…………nerve growth factor-beta (NGFB) and its receptor (NGFR),

………….estrogen receptor-alpha (ERA),

…………..estrogen receptor-beta (ERB) and the

………….pituitary tumor transforming gene (PTTG).

Results: Median DRD(2) and NGFR expression in responsive patients was significantly higher than in resistant ones

………..Moreover, the expressions of DRD(2) and NGFR were positively correlated with PRL decrease during treatment

………. Furthermore, ERB expression was positively correlated to PTTG expression …and negatively correlated to NGFB expression

Conclusions: DRD(2) and NGFR expressions are related to the responsiveness of prolactinoma to DA. However, PTTG, ERB and ERA expressions are not. Also ERB, ERA and PTTG expressions did not present a clear correlation to tumor aggressiveness. Furthermore, the response of prolactinomas [tumors of pituitary lactotrophs that produce prolactin] to DA should be viewed as a spectrum ranging from the most responsive to the most resistant ones.


Wallace & Hughes 2008

Abstract – Ohio State U

Results from several experiments monitoring extracellular dopamine (DA) after stimulating axons at high frequencies have been interpreted as evidence for release from two populations of vesicles in dopaminergic varicosities [refers to dilated, tortuous veins which result from incompetent values within those veins].

………….In addition, these experiments have suggested that cocaine and other dopamine transporter (DAT) inhibitors promote transfer of vesicles or dopamine itself from a reserve pool to a readily available pool.

…………We developed a computer model simulation of these experiments with the goal of determining a set of mathematical formulas that describe dopamine movement between multiple storage compartments.

……….However, the simulations show that data can be accurately simulated with release largely from a homogeneous population of vesicles, and

……..that effects of dopamine transporter inhibitors can be explained without requiring that these drugs promote movement of dopamine from a reserve to an available pool.

…………The data also suggest that dopamine recycling is highly efficient, even under high-frequency signaling conditions, and that the “kiss and run” mechanism of dopamine release probably predominates under conditions of very rapid neuron firing.


Zhang, Zhou & McMahon 2007

Abstract – Nashville

Dopaminergic neurons play key roles in the CNS, mediating basic mechanisms of vision, movement, motivation, and mood.

The most accessible dopaminergic neurons of the vertebrate CNS are the dopaminergic amacrine cells of the retina. Here, we have characterized the intrinsic neural activity, synaptic input, and light responses of retinal dopaminergic neurons in situ, using targeted electrophysiological recordings of fluorescent neurons in TH::RFP (tyrosine hydroxylase gene promoter: red fluorescent protein) transgenic mice.

…………Dopaminergic amacrine cells exhibit

………. two classes of intrinsic bursting in the dark, shaped by inhibitory synaptic inputs, and

………….two classes of light responses, ON-transient and ON-sustained,

as well as light-independent activity, tuned to mediate specific dopaminergic functions in vision.

The functional heterogeneity revealed in dopaminergic amacrine cells provides a cellular basis for the multiple roles of dopaminergic amacrine neurons in vision and is likely a general property of dopaminergic neurons throughout the CNS.


Brandies & Yehuda 2008

Abstract – Israel

It is a well-known fact that the retina is one of the tissues in the body, which is richest in dopamine (DA), yet the role of this system in various visual functions remains unclear.

……… We have identified 13 types of DA retinal pathologies, and 15 visual functions. The pathologies were arranged in this review on a net grid, where one axis was “age” (i.e., from infancy to old age) and the other axis the level of retinal DA (i.e., from DA deficiency to DA excess, from Parkinson disorder to Schizophrenia). The available data on visual dysfunction(s) is critically presented for each of the DA pathologies. Special effort was made to evaluate whether the site of DA malfunction in the different DA pathologies and visual function is at retinal level or in higher brain centers. The mapping of DA and visual pathologies demonstrate the pivot role of retinal DA in mediating visual functions and

………….also indicate the “missing links” in our understanding of the mechanisms underlying these relationships.


Bartell et al 2007

Abstract – VA

Circadian physiology in the vertebrate retina is regulated by several neurotransmitters. In the lateral eyes of the green iguana the circadian rhythm of melatonin content peaks during the night while the rhythm of dopamine peaks during the day. In the present work, the authors explore the interaction of these 2 neurotransmitters during the circadian cycle. They depleted retinal dopamine with intravitreal injections of 6-hydroxydopamine (6-OHDA) and measured ocular melatonin content in vivo throughout 1 circadian cycle. The circadian rhythm of ocular melatonin not only persisted but increased 10-fold in amplitude. This increase was substantially reduced by the intraocular administration of dopamine. 6-OHDA-treated retinas, unlike those from untreated animals, did not express a circadian rhythm of melatonin synthesis in vitro. To deplete retinal melatonin, the authors pinealectomized iguanas and blocked retinal melatonin synthesis by depleting serotonin with intraocular injections of 5,6-dihydroxytryptamine. In animals so treated, they found that the circadian rhythm of retinal dopamine content was abolished, the levels of dopamine were lowered, and the levels of dopamine metabolites were greatly increased. The data suggest that in iguanas, the amplitude of the circadian rhythm of melatonin synthesis in the eye is suppressed by dopamine while the rhythm of dopamine depends, at least in part, on the presence of melatonin.


Racagni, Riva & Popoli 2007

Abstract – Italy

Sleep disturbances are often associated with depression and mood disorders, and certain manipulations of the sleep-wake cycle are effective as therapeutic interventions in the treatment of depression. Dysregulated circadian rhythms are thereby considered as causal.

Circadian rhythms in mammals are mainly regulated by a core biological clock, located in the hypothalamic suprachiasmatic nucleus; its pacemaker activity is regulated by light and nonphotic modulatory pathways, and the driving mechanisms are serotonergic input from the raphe and the hormone melatonin originating from the pineal gland.

In line, the concentration of brain serotonin and the levels of 5-HT2C receptors are high and highly expressed there. Agomelatine, a novel antidepressant drug with proven clinical efficacy in major depressive disorder, has a unique mechanism of action; it acts as an agonist at melatonergic MT1 and MT2 receptors and as an antagonist at 5-HT2C receptors. In animals, agomelatine was shown to increase noradrenaline and dopamine (but not serotonin) in the frontal cortex, to resynchronize the sleep-wake cycle in models with disrupted circadian rhythms, and to exhibit a clear antidepressant effect in various animal models of depression. On the basis of the functional relationship between melatonergic and serotonergic signaling in the suprachiasmatic nucleus, and given agomelatine’s affinity at melatonergic and 5-HT2C receptors, the therapeutic efficacy of the drug may be due to the potential synergy of its action at these different receptors.


Mateo et al 2004

Abstract – US

The mesolimbic dopaminergic system,

………especially the nucleus accumbens,

has received attention for its involvement in the reinforcing and addictive properties of cocaine and other drugs of abuse.

……….It is generally accepted that the ability of cocaine to inhibit the dopamine transporter (DAT) is directly related to its reinforcing actions. …………However, mice with a genetic deletion of the DAT (DAT-KO mice) still experience the rewarding effects of cocaine.

………..These behavioral findings suggest that there is an alternate site for cocaine reinforcement.

We demonstrate here that

………modulation of the serotonergic system in the

ventral tegmental area,

……….where the mesolimbic dopamine system originates, is a target of cocaine action.

………….The ultimate effect of this serotonin mechanism in animal models with sustained elevations of dopamine may be a


…………enhancement of dopamine levels in the nucleus accumbens. Mateo et al 2004, abstract

“Cocaine is one of the most powerful drugs of abuse known. Despite this fact, to this date there are no effective medications for cocaine abuse, dependence, or withdrawal.” P 1 online

“Although cocaine also binds to serotonin and norepinephrine transporters, the predominant hypothesis has been that the reinforcing effects of cocaine are related to its ability to inhibit the dopamine transporter (DAT), especially in the NAc”

Serotonin has also been implicated in the paradoxical calming effect that psychostimulants have on locomotor hyperactivity in DAT-KO mice

….. dopamine cell bodies in the ventral tegmental area (VTA) have been implicated as important targets of cocaine reinforcement in these mice (12).

high density of serotonin immunoreactive fibers in the VTA

existence of a functional relationship between serotonin and dopamine neurons in the mesolimbic dopamine system has been confirmed

Psychostimulant-induced neuroadaptations in the VTA have also been reported to play an important role in the sensitization process …. In addition, 5-HT1B serotonin receptors have been shown to modulate the effects of cocaine

… rule out the possibility that the SERT is an alternative site for dopamine clearance in DAT-KO mice… Therefore, SERT inhibition does not affect dopamine clearance. This result leaves elevated VTA serotonin as the most likely mediator of cocaine effects.

In a previous study (12), our laboratory began to narrow the possibilities by showing that, contrary to published hypotheses (11), cocaine did not alter dopamine uptake in the NAc of DAT-KO mice. The main findings from the present study are that a serotonin mechanism is present in the VTA of DAT-KO mice that, when activated, leads to an increase in dopamine levels in the NAc, just as cocaine does by DAT blockade in wild-type animals. This serotonin mechanism is not present in naive wild-type mice and could be mediating the reinforcing properties of cocaine and fluoxetine in the DAT-KO mice.

The interactions between dopamine and serotonin systems have been an extensive subject of study. Neuroanatomical studies have shown a high density of serotonin immunoreactive fibers in the VTA (13), and there is evidence that the mesolimbic dopaminergic system originating in the VTA is under inhibitory control by the serotonin system, although the situation is complex (1315). There is evidence suggesting that the serotonin system can negatively modulate cocaine-maintained behaviors. For example, the reinforcing efficacy of cocaine can be enhanced by partial depletion of brain serotonin (33), and increasing serotonin activity may attenuate the reinforcing effects of this drug (3436). Although serotonin-specific drugs do not seem to have significant reinforcing efficacy (37, 38), serotonin could play a different role in animals with chronically elevated dopamine, as occurs in DAT-KO mice or in wild-type animals after pharmacological blockade of the DAT or other pathophysiological conditions.

Although a serotonin-mediated mechanism has been postulated previously to mediate the rewarding effects of cocaine in animals with a genetic deletion of the DAT (8, 9), noradrenergic neurotransmission has also been implicated.

There is considerable crosstalk between dopaminergic, noradrenergic, and serotonergic systems that occurs on systemic administration of cocaine (43), and more studies are needed to define the importance of each monoamine and the role of the VTA in the reward process (44).

These results indicate that serotonin does play a different role in animals with reduced dopamine transporter function.  This demonstration of the induction of a VTA serotonin “switch” in wild-type animals makes the DAT-KO findings relevant to other cases of chronic DAT blockade. This switch/alteration may be mediated by changes in serotonin receptors and/or effectors regulating VTA dopamine neurons.  Of the 14 characterized serotonin receptors (47), there is a sizeable amount of literature supporting a functional role for 5-HT2A and 5-HT2C receptors in the regulation of dopamine neurotransmission (48, 49). Other serotonin receptor subtypes, including 5-HT3 and 5-HT1A, have also been shown to modulate the activity of mesolimbic dopaminergic cells in the VTA (49, 50). In addition, serotonin actions at 5-HT1B receptors in the VTA modulate cocaine-induced dopamine release in then NAc and alter the rewarding and stimulant properties of cocaine (23). A recent report (22) indicated that elevated expression of 5-HT1B receptors in the VTA increased cocaine-induced locomotor hyperactivity and also shifted the dose-response curve for cocaine-CPP to the left, suggesting enhanced rewarding effects of cocaine. The additional use of anatomical and physiological approaches will be necessary to clarify the complex roles of these serotonin receptors in cocaine addiction.

Taken together, these findings describe a serotonin “switch” that occurs in the VTA after reduced DAT function, as in the case of a genetic deletion of the DAT or treatment with a long-acting DAT inhibitor, and mediates the effects of cocaine. In pathophysiological conditions that involve an elevated dopamine tone, this switch in serotonin function may cause cocaine to induce a potentiated enhancement of dopamine levels in the NAc.


Bozina et al 2006

Abstract – Croatia

OBJECTIVES: Differences in serotonin transporter (SERT) expression and function produced by gene polymorphisms are associated with several behavioral and psychiatric traits. Two polymorphic regions of SERT gene: a 44-base-pair (bp) insertion / deletion polymorphism in the promoter region (SERTPR), and variable number of tandem repeats (VNTR) in second intron (SERT-in2) have been characterized. In this study we investigated the frequency distribution of polymorphic variants of short (S, s) and long (L, l) alleles, genotypes and haplotypes of SERTPR, and SERTin2, in patients with major depressive disorder (MDD) and compared it with results obtained from the Croatian healthy population. SUBJECTS AND METHODS: one hundred and fourteen patients who fulfilled DSM-IV criteria for a diagnosis of MDD were included in the study. Comparisons were made with the results obtained for 120 healthy volunteers representing a mixed Croatian population. SERT genotyping was performed by the PCR (polymerase-chain reaction) method. RESULTS: The frequency distribution of L and S alleles and genotypes of SERTPR was not statistically different between MDD patients and control participants. The proportion of SERT-in2 short (s) alleles was significantly higher among MDD patients in comparison to healthy subjects (p = 0.04).

CONCLUSION: “s” allele variant in the intron 2 of SERT gene could be associated with susceptibility to MDD.


Dorado et al 2007

Abstract – Spain

In the present study, we aimed to analyze the potential relevance of the polymorphism in the promoter region of the serotonin transporter (SERT or 5-HTT) gene (5-HTTLPR) and the risk of suffering major depression (MDD) in a population of patients previously genotyped for CYP2C9.

……..Seventy white European psychiatric outpatients suffering from MDD and a group of 142 healthy volunteers (HVs) were studied.

……The frequency of subjects carrying the

….. 5-HTTLPR-S allele was higher (P < 0.05) among MDD than in HV. The odds ratio associated with 5-HTTLPR-S allele was 2.03 for the MDD patients in comparison with the HV group. Previously, we found in this population that the CYP2C9*3 allele frequency was higher among this population of MDD patients than in HV.

The frequency of subjects with the combination 5-HTTLPR-S and CYP2C9*3 alleles was higher (P < 0.01, odds ratio 3.47) in MDD than in HV.

The present findings provide preliminary evidence about the greater risk of suffering MDD for individuals carrying

…. both 5-HTTLPR-S

……..and CYP2C9*3 alleles.

So we could equally as well ask why everyone with these allele combinations do not suffer from depression!  We can ask how we feel and what we think – and then ask how and what in our genes is determining these outcomes, because we cannot feel and think separate from what is on the inside of the inside of us.  We therefore are learning through genetic studies to see even more clearly into our insides where the division between who we are and who we think we are, between how we operate in comparisons to others – is affected so differently from the core of who we are, which lies in our genetic code – which manifests in interaction with our environment – and somehow in interaction with our “self.”  We are the offspring of the people before us who have left us with these genes – our inheritance, their legacy.


Heinz et al 2007

Abstract – Department of Psychiatry, Charité University Medicine Berlin, Campus Charité Mitte, Germany.

BACKGROUND: A polymorphism of the human serotonin transporter gene (SCL6A4) [(5-HTTLPR):] has been associated with serotonin transporter expression and with processing of aversive stimuli in the amygdala. Functional imaging studies show that during the presentation of aversive versus neutral cues, healthy carriers of the short (s) allele showed stronger amygdala activation than long (l) carriers.

However, a recent report suggested that this interaction is driven by amygdala deactivation during presentation of neutral stimuli in s carriers. METHODS: Functional MRI was used to assess amygdala activation during the presentation of a fixation cross or affectively aversive or neutral visual stimuli in 29 healthy men. RESULTS: Amygdala activation was increased in s carriers during undefined states such as the presentation of a fixation cross compared with emotionally neutral conditions. CONCLUSIONS: This finding suggests that

s carriers show stronger amygdala reactivity

to stimuli and contexts that are

relatively uncertain,

which we propose are stressfull


Dannlowski et al 2008b

Abstract – [1] 1Department of Psychiatry, University of Münster, Münster, Germany [2] 2IZKF-Research Group 4, IZKF Münster, University of Münster, Münster, Germany.

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. Increased amygdala reactivity has been discussed in the context of major depression.

Recent studies reported that amygdala activity during conscious emotion processing is modulated by a functional polymorphism in the serotonin transporter gene (5-HTTLPR) in healthy subjects. In the present study, amygdala reactivity to displays of emotional faces was measured by means of fMRI at 3T in 35 patients with major depression and 32 healthy controls. Conscious awareness of the emotional stimuli was prevented via backward-masking to investigate automatic emotion processing. All subjects were genotyped for the 5-HTTLPR polymorphism.

Risk allele carriers (S or L(G)) demonstrated increased

amygdala reactivity to masked emotional faces,

which in turn was significantly correlated with life-time

psychiatric hospitalization as an index of chronicity.

This might indicate that genetic variations of the serotonin transporter could increase the risk for depression chronification via altering limbic neural activity on a

preattentive level of emotion processing.

How might this polymorphism be affected differently after major childhood maltreatment?


Masuda 2008

Abstract – Department of Psychology, University of Alberta, Edmonton, AB, Canada. tmasuda@ualberta.ca

Two studies tested the hypothesis that in judging people’s emotions from their facial expressions, Japanese, more than Westerners, incorporate information from the social context. In Study 1, participants viewed cartoons depicting a happy, sad, angry, or neutral person surrounded by other people expressing the same emotion as the central person or a different one. The surrounding people’s emotions influenced Japanese but not Westerners’ perceptions of the central person.

These differences reflect differences in attention, as indicated by eye-tracking data (Study 2): Japanese looked at the surrounding people more than did Westerners.

Previous findings on East-West differences in contextual sensitivity generalize to social contexts, suggesting that

Westerners see emotions as individual feelings, whereas

Japanese see them as inseparable from the feelings of the group.


Marsh, Elfenbein & Ambady 2003

Abstract – Department of Psychology, Harvard University, Cambridge, MA 02138, USA. amarsh@wjh.harvard.edu

We report evidence for nonverbal “accents,” subtle differences in the appearance of facial expressions of emotion across cultures. Participants viewed photographs of Japanese nationals and Japanese Americans in which posers’ muscle movements were standardized to eliminate differences in expressions, cultural or otherwise. Participants guessed the nationality of posers displaying emotional expressions at above-chance levels, and with greater accuracy than they judged the nationality of the same posers displaying neutral expressions. These findings indicate that facial expressions of emotion can contain nonverbal accents that identify the expresser’s nationality or culture.

Cultural differences are intensified during the act of expressing emotion, rather than residing only in facial features or other static elements of appearance. This evidence suggests that extreme positions regarding the universality of emotional expressions are incomplete.


ties in with information on facial expressions and emotion in attachment


Simon et al 2008

Abstract – Department of Clinical Psychology, Humboldt University of Berlin, Germany. daniela.simon@psychologie.hu-berlin.de

Facial expressions of pain and emotions provide powerful social signals, which impart information about a person’s state. Unfortunately, research on pain and emotion expression has been conducted largely in parallel with few bridges allowing for direct comparison of the expressive displays and their impact on observers. Moreover, although facial expressions are highly dynamic, previous research has relied mainly on static photographs. Here we directly compare the recognition and discrimination of dynamic facial expressions of pain and basic emotions by naive observers. One-second film clips were recorded in eight actors displaying neutral facial expressions and expressions of pain and the basic emotions of anger, disgust, fear, happiness, sadness and surprise. Results based on the Facial Action Coding System (FACS) confirmed the distinct (and prototypical) configuration of pain and basic emotion expressions reported in previous studies. Volunteers’ evaluations of those dynamic expressions on intensity, arousal and valence demonstrate the high sensitivity and specificity of the observers’ judgment. Additional rating data further suggest that,

for comparable expression intensity, pain is perceived as more arousing and more unpleasant.

This study strongly supports the claim that the facial expression of pain is distinct from the expression of basic emotions. This set of dynamic facial expressions provides unique material to explore the psychological and neurobiological processes underlying the perception of pain expression, its impact on the observer, and its role in the regulation of social behavior.

Do expressions of emotional and physical pain look the same?  Do people respond to them the same way?  How do we know the difference between sadness and pain?  This study is saying that perception and expression of sadness differs from pain.


Jermann, van der Linden & D’Argembeau 2008

Abstract – Geneva University Hospitals, Adult Psychiatry Department, University of Geneva, Geneva, Switzerland. Francoise.Jermann@hcuge.ch

Relatively few studies have examined memory bias for social stimuli in depression or dysphoria. The aim of this study was to investigate the influence of depressive symptoms on memory for facial information. A total of 234 participants completed the Beck Depression Inventory II and a task examining memory for facial identity and expression of happy and sad faces.

For both facial identity and expression, the recollective experience was measured with the Remember/Know/Guess procedure (Gardiner & Richardson-Klavehn, 2000). The results show no major association between depressive symptoms and memory for identities. However,

dysphoric individuals consciously recalled (Remember responses) more sad facial expressions than non-dysphoric individuals.

These findings suggest that sad facial expressions led to more elaborate encoding, and thereby better recollection, in dysphoric individuals.


Lee et al 2008

Abstract – Department of Psychiatry, The Catholic University of Korea, Seoul, Korea.

We investigated the neural basis underlying the effect of race on incidental facial emotional processing using functional MRI. Thirteen healthy Korean men underwent functional MRI while viewing photographs of Korean (own-race) and Caucasian (other-race) emotional faces while performing a sex discrimination task.

Responses to other-race relative to own-race neutral faces replicated previous studies: activations were obtained in dorsolateral prefrontal cortex/medial frontal cortex.

Direct contrasts between-race emotional faces (happy and sad) also showed differential effects: the

contrast of own-race relative to other-race had more activations in limbic areas (amygdala and hippocampus), whereas the

contrast of other-race relative to own-race had more activations in frontal, occipital, and parietal lobes. Our findings provide evidence for differential processing of emotional faces as a function of race.


Kronenberg et al 2007

Abstract – Israel

OBJECTIVE: The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram [Citalopram is a selective serotonin reuptake inhibitor (SSRI) antidepressant drug that is sold in the United States under brand name Celexa] effectiveness and side effects in children and adolescents with major depressive disorder (MDD) and/or anxiety disorders.

METHODS: Outpatients, aged 7- 18 years with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) MDD and/or anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. Subjects were genotyped with respect to short (s) versus long (l) forms of the 5-HTTLPR polymorphism of the serotonin transporter, and the relationship between genotype and outcome and side effects was assessed. RESULTS: Subjects with 5-HTTLPR ss genotype showed a less vigorous response with regard to depressive symptoms measured by the Children’s Depression Rating Scale-Revised (CDRS-R) scores over time compared to subjects with sl/ll genotypes (beta = 0.67, z = 2.02, p = 0.04). In addition, the 5-HTTLPR ss group exhibited lower rates of agitation compared to those with sl/ll genotype (6.3% vs. 32.8%, p = 0.05).

……..Also, subjects with 5-HTTLPR ss genotype had consistently higher scores of suicidality at each week compared to the sl/ll group (beta = 0.76, z = 2.04, p = 0.04) as measured by item number 13 of the CDRS-R. CONCLUSIONS: The 5-HTTLPR ss genotype was associated with a poorer clinical response with regard to depressive symptoms as well with fewer reports of agitation. The 5-HTTLPR polymorphism may be a genetic marker of response to citalopram in children and adolescents with depression and/or anxiety.


Zalsman et al 2006

Abstract – NY

OBJECTIVE: The lower expressing allele of the serotonin transporter gene 5′ promoter region (5-HTTLPR) polymorphism is reported to be

……..associated with susceptibility to depression and suicidality

……………in response to stressful life events.

The authors examined the relationship of a triallelic 5-HTTLPR polymorphism to stressful life events, severity of major depression, and suicidality. METHOD: Mood disorder subjects (N=191) and healthy volunteers (N=125), all Caucasian subjects of European origin, were genotyped for the triallelic 5-HTTLPR polymorphism (higher expressing allele: L(A); lower expressing alleles: L(G), S). All subjects underwent structured clinical interviews to determine DSM-IV diagnoses, ratings of psychopathology, stressful life events, developmental history, and suicidal behavior. CSF 5-HIAA was assayed in a subgroup of subjects.

RESULTS: Lower expressing alleles independently predicted greater depression severity and predicted greater severity of major depression with moderate to severe life events compared with the higher expressing L(A) allele.

………. No associations with suicidal behavior and CSF 5-HIAA were found. CONCLUSIONS:

Lower expressing transporter alleles, directly and by increasing the impact of stressful life events on severity, explain 31% of the variance in major depression severity. The biological phenotype responsible for these effects remains to be elucidated.


Hayden et al 2008

Abstract – Ontario

Serotonin transporter promoter (5-HTTLPR) genotype appears to increase risk for depression

in the context of stressful life events.

However, the effects of this genotype on measures of stress sensitivity are poorly understood.

………Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood.

Well, in my case, there certainly wasn’t any POSITIVE way to process the information I was given through that horrific abuse!

METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene.

How did they measure their negative experiences?

RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes.

……5-HTTLPR genotype was not significantly associated with positive schematic processing.

LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the “stress-sensitivity” conferred by this genotype.


Hariri et al 2005

Abstract – Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland 20892-1384, USA.

BACKGROUND: A common regulatory variant (5-HTTLPR) in the human serotonin transporter gene (SLC6A4), resulting in altered transcription and transporter availability, has been associated with vulnerability for affective disorders, including anxiety and depression.

A recent functional magnetic resonance imaging study suggested that this association

may be mediated by 5-HTTLPR effects

on the response bias of the human amygdala

a brain region critical for emotional and social

behavior-to environmental threat.

Well, this could certainly be a “giant step” in creating individual variations as per dove and hawk in relation to sensitivities to self in regard to the environment!

OBJECTIVES AND DESIGN: To examine the effects of 5-HTTLPR genotype on the reactivity of the human amygdala to salient environmental cues with functional magnetic resonance imaging in a large (N = 92) cohort of volunteers carefully screened for past and present medical or psychiatric illness, and to explore the effects of 5-HTTLPR genotype as well as amygdala reactivity on harm avoidance, a putative personality measure related to trait anxiety.

RESULTS: We now confirm the finding of 5-HTTLPR short allele-driven amygdala hyperreactivity in a large independent cohort of healthy subjects with no history of psychiatric illness or treatment.

Furthermore, we demonstrate that these genotype effects on amygdala function are consistent with a dominant short allele effect and are equally prominent in men and women.

However, neither 5-HTTLPR genotype,

amygdala reactivity,

nor genotype-driven variability in this reactivity

was reflected in harm avoidance scores.

CONCLUSIONS: Our results reveal a potent modulatory effect of the 5-HTTLPR on amygdala reactivity to environmental threat. Since this genetically driven effect exists in healthy subjects, it does not, in and of itself, predict dimensions of mood or temperament.

As such, the 5-HTTLPR may represent

a classic susceptibility factor for affective disorders

by biasing the functional reactivity of the human amygdala

in the context of stressful life experiences

and/or deficient cortical regulatory input.

Interesting that this same polymorphism is connected to an altered resting brain state


Pezawas et al 2005

Abstract – Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, 10 Center Drive 4S235, Bethesda, Maryland 20892-1379, USA.

“5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression”

Carriers of the short allele of a functional 5′ promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression.

Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed

reduced gray matter volume in short-allele carriers

in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala.

Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect.

Short-allele carriers

showed relative uncoupling of this circuit.

Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These

genotype-related alterations in anatomy and function

of an amygdala-cingulate feedback circuit

critical for emotion regulation

implicate a developmental, systems-level mechanism

underlying normal emotional reactivity and genetic susceptibility for depression.

What are the contextual interactions for this effect if it is developmental?  This information seems to totally overlap with the cannabinoid information!


Rao et al 2007

Abstract – Center for Functional Neuroimaging, Department of Neurology and Radiology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. hengyi@mail.med.upenn.edu

default mode network

Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4)

on resting brain function of healthy individuals.

METHODS: Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. RESULTS: Compared with the l/l group,

the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood.

The 5-HTTLPR genotype

alters resting brain function

in emotion-related regions in healthy individuals,

including the amygdala and ventromedial prefrontal cortex.

Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.

How is resting brain function related to genetic susceptibility for mood disorders?  Does increased blood flow mean more noise?

I wanted to put resting brain with self – but here it is showing up with serotonin gene!


Ghosh et al 2008

Abstract – Theoretical Neuroscience Group, Institut des Sciences du Mouvement, Marseille, France. Anandamohan.GHOSH@univmed.fr

default mode network

Traditionally brain function is studied through measuring physiological responses in controlled sensory, motor, and cognitive paradigms. However, even at rest, in the absence of overt goal-directed behavior, collections of cortical regions consistently show temporally coherent activity.

In humans, these resting state networks have been shown to

greatly overlap with functional architectures

present during consciously directed activity,

which motivates the interpretation of rest activity

as day dreaming, free association, stream of consciousness, and inner rehearsal.

Here is where I see it overlapping with information on the SELF – reference

In monkeys, it has been shown though that similar coherent fluctuations are present during deep anesthesia when there is no consciousness. Here, we show that comparable resting state networks emerge from a stability analysis of the network dynamics using biologically realistic primate brain connectivity, although anatomical information alone does not identify the network. We specifically demonstrate that noise and time delays via propagation along connecting fibers are essential for the emergence of the coherent fluctuations of the default network.

The spatiotemporal network dynamics evolves on multiple temporal scales and displays the intermittent neuroelectric oscillations in the fast frequency regimes, 1-100 Hz, commonly observed in electroencephalographic and magnetoencephalographic recordings, as well as the hemodynamic oscillations in the ultraslow regimes, <0.1 Hz, observed in functional magnetic resonance imaging.

So this is the brain exploring itself?

The combination of anatomical structure

and time delays creates a space-time structure

in which the neural noise enables the brain

to explore various functional configurations

representing its dynamic repertoire.


Greicius et al 2008

Abstract – Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, CA 94305-5719, USA. greicius@stanford.edu

default mode network

Resting-state functional connectivity magnetic resonance imaging (fcMRI) studies constitute a growing proportion of functional brain imaging publications. This approach detects temporal correlations in spontaneous blood oxygen level-dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Although distinct resting-state networks related to vision, language, executive processing, and other sensory and cognitive domains have been identified, considerable skepticism remains as to whether resting-state functional connectivity maps reflect neural connectivity or simply track BOLD signal correlations driven by nonneural artifact. Here we combine diffusion tensor imaging (DTI) tractography with resting-state fcMRI to test the hypothesis that resting-state functional connectivity reflects structural connectivity. These 2 modalities were used to investigate connectivity within the

default mode network, a set of brain regions-including

medial prefrontal cortex (MPFC),

medial temporal lobes (MTLs), and

posterior cingulate cortex (PCC)/retropslenial cortex (RSC)-implicated in episodic memory processing. Here again, with episodic memory, I suspect that the default mode relates to self information processing

Using seed regions from the functional connectivity maps, the DTI analysis revealed

robust structural connections between the MTLs and the retrosplenial cortex whereas tracts from the MPFC contacted the PCC (just rostral to the RSC).

The results demonstrate that resting-state functional connectivity reflects structural connectivity and that combining modalities can enrich our understanding of these canonical brain networks.


Greicius et al. 2003

Default mode

Certain brain regions show greater activity during resting than during cognitive (e.g. working memory) tasks including

PCC – posterior cingulate cortex

vACC – ventral anterior cingulate cortex

These regions “constitute a network supporting a default mode of brain function”

…..they are functionally connected during rest

PCC strongly coupled with vACC and “several other brain regions implicated in the default mode network”

the functional connectivity maps of the PCC and vACC during visual processing task “are virtually identical to those obtained during rest.”

(Which ones?) – “all three lateral prefrontal regions and PCC” decrease activity from default mode to resting during active cognitive processing tasks

“provides the most compelling evidence to date for the existence of a cohesive default mode network….is modulated by task demands….”


Greicius et al 2007


In depression, resting-state abnormalities in

Prefrontal cortices

Cingulate cortices

Examine connectivity within a specific resting-state neural network – the default-mode network that includes

Medial prefrontal

Anterior cingulate cortices

Study examined resting-state, default-mode network functional connectivity

Had to isolate the default-mode network in each subject – group maps were compared between major depressed and healthy controls

Explored effects of depression refractoriness on functional connectivity



subgenual cingulate and

thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects.

“This is the first study to explore default-mode functional connectivity in major depression.”

Increased thalamic and subgenual cingulate activity in major depression

Brings these previously isolated regions of hypermetabolism into the context of a disordered neural network

Correlation between refractoriness and subgenual cingulate functional connectivity within the network


Castellanos et al 2008

Abstract – Phyllis Green and Randolph Cōwen Institute for Pediatric Neuroscience, New York University Child Study Center, New York, NY 10016, USA. castef01@nyumc.org

BACKGROUND: Pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) have focused on frontal-striatal circuitry with alternative hypotheses relatively unexplored. On the basis of evidence that negative interactions between frontal foci involved in cognitive control and the non-goal-directed “default-mode” network prevent attentional lapses, we hypothesized abnormalities in functional connectivity of these circuits in ADHD. METHODS: Resting-state blood oxygen level-dependent functional magnetic resonance imaging (fMRI) scans were obtained at 3.0-Tesla in 20 adults with ADHD and 20 age- and sex-matched healthy volunteers. RESULTS: Examination of healthy control subjects verified presence of an antiphasic or negative relationship between activity in dorsal anterior cingulate cortex (centered at x = 8, y = 7, z = 38) and in default-mode network components. Group analyses revealed ADHD-related compromises in this relationship, with decreases in the functional connectivity between the anterior cingulate and

precuneus/posterior cingulate cortex regions

Secondary analyses revealed an extensive pattern of ADHD-related decreases in connectivity between precuneus and other default-mode network components, including ventromedial prefrontal cortex …and portions of posterior cingulate CONCLUSIONS: Together with prior unbiased anatomic evidence of posterior volumetric abnormalities, our findings suggest that the long-range connections linking dorsal anterior cingulate to posterior cingulate and precuneus should be considered as a candidate locus of dysfunction in ADHD.

I also wanted precuneus with self – but starts here, I guess – in direct connection to the default mode.  Interesting…



Yin, Ostlund & Balleine 2008

Abstract – NC

Here we challenge the view that reward-guided learning is solely controlled by the mesoaccumbens pathway arising from dopaminergic neurons in the ventral tegmental area and projecting to the nucleus accumbens. This widely accepted view assumes that reward is a monolithic concept, but recent work has suggested otherwise.

It now appears that,

….in reward-guided learning,

… the functions of ventral and dorsal striata,

….and the cortico-basal ganglia circuitry associated with them, can be dissociated.

Whereas the nucleus accumbens is necessary for the acquisition and expression of certain appetitive Pavlovian responses and contributes to the motivational control of instrumental performance,

………..the dorsal striatum is necessary for the acquisition and expression of instrumental actions.

Such findings suggest the existence of

………..multiple independent yet interacting functional systems

………. that are implemented in iterating and hierarchically organized

……..cortico-basal ganglia networks

……..engaged in appetitive behaviors ranging from Pavlovian approach responses t

………o goal-directed instrumental actions controlled by action-outcome contingencies.


Loiseau & Millan 2008

Abstract – France

Though D(3) receptor antagonists can enhance cognitive function, their sites of action remain unexplored. This issue was addressed employing a model of social recognition in rats, and the actions of D(3) antagonists were compared to D(1) agonists that likewise possess pro-cognitive properties.

………Infusion of the highly selective D(3) antagonists, S33084 and SB277,011 … into the frontal cortex (FCX) dose-dependently reversed the deficit in recognition induced by a delay.

……….By contrast, the preferential D(2) antagonist, L741,626 (0.63-5.0) had no effect.

………The action of S33084 was regionally specific inasmuch as its injection into the nucleus accumbens or striatum was ineffective.

……… A similar increase of recognition was obtained upon injection of the D(1) agonist, SKF81297 (0.04-0.63), into the FCX though it was also active (0.63) in the nucleus accumbens.

These data suggest that

D(3) receptors modulating social recognition are localized in frontal cortex (FCX), and underpin their pertinence as targets for antipsychotic agents.


Dreher et al 2008

Abstract – MD – need this one, not published yet  9/17/2008

The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging.

Significant losses over a normal lifespan have been reported for dopamine receptors and transporters,

……but very little is known about the neurofunctional consequences of this age-related dopaminergic decline.

In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of

a link between midbrain dopamine and reward-related neural response.

Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[(18)F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects,

we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans,

show that healthy aging induces functional alterations in the reward system,

and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity.

These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging.

Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging.


Schultz 2002

Abstract – Switzerland

Recent neurophysiological studies reveal that neurons in certain brain structures carry specific signals about past and future rewards.

Dopamine neurons display a short-latency, phasic reward signal indicating …………….the difference between actual and predicted rewards.

The signal is useful for enhancing neuronal processing and learning behavioral reactions.

It is distinctly different from dopamine’s tonic enabling of numerous behavioral processes.

Neurons in the striatum, frontal cortex, and amygdala

…………..also process reward information

…………….but provide more differentiated information

…………….for identifying and anticipating rewards

…………..and organizing goal-directed behavior.

The different reward signals have complementary functions, and the optimal use of rewards in voluntary behavior would benefit from interactions between the signals. Addictive psychostimulant drugs may exert their action by amplifying the dopamine reward signal.


Pecina et al 2003

Abstract – Ann Arbor, MI

What is the role of dopamine in natural rewards?

A genetic mutant approach was taken to examine the consequences of elevated synaptic dopamine on (1) spontaneous food and water intake, (2) incentive motivation and learning to obtain a palatable sweet reward in a runway task, and (3) affective “liking” reactions elicited by the taste of sucrose.

A dopamine transporter (DAT) knockdown mutation that preserves only 10% of normal DAT, and therefore causes mutant mice to have 70% elevated levels of synaptic dopamine,

…………was used to identify dopamine effects on food intake and reward.

We found that hyperdopaminergic DAT knockdown mutant mice have higher food and water intake. In a runway task, they demonstrated enhanced acquisition and greater incentive performance for a sweet reward.

….Hyperdopaminergic mutant mice leave the start box more quickly than wild-type mice, require fewer trials to learn, pause less often in the runway, resist distractions better, and proceed more directly to the goal.

Those observations suggest that hyperdopaminergic mutant mice attribute ….greater incentive salience (“wanting”) to a sweet reward

….in the runway test.

But sucrose taste fails to elicit higher orofacial “liking” reactions from mutant mice in an affective taste reactivity test.

These results indicate that

….chronically elevated extracellular dopamine

….facilitates “wanting” and learning of an incentive motivation task for a sweet reward,

…..but elevated dopamine does not increase “liking” reactions to the hedonic impact of sweet tastes.


Berridge 2007

Abstract – Ann Arbor, MI

INTRODUCTION: Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward.

There are three competing explanatory categories: ‘liking’, learning, and ‘wanting’.

………Does dopamine mostly mediate the hedonic impact of reward (‘liking’)?

………Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)?

………….Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli (‘wanting’)?

Each hypothesis is evaluated here, and it is suggested that the incentive salience or ‘wanting’ hypothesis of dopamine function may be consistent with more evidence than either learning or ‘liking’. In brief,

…………recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic ‘liking’ for sensory pleasures.

Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals.

By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience.

……….Dopamine appears necessary for normal ‘wanting’, and

……….dopamine activation can be sufficient to enhance cue-triggered incentive salience.

Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards.

Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals.

…………..That interaction sets the stage to cause compulsive ‘wanting’ in addiction,

but also provides opportunities for experiments to disentangle ‘wanting’, ‘liking’, and learning hypotheses. Results from studies that exploited those opportunities are described here. CONCLUSION:

In short, dopamine’s contribution appears to be chiefly to cause ‘wanting’ for hedonic rewards, more than ‘liking’ or learning for those rewards.


Pecina 2008

Abstract – MI

Whether we ‘like’ and ‘want’ stimuli depends partially on opioid neurotransmission within the nucleus accumbens.

But how are ‘liking’ and ‘wanting’ organized within this neural substrate?

……….Do ‘liking’ and ‘wanting’ originate from the same nucleus accumbens subregions?

………Or are there specific localized sites for opioid enhancement of reward ‘liking’ and ‘liking’?

The present review aims to summarize recent advances in the identification of brain substrates for food ‘liking’ and ‘wanting’ with a focus on opioid hotspots in the nucleus accumbens.

Our findings suggest that ‘liking’ and ‘wanting’ are anatomically dissociable:

… i) the nucleus accumbens contains a

…….. highly localized subregion corresponding to the rostro-dorsal quarter of the medial accumbens shell

…………dedicated to hedonic processing;

…..ii) by contrast, ‘wanting’ is widely distributed throughout the nucleus accumbens.

As a specific mechanism of ‘wanting’, opioid neurotransmission within the nucleus accumbens might increase incentive salience attribution to conditioned cues that predict reward.

How does this work in reference to attachment, wanting to be with our species, wanting one another – which leads to the huge problem of pain when we lose someone we love – one of the world’s leading problematic traumas – keeping our attachment system in full swing so easily – or is this information only in relation to food?  How about wanting material objects that we don’t need, fostered by advertising and packaging?

These findings provide insight into the identity of the nucleus accumbens mechanism of ‘liking’ and ‘wanting’ and suggest that

……opioid circuits in much of the accumbens outside the ‘liking’ hotspot may stimulate food intake by a neurobehavioral mechanism that is separable from hedonic impact.


Finlayson, King & Blundell 2007

Abstract – UK

Berridge’s model (e.g. [Berridge KC. Food reward: Brain substrates of wanting and liking. Neurosci Biobehav Rev 1996;20:1-25.; Berridge KC, Robinson T E. Parsing reward. Trends Neurosci 2003;26:507-513.; Berridge KC. Motivation concepts in behavioral neuroscience. Physiol Behav 2004;81:179-209])

………outlines the brain substrates thought to mediate food reward with distinct

‘liking’ (hedonic/affective) and

‘wanting’ (incentive salience/motivation)

components. Understanding the dual aspects of food reward could throw light on food choice, appetite control and overconsumption.

The present study reports the development of a procedure to measure these processes in humans. A computer-based paradigm was used to assess ‘liking’ (through pleasantness ratings) and ‘wanting’ (through forced-choice photographic procedure) for foods that varied in fat (high or low) and taste (savoury or sweet). 60 participants completed the program when hungry and after an ad libitum meal. Findings indicate a state (hungry-satiated)-dependent, partial dissociation between ‘liking’ and ‘wanting’ for generic food categories.

…… In the hungry state, participants ‘wanted’ high-fat savoury>low-fat savoury with no corresponding difference in ‘liking’, and ‘liked’ high-fat sweet>low-fat sweet but did not differ in ‘wanting’ for these foods.

…….. In the satiated state, participants ‘liked’, but did not ‘want’, high-fat savoury>low-fat savoury, and ‘wanted’ but did not ‘like’ low-fat sweet>high-fat sweet.

More differences in ‘liking’ and ‘wanting’ were observed when hungry than when satiated.

This procedure provides the first step in proof of concept that ‘liking’ and ‘wanting’ can be dissociated in humans and can be further developed for foods varying along different dimensions. Other experimental procedures may also be devised to separate ‘liking’ and ‘wanting’.


Ikemoto 2007

Abstract – MD

Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed.

Present experiments suggest that dopaminergic

………..neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), ………….whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle).

These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum.

Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA.

A review of the literature suggests that

………….(1) the midbrain has corresponding zones for the accumbens core and medial shell;

…………. (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and

………….(3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function.

………….The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than

………….. the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.


Ikemoto, Qin & Liu 2005

abstract – MD

When projection analyses placed the nucleus accumbens and olfactory tubercle [A structure in the base of the telencephalon that acts as a relay centre for olfactory information] in the striatal system

………….functional links between these sites began to emerge.

The accumbens has been implicated in the rewarding effects of psychomotor stimulants,

whereas recent work suggests that the medial accumbens shell and medial olfactory tubercle mediate the rewarding effects of cocaine.

Interestingly, anatomical evidence suggests that medial portions of the shell and tubercle receive afferents from common zones in a number of regions.

Here, we report results suggesting that the current division of the ventral striatum into the accumbens core and shell and the olfactory tubercle does not reflect the functional organization for amphetamine reward.

Rats quickly learned to self-administer D-amphetamine into the medial shell or medial tubercle, whereas they failed to learn to do so into the accumbens core, ventral shell, or lateral tubercle.

Our results suggest that primary reinforcement of amphetamine is mediated via the medial portion of the ventral striatum.

Thus, the medial shell and medial tubercle are more functionally related than the medial and ventral shell or the medial and lateral tubercle. The current core-shell-tubercle scheme should be reconsidered in light of recent anatomical data and these functional findings.


Sleipness et al 2008

Abstract – WA

Circadian rhythms influence cocaine-seeking behavior in rats,

and this behavior may be mediated by variability in the rate of extracellular dopamine clearance across the day:night cycle.

…. We conclude that dopamine clearance varies both in a diurnal and possibly in a circadian manner in the mPFC, and in a diurnal manner in the NAc.

These results indicate that light itself may be used to manipulate molecules implicated in drug addiction.


Flaherty 2005

Abstract – Harvard

This article presents a three-factor anatomical model of human idea generation and creative drive,

….focusing on interactions between the temporal lobes, frontal lobes, and limbic system.

Evidence is drawn from functional imaging, drug studies, and lesion analysis. Temporal lobe changes, as in hypergraphia, often increase idea generation, sometimes at the expense of quality. Frontal lobe deficits may decrease idea generation, in part because of rigid judgments about an idea’s worth.

……….These phenomena are clearest in verbal creativity, and roughly parallel the pressured communication of temporal lobe epilepsy, mania, and Wernicke’s aphasia-compared to the sparse speech and cognitive inflexibility of depression,

Broca’s aphasia, and other frontal lobe lesions.

The phenomena also shape non-linguistic creativity, as in that of frontotemporal dementia. The appropriate balance between frontal and temporal activity is mediated by mutually inhibitory corticocortical interactions.

Mesolimbic dopamine

……… influences novelty seeking and creative drive.

Dopamine agonists and antagonists have opposite effects on goal-directed behavior and hallucinations.

Creative drive is not identical to skill-the latter depends more on neocortical association areas.

However, drive correlates better with successful creative output than skill does. Traditional neuroscientific models of creativity, such as the left brain – right brain hemispheric model, emphasize skills primarily, and stress art and musical skill at the expense of language and mathematics. The three-factor model proposed here predicts findings in a broad range of normal and pathological states and can be tested in many experimental paradigms.


Pollak, Mulvenna & Lythgoe 2007

Abstract – UK – from book article

Pollak, Mulvenna & Lythgoe 2007

Abstract – UK

Pollak TA, Mulvenna CM, Lythgoe MF.

De novo artistic behaviour following brain injury.

Front Neurol Neurosci. 2007;22:75-88.

The effect of brain injury and disease on the output of established artists is an object of much study and debate. The emergence of de novo artistic behaviour following such injury or disease, while very rare, has been recorded in cases of frontotemporal dementia, epilepsy, subarachnoid haemorrhage and Parkinson’s disease. This may be an underdiagnosed phenomenon and may represent an opportunity to further understand the neural bases of creative thought and behaviour in man and those of cognitive change after brain injury.

There is clearly an important role for hemispheric localization of pathology, which is usually within the temporal cortex, upon the medium of artistic expression, and a likely role for mild frontal cortical dysfunction in producing certain behavioural and cognitive characteristics that may be conducive to the production of art.

Possible mechanisms of ‘artistic drive’ and ‘creative idea generation’ in these patients are also considered. The increased recognition and responsible nurturing of this behaviour in patients may serve as a source of great comfort to individuals and their families at an otherwise difficult time.


de novo artistic behavior in people who never showed interest or ability in art before brain damage, most commonly frontotemporal dementia (FTD)

“The emergence or maintenance of visual or musical artistic talent found in some FTD patients has been conceptualized as a ‘paradoxical functional facilitation [Kapur, 1996], or functional disinhibition of the posterior right parietal and temporal cortices in the context of an impairment in ‘language dominant patterns of thinking organized in the dominant frontal and anterior temporal regions’ [Mell et al., 2003].  The right parietal and temporal cortices are associated with visuoconstructive skills:  they are thought to be essential for accurate copying of images and drawing internally imagined images, as well as for representing the spatial relationships between parts of an image or visual array.  A similar functional disinhibition of posteriorly located, right-sided musical (p 77) ability is postulated as an explanation for the emergence of musical creative output in FTD [Miller et al., 2000].”  Pollak, Mulvenna & Lythgoe 2007, 77-79 (p 78 is a table)

So when the left frontal, left frontotemporal area is damaged, the right “artistic” side takes over, though this is a simplisitic model – this is making me think of the “austic” way I could play basketball when I was in the 8th grade in the new Chugiak high school – perfectly play it, too perfectly – and at the same time, too pathologically

Works are “…somewhat bereft of a symbolic element…..relatively few whose elements are representationally symbolic….given the pathological involvement of the hemisphere dominant for symbol manipulation, but it also raises potential questions regarding the ‘creativeness’ per se of such works.”  Pollak, Mulvenna & Lythgoe 2007, 77-79

Hypergraphia [Can also happen that there is a disinhibition of left-sided language function due to right hemisphere damage, though very rare that the compulsion to write actually occurs at the level called creative]

“…it is possible that the lesion confers a drive and a mode of expression (i.e. the written word) and that the content of the writing is partly determined by premorbid and environmental factors.”  Pollak, Mulvenna & Lythgoe 2007, 80

Schrag and Trimble [2001] report on a male patient with Parkinson’s disease who developed previously non-existent poetic talents (leading to publication and prizes) within a month of starting dopamine agonist treatment at age 44 years.  Interestingly, the patient’s symptoms started on the left side, suggesting a right-sided pathology – hence again opening the possibility of right-sided pathology disinhibiting left-sided language function.  The authors speculate that the drugs may have led to the development of either a cognitive enhancement, increased perception or a hypomanic syndrome, in addition to a selective frontal cortical dysfunction, leading to the unmasking of poetic talent.  This speculation raises the question of the neurochemical basis of creative drive as well as the cognitive changes required for the creative process to flourish….”  Pollak, Mulvenna & Lythgoe 2007, 81

“…creative activity became manifest after initiation of dopamine agonist therapy.  Since dopamine agonism can reduce latent inhibition, it seems plausible that the patient’s idea generation could be explained in this way.”  Pollak, Mulvenna & Lythgoe 2007, 84

“…the role of dopaminergic influences may be important.”  Pollak, Mulvenna & Lythgoe 2007, 84

“The drive to create art may be usefully distinguished from the faculty by which ‘creative’ ideas are generated.”  Pollak, Mulvenna & Lythgoe 2007, 82

“Disinhibited behaviour may appear very much like such a disregard for societal constraints or, indeed, such a disregard may be part of the general picture of disinhibited behaviour.”  Pollak, Mulvenna & Lythgoe 2007, 83

strange – this is related to what I call my ability to focus.  Yet, that is really what the playing basketball was like.  I evidently had talent anyway, but I was also not “self-conscious” when I played, not distracted, as if the playing was all that existed in the world – maybe a kind of dissociation?

“One characteristic shown by patients with even mild frontal cortical dysfunction that becomes evident in neuropsychological testing is a degree of

perseveration or a failure of task disengagement.

I have research somewhere in here that ties this in with genetics

In terms of macroscopic behaviour it is certainly possible that preservative tendencies are central to understanding these patients’ drive and could be integral to their sustained and voluminous output of often thematically similar work…..It may be that the emergence of de novo artistic behaviour after brain injury actually requires some mild frontal cortical dysfunction but is restricted by severe dysfunction.”  Pollak, Mulvenna & Lythgoe 2007, 83  authors also mention how this can interfere with previous social life of the patients after brain damage

something that those of us with infant abuse developmental brain damage are likely to have had since birth, anyway – so latent inhibition is something like cleaning the blackboard, wiping the slate clean, so we can start over again without the extraneous information we don’t need – and creative people might not send into the trash quite as much “stuff.”  We keep it around.  The “doves” might be more prone to do the keeping because we probably notice the value in the smaller things that the “hawks” would not see – the looming and fluttering difference between our natures and what we are genetically geared to pay attention to.  Clutter.  How do we handle clutter?  How sensitive are we – to the little things?  Like the article in allostatic load, these differences show themselves even in the way our immune systems are geared to operate – hawks being geared to fight the large things, doves being prepared to fight against the tiny things.  Does this immune system patterning manifest itself in our brains in regard to what we keep around and what we let go of?  Does this all relate to a continuum of what we determine is toxic and what is useful to us – now, or later on?  Perhaps related to hoarding – which they have found brain regions and therefore no doubt genetics that are related?

Latent inhibition, then, must be about forgetting.  It must also be about NOT remembering, something that seems amiss (or remiss?) in PTSD, and possibly with depression, too, where we don’t forget what hurt us.  This must be like the opposite of avoidant attachment.  By definition it also seems to be about consciousness – what we keep in or near consciousness.  So how much of this process is under conscious control?  How much of this process is open to decision and choice?  How is it organized around our values, goals, drives, what attracts us?  What we decide is necessary, important, and meaningful?  I look at the papers I have accumulated and think of my grandmother, who did the same thing.  How are genes related to this?

So there has to be some sort of filter that we screen our “letting go” through – a fine or a larger screen-size mesh, that helps our brains determine what is or might be useful, and what is worthless to us – hence, something we need to forget.  I know this is also implicated in associational learning.  Forgetting, remembering, learning – have to all be a part of the same matrix or spectrum.  What belongs, what does not belong, what we are attached to, what we are not attached to.  Like what of this volumous information belongs in this book?  Here I am trying to find information on PTSD and depression on the molecular level – knowing that here is where the problems start that change our behavior and influence the quality of our lives.  Behavior and conscious choice is at the tip of the iceberg.  And yet I also believe that more information on molecules and genes can inform our consciousness and bring the healing light us understanding through awareness that can move up through all of our considerations of “problems” to understand that in the body they all have some use – to our species if not to ourselves as individuals.

This also has to be related to efficiency and productivity – and hence to chances of survival.  Interesting that most of the information on latent inhibition is in the area of schizophrenia – and creativity.

In my research I often think about “connecting the dots,” but I also see that I am having to draw the circles that are the dots before I can connect them together, before I can rise, somehow to the level of “the bigger picture” and find the pattern I am looking for.  Right now I see the lines that connect the dots as being somehow within the cannabinoid system.  That system seems to be about information and signaling – which is, to my thinking, about communication within the body in interaction with both the external environment and the individualized SELF within each body.  And it is about the immune system, and the brain as part of that system, that creates and delineates our boundaries so that we can exclude what is useless or toxic or include what is not.  That is the job of the immune system.

All of this is ultimately and intimately about relationships and relevance.  It comes down to what, and sometimes to whom, we allow near us – we establish the distances in our relationships – time matters as does timing, as does distance and “space.”.  It is about our well-being or our ill-being.  What contributes to what in an organism as complex as a human being?  What matters?

It probably has to do with what we love, cherish and value.  If life didn’t matter to us then death would not hold terror, and trauma would hardly exist at all.  There has to be a contrast.  When I was little and young, I never had respect, freedom or joy, so I had no internal points of comparison unless those “items” were stored somehow in genetic memory.  I could not fight for what I did not know, what I had no experience of or with.  I was told I was different from my siblings and I believed it.  I had no choice.  Therefore the treatment I received made “sense” to me as it was somehow innately required that they be treated differently from me.  We did not start on the same foundation ground.  I could not compare myself to them – my mother did all of that for me from the first breath I inhaled and exhaled.

Speaking of what we keep and what we discard – it’s even at the level of our breathing, our digestion.  It’s in our bodies.  The wisdom of retention and elimination.  Which works better if we are not overwhelmed!  A grand old game of “Dancing with the Stars.” And how we know which is which, and how we make use of what lies in between…

“…it has been demonstrated that reduced latent inhibition

[latent inhibition] described as the capacity of the brain to filter from conscious awareness stimuli previously perceived as irrelevant

.is associated with psychotic states or psychotic susceptibility as well as high dopamine levels [Gray, 1998].  Much of the phenomenology of psychosis includes the formation of associations between unrelated or irrelevant stimuli and this has led some researchers to speculate that creativity, which involves ’original recombinant ideation’ [Carson et al., 2003], may involve a reduction in latent inhibition.”  Pollak, Mulvenna & Lythgoe 2007, 83

“Carson et al. [2003] measured creativity in a sample of high-IQ individuals using a range of indicators of creativity from divergent thinking scales to eminent creative achievement and found that high scorers showed reduced latent inhibition.  They suggest that ‘the results of these studies and analyses indicate a substantial and significant relationship between a variety of indicators of creativity and reduced LI’.”  Pollak, Mulvenna & Lythgoe 2007, 83

Interesting – how does capacity of the brain to filter from conscious awareness stimuli previously perceived as irrelevant relate to memory?  This also sounds like an avoidant attachment disorder!!  They control feelings this way, making the feeling disappear, and also making things that might trigger feelings “vanish.”  So these creative people either don’t make the decisions that things are “irrelevant” and consider that they might be useful in the future?  Like that plaque I used to have, “Creative minds are rarely tidy.”  We collect and keep things “to make something out of later.”  Maybe we have a tendency to do that with experience, also.  (and what about that article linking PTSD to narcissistic personality?  Are artists more narcissistic?)

Put in that light, PTSD is a creative act, then – the trauma experience is not put away as easily as other things might be – so does that mean creative people, and/or PTSD folks have higher dopamine levels?

“It is far from obvious that all the patients who exhibit de novo artistic behaviours are ‘creative’ in the sense that psychologists understand that term.”  Pollak, Mulvenna & Lythgoe 2007, 84




Shalev & Segman 2008

Abstract – Israel – I need this article

Summarizing the contributions in this section of the book, this chapter addresses questions regarding the complex etiology of PTSD, and the relative strength of discernable biological indicators of the disorder.

…….. It outlines two major approaches to exploring the biology of the disorder and discusses the reason for the many non-replications of findings.

………… It defines the constructs of

multicausality, equifinality, and multifinality,

and evaluates their main implication for studies of PTSD, namely that no biological signal can be properly appraised without taking into account its context.

……..Such context, in PTSD, includes both

……….concurring biological systems and regulatory mechanisms,

………and environmental-psychosocial input.

Studies of gene expression of PTSD exemplify one way of studying the context of putative biological signals. The role of biological alterations as templates for responding to psychosocial challenges is discussed.


Segman & Shalev 2003

Abstract – Israel

Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. …..A twin study of Vietnam veterans has shown significant genetic contribution to PTSD.

….The fact that PTSD’s underlying genotypic vulnerability is only expressed following trauma exposure limits the usefulness of family-based linkage approaches.

….In contrast to the other major psychiatric disorders, large studies for the search of underlying genes have not been described in PTSD to date. Complementary approaches for locating involved genes include association-based studies employing case-control or parental genotypes for transmission dysequilibrium analysis and quantitative trait loci studies in animal models. ………Identification of susceptibility genes will increase our understanding of traumatic stress disorders and help to elucidate their molecular basis. The current review provides an up-to-date outline of progress in the field of PTSD.



You et al 2005

Abstract – China

BACKGROUND: The serotonin transporter (5-HTT) and tryptophan hydroxylase (TPH) gene are important candidate genes for the psychiatric disorders. Many studies of patients with anxiety disorders have found abnormalities of serotonin metabolism and dysfunction of regulation in the transporter itself.

……. In this study, we hypothesize that genetic variation in the 5-HTT and TPH gene may have an effect on the etiology of generalized anxiety disorder (GAD). METHODS: Using a polymerase chain reaction-based technique, the allele and genotype frequencies of

….three polymorphisms in the serotonin transporter gene

…(a deletion/insertion polymorphism in the transcriptional control region ……and a variable number of tandem repeats in intron 2)

….and TPH gene (A218C in intron 7)

were analyzed in 138 patients with GAD and 90 healthy controls. These two groups were matched for ethnic and geographic origin. RESULTS: The

frequencies of 5-HTT gene-linked functional polymorphic region (5-HTTLPR) SS (short/short) genotype were significantly higher in GAD patients

than in control subjects (68% versus 49%, chi = 12.274, df = 2, P = 0.002), and the frequencies of S (short) allele observed in the GAD patients were [significantly] higher than those in healthy subjects (79 versus 71%, chi = 4.063, df = 1, P = 0.044).

….The odds ratio for the SS genotype versus the other two genotypes was 2.33

….Similarly, the odds ratio for the S allele versus L allele was 1.

….. The genotypic and allelic distribution of 5-HTT VNTR and TPH A218C polymorphisms did not show statistically significant differences between patients and controls.

……CONCLUSION: Our findings support that the presence of

5-HTTLPR-SS genotype may increase the risk of GAD.


Abdolmaleky, Thiagalingam & Wilcox 2005

Abstract – Harvard

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy [index as the number of classes a gene is assigned to].

………..Most study designs currently in use are inadequate to uncover these mechanisms.

……….However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders.

……….There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors.

For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder.

……..Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions.

Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.


Hamshere et al 2005

Abstract – Wales

CONTEXT: Traditionally, the search for genes involved in predisposition to major psychoses has proceeded with separate studies of schizophrenia and bipolar disorder. However,

twin data suggest that, in addition to genes with specificity for these phenotypes, there exist genes that simultaneously influence susceptibility to schizophrenia, bipolar disorder, and schizoaffective disorder.

OBJECTIVE: To undertake, to our knowledge, the first systematic search for such loci. DESIGN: Genomewide linkage scan. SETTING: Affected individuals were ascertained in the United Kingdom and Ireland from general psychiatric inpatient and outpatient services.

PARTICIPANTS: The families were selected for linkage studies of either schizophrenia or bipolar disorder. Pedigrees were selected for the current analysis where there was at least 1 member with DSM-IV schizoaffective disorder, bipolar type. Within these pedigrees, individuals were coded as affected if they had been diagnosed with DSM-IV schizophrenia, schizoaffective disorder of bipolar type, or bipolar I disorder. A total of 24 pedigrees contributed 35 affected sibling pairs to the sample. METHOD: A 10-centimorgan genome scan using microsatellite markers was analyzed using MAPMAKER/SIBS software.

RESULTS: A genomewide significant signal (LOD = 3.54) was observed at chromosome 1q42 (near D1S2800), and suggestive LOD scores were observed at chromosomes 22q11 (LOD = 1.96) and 19p13 (LOD = 1.85).

………..No linkage was observed in these regions in our original schizophrenia or bipolar scans in individuals from the United Kingdom.

CONCLUSIONS: Our linkage findings strongly support the existence of loci that influence susceptibility across the functional psychosis spectrum.

The DISC1 gene lies within 2.5 megabases of our peak marker on chromosome 1q42 and has been previously implicated in schizophrenia, bipolar disorder, and, recently, schizoaffective disorder. Follow-up of this region should use samples enriched for cases of schizoaffective disorder. Our findings have similar implications for the search for genetic variation on

chromosome 22q11

that influences susceptibility to psychosis.


Domschke et al 2008

Abstract – Germany

Panic disorder is an anxiety disorder with an estimated heritability of up to 48%.

….The functional val158met polymorphism in the catechol-O-methyltransferase (COMT) gene has been found to be associated with panic disorder and to influence limbic and prefrontal brain activation in response to unpleasant stimuli.

In the present study, neuronal activation following emotional stimulation was used as an endophenotype and investigated for association with the COMT val158met polymorphism in panic disorder. Twenty patients with panic disorder were scanned by means of functional magnetic resonance imaging at 3 Tesla under visual presentation of emotional faces and genotyped for the COMT val158met polymorphism.

………In response to fearful faces, increased activation in the right amygdala was observed in patients carrying at least one 158val allele.

Increased activation or less deactivation associated with the 158val allele was seen upon presentation of fearful, angry and happy faces in the orbitofrontal and ventromedial prefrontal cortex, respectively.

Our data provide preliminary evidence for a role of the functional val158met COMT polymorphism in amygdala and prefrontal activation in response to emotional faces in panic disorder.

……….This COMT variant might increase the vulnerability to panic disorder by modulating dopaminergic tonus in relevant brain regions and thus altering neuronal processing of anxiety-related emotional cues.


Stein et al 2005

Abstract – San Diego

High neuroticism and low extraversion are characteristic of anxiety-prone individuals.

A functional variant in the catechol-O-methyltransferase (COMT) gene, the Val158Met (‘val/met’) polymorphism, has been associated in some prior studies with several phenotypes, including neuroticism.

We tested the hypothesis that the val158met polymorphism would be associated with both high neuroticism and low extraversion, making it a plausible candidate locus for anxiety susceptibility. To determine whether val158met is responsible for these effects, we also evaluated the association with haplotypes that included two other SNPs within the COMT gene. We collected a sample of 497 undergraduate college students who were phenotyped on a personality inventory (the NEO-Personality Inventory-Raised (NEO-PI-R)). Subjects were genotyped for three COMT polymorphisms: the well-studied nonsynonymous SNP rs4680 that generates a valine-to-methionine substitution


….rs737865 (near exon #1), and

…. rs165599 (also functional, near the 3′-UTR).

Together, these three SNPs define a haplotype that is associated with reduced COMT expression in human brain.

…Two of the SNPs (rs4680 (‘val/met’) and rs737865) were significantly associated with (low) extraversion and, less consistently, with (high) neuroticism, with effects confined to women.

A significant association between COMT haplotype and (low) extraversion and (high) neuroticism was also observed.

………….These data suggest that involvement of the COMT locus in susceptibility to anxiety-related traits (ie low extraversion and high neuroticism) is unlikely to be wholly accounted for by the well-studied rs4680 (‘val/met’) polymorphism. Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained.




Panic disorder, susceptibility to

MIM: 167870


Schmahl et al 2003

Abstract – Germany

BACKGROUND: Borderline personality disorder (BPD)

…….. is a common psychiatric disorder that is often linked to early stressors. One particularly salient feature of the disorder is fear of abandonment. This pilot study was conducted to measure neural correlates of memories of abandonment in women with and without BPD.

METHODS: Twenty women with a history of childhood sexual abuse underwent measurement of brain blood flow with positron emission tomography imaging while they listened to scripts describing neutral and personal abandonment events. Brain blood flow during exposure to abandonment and neutral scripts was compared among women with and without BPD.


Memories of abandonment were associated with

….greater increases in blood flow in bilateral dorsolateral prefrontal cortex ….(middle frontal gyrus,

….Brodmann’s areas 9 and 10) as well as

….right cuneus (area 19) in women with BPD than in women without BPD.

Abandonment memories were associated with

…..greater decreases in right anterior cingulate (areas 24 and 32) in women with BPD than in women without BPD.

CONCLUSIONS: These findings implicate dysfunction of …dorsolateral and

….medial prefrontal cortex including anterior cingulate, …left temporal cortex, and

….visual association cortex in memories of abandonment in women with BPD. These brain areas may mediate symptoms of BPD.


Silbersweig et al 2007

Abstract – NY

OBJECTIVE: The authors sought to test the hypothesis that in patients with borderline personality disorder, the ventromedial prefrontal cortex and associated regions would not be activated during a task requiring motor inhibition in the setting of negative emotion. Such a finding would provide a plausible neural basis for the difficulty borderline patients have in modulating their behavior during negative emotional states and a potential marker for treatment interventions.

METHOD: A specifically designed functional magnetic resonance imaging (fMRI) activation probe was used, with statistical parametric mapping analyses, to test hypotheses concerning decreased prefrontal inhibitory function in the context of negative emotion in patients with borderline personality disorder (N=16) and healthy comparison subjects (N=14). 3-T fMRI scanning was used to study brain activity while participants performed an emotional linguistic go/no-go task. RESULTS: Analyses confirmed that

under conditions associated with the interaction of behavioral inhibition and negative emotion, borderline patients showed relatively

……..decreased ventromedial prefrontal activity (including medial orbitofrontal and subgenual anterior cingulate) compared with healthy subjects.

In borderline patients, under conditions of behavioral inhibition in the context of negative emotion, decreasing ventromedial prefrontal and increasing extended amygdalar-ventral striatal activity correlated highly with measures of decreased constraint and increased negative emotion, respectively.

CONCLUSIONS: These findings suggest specific frontolimbic neural substrates associated with core clinical features of emotional and behavioral dyscontrol in borderline personality disorder.


Goldstein et al 2007

Abstract – Mt. Sinai, NY

Neural substrates of behavioral inhibitory control have been probed in a variety of animal model, physiologic, behavioral, and imaging studies, many emphasizing the role of prefrontal circuits.

………. Likewise, the neurocircuitry of emotion has been investigated from a variety of perspectives.

Recently, neural mechanisms mediating the interaction of emotion and behavioral regulation have become the focus of intense study.

……. To further define neurocircuitry specifically underlying the interaction between emotional processing and response inhibition, we developed an emotional linguistic go/no-go fMRI paradigm with a factorial block design which joins explicit inhibitory task demand (i.e., go or no-go) with task-unrelated incidental emotional stimulus valence manipulation, to probe the modulation of the former by the latter.

……..In this study of normal subjects focusing on negative emotional processing, we hypothesized activity changes in specific frontal neocortical and limbic regions reflecting modulation of response inhibition by negative stimulus processing.

We observed common fronto-limbic activations (including orbitofrontal cortical and amygdalar components) associated with the interaction of emotional stimulus processing and response suppression.

……Further, we found a distributed cortico-limbic network to be a candidate neural substrate for the interaction of negative valence-specific processing and inhibitory task demand. I don’t have the article to tell what this network is

………These findings have implications for elucidating neural mechanisms of emotional modulation of behavioral control [would this also include how we FEEL at the time we have an emotion – intensity, distress of the experience, how we self sooth, etc?], with relevance to a variety of neuropsychiatric disease states marked by behavioral dysregulation within the context of negative emotional processing.





McIntosh et al 2007

Abstract – UK

BACKGROUND: There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons.

METHODS: In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known.

RESULTS: The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner.

……….Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex.

………….n addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance.

CONCLUSIONS: The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function.

These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.


Pelayo-Teran et al 2008

Abstract – Spain

Catechol-O-methyltransferase (COMT)

Val158Met polymorphism

has been identified as a potential etiologic factor in schizophrenia.

………It has been proposed that this polymorphism could be associated with specific clinical markers.

The aim of the study was to evaluate the influence of COMT Val158Met polymorphism genotype in the phenotypic expression of first episode psychosis at onset.

Age of onset, DUP, SANS, and SAPS (positive, disorganized, and negative dimensions) were studied in 169 Caucasian drug-naïve patients with a first-episode of non-affective psychosis.

………… The COMT Val158Met polymorphism …. Patients with Val/Val genotype had significantly higher levels of SANS negative dimension scores (F: 3.539; P = 0.031) and had a younger age of onset (F: 4.649; P = 0.011) than Met carriers.

Our findings suggest that the Val allele is associated with onset phenotypic features related to a poor prognosis of the illness.

…………These data would indicate that COMT genotype may have a role in the etiological model for schizophrenia and other psychotic disorders.


Gallinat et al 2003

Abstract – MD

BACKGROUND: A common functional polymorphism,


of the catechol-O-methyltransferase (COMT) enzyme

………has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function.

An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. METHODS: The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. RESULTS: We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. CONCLUSIONS: The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine.


Han et al 2008

Abstract – South Korea

The methionine variant of Val66Met brain-derived neurotrophic factor BDNF met and catecholamine-O-methyltransferase (COMT L)

………… is associated with a deficit in attention and aggravation of delusions in schizophrenia.

We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited.

The patients who were BDNF met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions.

……….The current results suggest that patients with the BDNF met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions.


Smolka et al 2007

Abstract – Germany

Moved to epigenetics

Emotional reactivity and regulation

…………are fundamental to human behavior.

As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli.

These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene.


Caldu et al 2007

Abstract – Spain

Two limiting factors of dopamine activity are the

……………catechol-o-methyltransferase (COMT) – terminates dopamine activity by degradation  – genetic variants of COMT – related to the enzymatic activity

……………and the dopamine transporter (DAT) – terminates dopamine activity by uptake – genetic variants of DAT – related to protein availability

………..The Met allele of the COMT Val108/158 Met polymorphism has been associated to lower enzymatic activity and

………… the 9-repeat allele of the DAT 40 base-pair (bp) variable number of tandem repeat (VNTR) polymorphism has been related to lower protein availability.

Genotypes for COMT and DAT were determined in a sample of 75 healthy subjects, who underwent functional magnetic resonance imaging (fMRI) while performing an N-back task. To further assess the effects of the genotypes on cognition, subjects were administered the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test (CPT). Analysis of fMRI data revealed an additive effect of these two genes on brain activation in an N-back task,

…………… with subjects homozygous for the Val and the 9-repeat alleles showing the

……………highest activation for the

…………same level of performance.

……………….Moreover, the Val allele was related to

…………….higher number of perseverative errors on the WCST and with a ……………higher number of commission errors on the CPT.

The 10-repeat allele was associated with

……………faster reaction times but also with a

…………….higher number of commission errors.

Our results support a role of the COMT Val108/158 Met and the DAT 40 bp VNTR in both brain activation and cognition


Ago et al 2008

Abstract – Japan   depression

Chronic corticosterone and isolation rearing paradigms may provide reliable mouse models of depression.

Using these models, the present study examined if the specific glucocorticoid receptor antagonist, RU-43044, has an antidepressant-like effect, and studied the possible role of prefrontal neurotransmission on the behavioral effects. Chronic administration of corticosterone and isolation rearing increased the immobility time in the forced swim and tail suspension tests.

……… Subchronic treatment with RU-43044 decreased the immobility time in the forced swim test in chronic corticosterone-treated and isolation-reared mice, but not the control mice. .

Chronic corticosterone decreased the levels of cortical glucocoriticoid receptors and stress-induced increases in plasma corticosterone levels, and blocked the response of plasma corticosterone to dexamethasone, ……….while isolation rearing did not cause any changes in the glucocorticoid receptor system.

Both chronic corticosterone and isolation rearing markedly increased high K(+)-induced dopamine release,

………..but not serotonin release, in the prefrontal cortex.

Subchronic RU-43044 reversed the enhanced release of dopamine in the prefrontal cortex of chronic corticosterone-treated and isolation-reared mice. These results suggest that chronic corticosterone and isolation rearing increase the depressive-like behavior in glucocorticoid receptor-dependent and independent manners, respectively,

and that RU-43044 [steroidal GR antagonist]

……………shows an antidepressant-like effect, probably via an inhibition of enhanced prefrontal dopaminergic neurotransmission in these mouse models.


Dhir & Kulkarni 2007

Abstract – India                              depression

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression.

Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission,

………most notably a sensitization of behavioural responses to agonists acting at D2/D3 dopamine receptors within the nucleus accumbens.

Recent clinical evidences have shown that ropinirole, a D2/D3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain

In the mouse forced swim test …The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels.

The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.


Haeffel et al 2008

Abstract – Nortre Dame, IN

Previous research has generated examples of how genetic and environmental factors can interact to create risk for psychopathology. Using a gene-by-environment (G x E) interaction design, we tested whether three polymorphisms in the dopamine transporter gene (DAT1, also referred to as SLC6A3, located at 5p15.33)

………….interacted with maternal parenting style to predict first-onset episodes of depression.

……….Participants were male adolescents (N= 176) recruited from a juvenile detention center in northern Russia.

As hypothesized, one of the

polymorphisms (rs40184)

moderated the effect of perceived maternal rejection on the onset of major depressive disorder, as well as on suicidal ideation.

…….. Further, this G x E interaction was specific to depression; it did not predict clinically significant anxiety. These results highlight the need for further research investigating the moderating effects of dopaminergic genes on depression.



Alberto et al 2006

Abstract – Newfoundland, Canada

Orexin neurons

….in the lateral hypothalamus (LH)/perifornical area (PFA) are …….known to promote food intake as well as

……provide excitatory influence on the dopaminergic reward pathway.

Dopamine (DA), in turn,

….inhibits the reward pathway and food intake

……through its action in the LH/PFA.

However, the cellular mechanism by which DA modulates orexin neurons remains largely unknown. Therefore, we examined the effect of DA on the excitatory neurotransmission to orexin neurons.

………..Whole-cell patch-clamp recordings were performed using acute rat hypothalamic slices, and

……….orexin neurons were identified by their electrophysiological and immunohistochemical characteristics.

……..Pharmacologically isolated action potential-independent miniature EPSCs (mEPSCs) were monitored. Bath application of DA induced a bidirectional effect on the excitatory synaptic transmission dose dependently. A low dose of DA (1 microM) increased mEPSC frequency, which was blocked by the D1-like receptor antagonist SCH 23390, and mimicked by the D1-like receptor agonist SKF 81297. In contrast, higher doses of DA (10-100 microM) decreased mEPSC frequency, which could be blocked with the D2-like receptor antagonist, sulpiride. Quinpirole, the D2-like receptor agonist, also reduced mEPSC frequency. None of these compounds affected the mEPSCs amplitude, suggesting the locus of action was presynaptic. Furthermore, DA (1 microM) induced an increase in the action potential firing, whereas DA (100 microM) hyperpolarized and ceased the firing of orexin neurons, indicating the effect of DA on excitatory synaptic transmission may influence the activity of the postsynaptic cell.

In conclusion, our results suggest that D1- and D2-like receptors have opposing effects on the excitatory presynaptic terminals impinging onto orexin neurons.


Williams et al 2007

Article – Cambridge, UK



….orexin/hypocretin neurons recently emerged as

…..key orchestrators of brain states and adaptive behaviors.

They are critical for normal stimulation of wakefulness and breathing: Orexin loss causes narcolepsy and compromises vital ventilatory adaptations. However, it is unclear how orexin neurons generate appropriate adjustments in their activity during changes in physiological circumstances. Extracellular levels of acid and CO2 are fundamental physicochemical signals controlling wakefulness and breathing, but their effects on the firing of orexin neurons are unknown. Here we show that the spontaneous firing rate of identified orexin neurons is profoundly affected by physiological fluctuations in ambient levels of H+ and CO2. These responses resemble those of known chemosensory neurons both qualitatively (acidification is excitatory, alkalinization is inhibitory) and quantitatively (≈100% change in firing rate per 0.1 unit change in pHe). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pHe: Acidification increases intrinsic excitability, whereas alkalinization depresses it.

………The effects of pHe involve acid-induced closure of leak-like K+ channels in the orexin cell membrane.

……..These results suggest a new mechanism of how orexin/hypocretin networks generate homeostatically appropriate firing patterns. – abstract

Even small changes in extracellular levels of protons ([H+]e) are fatal to mammalian cells and tissues.

…..The brain rapidly counteracts such changes with finely tuned adaptations in breathing, behavioral arousal, and aversive panic responses

….. Breathing controls [H+]e through CO2 removal (in the body, H+ + HCO3 ↔ CO2 + H2O), while behavioral arousal ensures that any obstructions to breathing can be effectively removed.

…..For example, respiratory acidosis produced by sleep apnea causes awakening and stimulates breathing, which normalizes [H+]e. Failure of such reflexes is thought to contribute to fatal conditions such as sudden infant death syndrome

To elicit appropriate changes in breathing and arousal, neurons need to translate changes in [H+]e into appropriately coordinated responses. In many neurons, [H+]e depresses electrical excitability (i.e., acidosis is inhibitory and alkalosis is excitatory)

….. However, the opposite type of cellular response is thought to be important for the vital adaptive reflexes mentioned earlier: a steep increase in firing rate by physiological acidification and a steep decrease in firing upon alkalinization

…….Such specialized chemosensory firing responses are traditionally associated with neurons of the brainstem, a key center in the control of arousal and breathing

Although until now most work on neuronal chemosensing has focused on the brainstem, historical evidence indicates that the hypothalamus is also vital for maintaining normal breathing and arousal

…….Hypothalamic neurons responsible for these functions have only recently been identified and found to contain peptide transmitters called orexins/hypocretins

…….Orexin-containing neurons (orexin neurons) are located in the lateral hypothalamus (LH), but project widely throughout the brain, where orexins act on two specific G protein-coupled receptors

……Both arousal and breathing centers receive stimulatory inputs from orexin neurons

….Orexin neurons attracted great attention when they proved to be targets in narcolepsy, where their destruction causes irresistible daytime sleepiness, disturbed night-time sleep, and cataplexy

………..The activity of orexin neurons is also essential for adaptive exploratory responses to food shortage

……….Furthermore, recent data show that orexin knockout severely compromises the ability to increase breathing during acidosis

These studies established that orexin neurons are essential for appropriate adjustments of brain and behavioral states to the internal and external environments

….However, the regulation of orexin neurons is much less understood. In particular, it is unknown whether the firing of orexin neurons is sensitive to physiologically relevant changes in fundamental homeostatic signals such as [H+] and [CO2]. To document such responses and compare them to known chemosensory neurons, we performed electrophysiological recordings from orexin neurons identified by targeted expression of GFP in transgenic mice. We show that orexin cell firing is potently stimulated by CO2 and H+ through a mechanism involving acid-induced inhibition of postsynaptic leak-like K+ channels.

………. We find that this enables orexin cell firing to encode small physiological changes in pH with high sensitivity, comparable to that of classical chemosensory neurons of the brainstem.

These results identify a new mechanism by which hypothalamic orchestrators of adaptive behavior generate homeostatically appropriate patterns of activity.

Living orexin neurons are difficult to identify because they exhibit few defining anatomical features and are intermixed with many other types of cells in the LH.

… the firing of orexin cells is regulated by diverse hormones and neurotransmitters

………Furthermore, orexin neurons were found to act as specialized electrical sensors of glucose, translating rises in ambient levels of the sugar into reductions in their firing rate

…………Our new data show that orexin cell firing is also specialized to encode physiological levels of acid and CO2. This ability to sense endocrine, neural, metabolic, and physicochemical signals is reminiscent of the classical polymodal chemosensory organs, such as the carotid body ….Combined with their ability to orchestrate diverse brain states (see below), this places orexin cells in a pivotal position to guard body homeostasis through appropriate behavioral corrections. The relative role of each type of input to orexin cells during different circumstances and stages of development is an important subject for future investigation.

In the field of chemosensing, our study supports an emerging concept that different chemosensory systems operate at different levels in the brain to link pH with breathing and arousal. In particular, there appear to be chemosensors tightly linked to the control of breathing, e.g., neurons of the retrotrapezoid nucleus of the brainstem (34) and, in parallel, systems that link pH to both breathing and arousal, such as serotonin and noradrenaline neurons of the brainstem (3, 4) and orexin neurons (this study). We estimated the chemosensitivity of orexin cell firing to be ≈100% rate increase per 0.1 pH unit. In the brainstem, this parameter varies from ≈100% for regions with the highest degree of chemosensitivity, such as the medullary raphe, to ≈15% for regions with the lowest chemosensitivity, such as the locus coeruleus (4). In terms of sensitivity of firing to pHe, orexin cells thus appear to be among the most sensitive known chemosensors.

With regard to behavioral arousal and alertness, it is well established that the activity of orexin neurons stimulates wakefulness by providing excitatory inputs to most classical arousal centers as well as directly to the cortex … In addition, orexins may also generate anxiety and stresslike states … probably due to the reciprocal excitatory interactions with neurons containing corticotropin-releasing factor …

This pathway is of particular interest in the context of this study because high CO2 levels are well known to induce anxiety responses, which are thought to be mediated in part by CO2/H+-sensitive neurons of the locus coeruleus … However, as noted above, the chemosensitivity of locus coeruleus neurons appears to be ≈6-fold lower than that of orexin neurons.

The orexin system may thus ensure a more graded transition to panic states during rising CO2 levels, possibly in cooperation with the serotonin system of the brainstem

Finally, it is noteworthy that orexin neurons have many additional central projections that exert critical influences on appetite and reward/addiction … Our findings may thus represent a new cellular link between acid-base balance and these behavioral drives.


Bubser et al 2005

Abstract – Nashville

Orexin/hypocretin neurons in the lateral hypothalamus and adjacent perifornical area (LH/PFA)

…………… innervate midbrain dopamine (DA) neurons

………that project to corticolimbic sites

……….and subserve psychostimulant-induced locomotor activity.

However, it is not known whether dopamine neurons in turn regulate the activity of orexin cells. We examined the ability of dopamine agonists to activate orexin neurons in the rat, as reflected by induction of Fos. The mixed dopamine agonist apomorphine increased Fos expression in orexin cells, with a greater effect on orexin neurons located medial to the fornix. Both the selective D1-like agonist, A-77636, and the D2-like agonist, quinpirole, also induced Fos in orexin cells, suggesting that stimulation of either receptor subtype is sufficient to activate orexin neurons.

…………Consistent with this finding, combined SCH 23390 (D1 antagonist)-haloperidol (D2 antagonist) pretreatment blocked apomorphine-induced activation of medial as well as lateral orexin neurons;

………in contrast, pretreatment with either the D1-like or D2-like antagonists alone did not attenuate apomorphine-induced activation of medial orexin cells. In situ hybridization histochemistry revealed that LH/PFA cells rarely express mRNAs encoding dopamine receptors, suggesting that orexin cells are transsynaptically activated by apomorphine.

………We therefore lesioned the nucleus accumbens, a site known to regulate orexin cells,

………..but this treatment did not alter apomorphine-elicited activation of medial or lateral orexin neurons.

………..Interestingly, apomorphine failed to activate orexin cells in isoflurane-anaesthetized animals.

These data suggest that apomorphine-induced arousal but not accumbens-mediated hyperactivity is required for dopamine to transsynaptically activate orexin neurons.  [Apomorphine is a type of dopaminergic agonist, a morphine derivative (but does not actually contain morphine, or bind to opioid receptors). Apomorphine is a relatively non-selective dopamine receptor agonist, having possible slightly higher affinity for D2-like dopamine receptors.]


Yoshida et al 2006

article – Boston 9has complete details on where orexin neurons are)

Emotions, stress, hunger, and circadian rhythms all promote wakefulness and behavioral arousal. Little is known about the pathways mediating these influences, but the orexin-producing neurons of the hypothalamus may play an essential role.

……….These cells heavily innervate many wake-promoting brain regions, and mice lacking the orexin neurons have narcolepsy and fail to rouse in response to hunger

To identify the afferents to the orexin neurons, we first injected a retrograde tracer into the orexin neuron field of rats. Retrogradely labeled neurons were abundant in the allocortex, claustrum, lateral septum, bed nucleus of the stria terminalis, and in many hypothalamic regions including the preoptic area, dorsomedial nucleus, lateral hypothalamus, and posterior hypothalamus. …………..Retrograde labeling in the brainstem was generally more modest, but labeling was strong in the periaqueductal gray matter, dorsal raphe nucleus, and lateral parabrachial nucleus.

………Injection of an anterograde tracer confirmed that most of these regions directly innervate the orexin neurons, with some of the heaviest input coming from the lateral septum, preoptic area, and posterior hypothalamus.

In addition, hypothalamic regions preferentially innervate orexin neurons in the medial and perifornical parts of the field, but most projections from the brainstem target the lateral part of the field.

………..Inputs from the suprachiasmatic nucleus are mainly relayed via the subparaventricular zone and dorsomedial nucleus.

These observations suggest that the orexin neurons may integrate a variety of interoceptive and homeostatic signals

…………to increase behavioral arousal in response to



….circadian signals, and

…..autonomic challenges

The hypothalamus contained the greatest number of CTB-labeled neurons, accounting for about one-third of all labeled cells throughout the brain

Most prior research on the orexin neurons has focused on their interactions with systems controlling sleep/wake behavior or appetite, but we find that the orexin neurons receive afferents from a wide variety of brain regions

……….The largest inputs are from other parts of the hypothalamus and from areas that regulate emotion and autonomic functions such as the infralimbic cortex, lateral septum, and BST. These observations suggest that the orexin neurons may be influenced by a variety of signals that govern homeostatic drives, behavioral state, and autonomic tone.


Baldo et al 2004

Abstract – Madison

Gamma-amino butyric acid (GABA)A receptor stimulation in the nucleus accumbens shell produces intense hyperphagia in rats and increases Fos expression in the lateral hypothalamus.

……….To explore the involvement of hypothalamic orexin/hypocretin- or melanin concentrating hormone-immunoreactive neurons in this effect, the GABAA agonist, muscimol (0, 50 ng), was infused directly into the nucleus accumbens shell of rats; 90 min later, their brains were collected and subsequently processed for immunohistochemistry.

………. A group exposed to a novel environment was included to evaluate the specificity of Fos expression changes with regard to general arousal. ……….Alternating sections through the hypothalamus were double-stained for orexin/hypocretin-Fos or melanin concentrating hormone-Fos combinations. Intra-accumbens shell muscimol treatment significantly increased the percentage of orexin/hypocretin-containing neurons expressing Fos in the lateral, but not medial, portion of the perifornical/lateral hypothalamic area.

………Regardless of treatment condition, greater percentages of orexin/hypocretin-containing neurons in the medial portion of the hypothalamus expressed Fos relative to cells located more laterally.

None of the manipulations increased Fos expression in melanin concentrating hormone-immunoreactive neurons.

Thus, orexin/hypocretin-containing neurons in lateral sectors of the hypothalamus, along with cells in the arcuate nucleus, display phasic increases in Fos expression after an orexigenic pharmacological manipulation of the nucleus accumbens shell,

but to a lesser degree after the heightened arousal associated with exposure to a novel environment.



Geuze et al 2008c

Abstract – Research Centre-Military Mental Healthcare, Ministry of Defense, Utrecht, The Netherlands. s.g.geuze@umcutrecht.nl

Gamma-aminobutyric acid (GABA(A)) receptors

are thought to play an important role

in modulating the central nervous system in response to stress.

Animal data have shown

alterations in the GABA(A) receptor complex by uncontrollable stressors.

SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA(A) receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA(A) receptor complex in veterans with and without PTSD using [(11)C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [(11)C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [(11)C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results.

The observed

global reduction of [(11)C]flumazenil binding

in patients with PTSD

provides circumstantial evidence for the role

of the benzodiazepine-GABA(A) receptor in the pathophysiology of PTSD

and is consistent with previous animal research and clinical psychopharmacological studies.


Nakamura et al 2007

Abstract – Japan

Exogenous administration of orexin can promote wakefulness and respiration.

Here we examined whether intrinsic orexin participates in the control of breathing in a vigilance state-dependent manner. Ventilation was recorded together with electroencephalography and electromyography for 6 h during the daytime in prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates. Respiratory parameters were separately determined during quiet wakefulness (QW), slow-wave sleep (SWS), or rapid eye movement (REM) sleep.

………Basal ventilation was normal in ORX-KO, irrespective of vigilance states. The hypercapnic ventilatory response during QW in ORX-KO (0.19 +/- 0.01 ml.min(-1).g(-1).%CO(2)(-1)) was significantly smaller than that in WT mice (0.38 +/- 0.04 ml.min(-1).g(-1).%CO(2)(-1)), whereas the responses during SWS and REM in ORX-KO were comparable to those in WT mice.

………..Hypoxic responses during wake and sleep periods were not different between the genotypes.

Spontaneous but not postsigh sleep apneas were more frequent in ORX-KO than in WT littermates during both SWS and REM sleep. Our findings suggest that orexin plays a crucial role both in CO(2) sensitivity during wakefulness and in preserving ventilation stability during sleep.


Deng et al 2007

Abstract – Japan

We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods

. …. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods.

…. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. …Our findings suggest that orexin plays a crucial role in CO(2) sensitivity at least during wake periods in mice.


Diniz et al 2008

Abstract – Boston

Orexin-producing neurons are clearly essential for the regulation of wakefulness and sleep because loss of these cells produces narcolepsy.

However, little is understood about how these neurons dynamically interact with other wake- and sleep-regulatory nuclei to control behavioral states.

……..Using survival analysis of wake bouts in wild-type and orexin knockout mice, we found that orexins are necessary for the maintenance of long bouts of wakefulness, but orexin deficiency has little impact on wake bouts <1 min.

Since orexin neurons often begin firing several seconds before the onset of waking, this suggests a surprisingly delayed onset (>1 min) of functional effects. ……….This delay has important implications for understanding the control of wakefulness and sleep because increasing evidence suggests that different mechanisms are involved in the production of brief and sustained wake bouts.

I had huge problems with this during chemo, either from the chemo or the steroids, crashing into sleep and crashing instantly awake over and over again.

Is orexin connected to PTSD and depression dleep difficulties?

……………..We incorporated these findings into a mathematical model of the mouse sleep/wake network. Orexins excite monoaminergic neurons and we hypothesize that orexins increase the monoaminergic inhibition of sleep-promoting neurons in the ventrolateral preoptic nucleus. We modeled orexin effects as a time-dependent increase in the strength of inhibition from wake- to sleep-promoting populations and the resulting simulated behavior accurately reflects the fragmented sleep/wake behavior of narcolepsy and leads to several predictions.

……….By integrating neurophysiology of the sleep/wake network with emergent properties of behavioral data, this model provides a novel framework for investigating network dynamics and mechanisms associated with normal and pathologic sleep/wake behavior.


Mochizuki et al 2004

Abstract – Boston

Narcolepsy is caused by a lack of orexin (hypocretin), but the physiologic process that underlies the sleepiness of narcolepsy is unknown.

………Using orexin knock-out (KO) mice as a model of narcolepsy, we critically tested the three leading hypotheses: poor circadian control of sleep and wakefulness, inadequate activation of arousal regions, or abnormal sleep homeostasis.

……Compared with wild-type (WT) littermates, orexin KO mice had essentially normal amounts of sleep and wake, but wake and non-rapid eye movement (NREM) bouts were very brief, with many more transitions between all behavioral states.

In constant darkness, orexin KO mice had normal amplitude and timing of sleep-wake rhythms, providing no evidence for disordered circadian control.

……….When placed in a new, clean cage, both groups of mice remained awake for approximately 45 min, demonstrating that, even in the absence of orexin, fundamental arousal regions can be engaged to produce sustained wakefulness.

………..After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal.

These experiments demonstrate that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems.

Instead, the fragmented behavior of orexin KO mice may be best described as behavioral state instability, with apparently

…………low thresholds to transition between states.

I know they are only talking about sleep and wakefulness here, but I also know that emotional dysregulation also creates difficulties in transitions between emotional states – does not go well – and is connected to disoriented and disorganized attachment – given the other research on the pervasiveness of orexin neurons, perhaps these difficulties between state shifts  are related


Mochizuki et al 2006

Abstract – Boston

Core body temperature (Tb) is influenced by many physiological factors, including behavioral state, locomotor activity, and biological rhythms.

……..To determine the relative roles of these factors, we examined Tb in orexin knockout (KO) mice, which have a narcolepsy-like phenotype with severe sleep-wake fragmentation. Because

orexin is released during wakefulness and is thought to promote heat production,

we hypothesized that orexin KO mice would have lower Tb while awake. Surprisingly, Tb was the same in orexin KO mice and wild-type (WT) littermates during sustained wakefulness. Orexin KO mice had normal diurnal variations in Tb, but the ultradian rhythms [a biological rhythm with an ultrashort period and much higher frequency–eg, heartbeat, breath] of Tb, locomotor activity, and wakefulness were markedly reduced. During the first 15 min of spontaneous sleep, the Tb of WT mice decreased by 1.0 degrees C, but Tb in orexin KO mice decreased only 0.4 degrees C. Even during intense recovery sleep after 8 h of sleep deprivation, the Tb of orexin KO mice remained 0.7 degrees C higher than in WT mice. This blunted fall in Tb during sleep may be due to inadequate activation of heat loss mechanisms or sustained activity in heat-generating systems.

These observations reveal an unexpected role for orexin in thermoregulation. ………In addition, because

heat loss is an essential aspect of sleep,

the blunted fall in Tb of orexin KO mice may provide an explanation for the fragmented sleep of narcolepsy.


Ma, Shaw & Mitrofanis 2008

Abstract – Australia

This study explores whether

………..melatonin neuroprotects dopaminergic cells of the substantia nigra pars compacta (SNc) from degeneration

…….. Our results – using unbiased stereology – showed that there were more TH(+) (50%) and Nissl-stained (30%) cells in the SNc of the Mel-MPTP group compared to the MPTP group, indicating a clear saving or neuroprotection of these cells. In fact, we found no significant difference between the number of TH(+) and Nissl-stained SNc cells in the Mel-MPTP group compared to the controls, namely Saline and Mel groups. This indicated that melatonin pre-treatment potentially neuroprotected all the SNc cells from MPTP toxicity and death.


Behr et al 2000

Abstract – Germany

Schizophrenia is considered to be associated with an abnormal functioning of the hippocampal output. The high clinical potency of antipsychotics that act as antagonists at dopamine (DA) receptors indicate a hyperfunction of the dopaminergic system.

……….The subiculum obtains information from area CA1 and the entorhinal cortex and represents the major output region of the hippocampal complex.

To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of DA on alveus- and perforant path-evoked excitatory postsynaptic currents (EPSCs) in subicular neurons was examined

…………..The results indicate that DA strongly depresses the hippocampal and the entorhinal excitatory input onto subicular neurons

…………by decreasing the glutamate release following activation of presynaptic D1-like DA receptors.


Aubert et al 2000

Abstract – France

The striatum is regulated by dopaminergic inputs from the substantia nigra.

These results demonstrate that the striatal organizational pattern of D1 and D2 receptor segregation in distinct neuronal populations described in rodent also exists in primate.


Lu, Ghasemzadeh & Kalivas 1998

Abstract – Washington

… to determine the distribution of messenger RNAs for the D1 dopamine receptor, D2 dopamine receptor, beta-preprotachykinin or preproenkephalin in the neurons projecting from the nucleus accumbens to the ventral pallidum and the ventral tegmental area.

Neurons were quantified in both the core and the shell of the nucleus accumbens to estimate the proportion of neurons projecting to the ventral pallidum or ventral tegmental area that contain transcripts for D1 receptors, D2 receptors, beta-preprotachykinin or preproenkephalin.

…. A high percentage of nucleus accumbens neurons innervating the ventral tegmental area expressed messenger RNAs for D1 receptors (72%) and beta-preprotachykinin (62%), while less than 3% of the neurons contained messenger RNAs for preproenkephalin or D2 receptors.

………..The neurons projecting to the ventral pallidum did not show the discrete distribution of transcripts as was observed in the accumbens-ventral tegmental area projection.

…….. Preproenkephalin messenger RNA was identified in 46% of the neurons innervating the ventral pallidum, and D2 receptor messenger RNA was found in approximately 40% of the cells.

………A large minority of neurons projecting from the nucleus accumbens to the ventral pallidum also expressed messenger RNAs for D1 receptors (37%) and beta-preprotachykinin (35%).

………..While a higher percentage of D1 receptor, and beta-preprotachykinin messenger RNA expressing cells were located in the shell than in the core of the nucleus accumbens, the percentage tended to be higher in the core for cells expressing D2 receptors or preproenkephalin messenger RNA.

These data indicate that messenger RNAs for D2 receptors and enkephalin are selectively expressed in the accumbens-pallidal projection while transcripts encoding D1 receptors and substance P are contained in the efferent projections to both the ventral pallidum and ventral tegmental area.

……….The presence of D1 receptor and beta-preprotachykinin messenger RNAs in both mesencephalic and pallidal projections contrasts output from the striatum where the expression of D1 receptor and beta-preprotachykinin messenger RNAs is primarily restricted to the mesencephalic projection.


Le Moine & Bloch 1996

Abstract – France

The D3 dopamine receptor,

………belonging to the D2-like receptor subfamily,

……….displays both specific pharmacology and a unique pattern of expression, especially compared to the D1 and D2 receptors.

A rat D3 complementary RNA probe labelled with [35S]UTP was used to map the neurons expressing the D3 receptor gene in the rat brain. In particular, we identified the phenotype of the neurons containing D3 messenger. RNA in the nucleus accumbens, with respect to the striatal segregated populations of enkephalin and substance P neurons, by using strategies of double in situ hybridization.

……..In addition, comparison with D1 and D2 receptor gene expression was performed to study the potential co-localization of several dopamine receptors within the same neurons in the ventral striatum.

……..The highest level of D3 messenger RNA was detected in the islands of Calleja and the nucleus accumbens.

………Other areas such as the caudate-putamen, some hypothalamic, thalamic and cortical areas and lobule 10 of the cerebellum also contained low but significant levels of D3 messenger RNA.

Our results demonstrate that the D3 receptor is co-expressed either with D1 or with D2 receptor, both in the core and shell regions, in a subpopulation of substance P and enkephalin neurons, respectively.

……….They also suggest that a significant part of the accumbal neurons only express either D1 or D2,

……without co-expression with the D3 receptor.

These data imply that dopamine in the nucleus accumbens may act on each population of efferent neurons via the co-expression of two distinct dopamine receptors (D1+D3 or D2+D3),

……….and that synergistic [simultaneous action of separate things that have a greater total effect than the sum of their individual effect.] D1-like/D2-like effects may occur at the level of a single neuron,

…………through the co-expression of D1 and D3 receptors in a significant proportion of substance P neurons (16% or 26% in the core and shell regions, respectively.



no authors listed 2008 – article in Ukrainian

[Antioxidants prevent experimental hemiparkinsonism in rats]

We studied the influence of antioxidants (trolox, melatonin and coenzyme Q10) on 6-hydroxydopamine-induced degeneration in the substantia nigra dopaminergic neurons from the left brain hemisphere.

………. It has been shown that all tested antioxidants reduced a number of animals with apomorphine-induced behavioral asymmetry in a different degree: ….coenzyme Q10 reduced it twofold,

…..trolox – fivefold and…

……melatonin – sevenfold.

We suggest that a neuroprotective effects of trolox, melatonin and coenzyme Q10 are associated with their ability to block the mitochondrial pore openings in the nervous cells under exploration, and this is the way to prevent apoptotic death.

…………..An oxidative stress has been proved to take part in the apoptosis in dopamine-producing neurons in the substantia nigra,

…………….and tested antioxidants have been shown to be effective in preventing neurodegeneration.


Talanov et al 2006

Abstract – Ukrainian

In the study the role of apoptosis in development of dopaminergic neuronal cell death within substantia nigra (parts compacta) and ventral tegmental area induced by 6-OHDA was investigated.

It was found that

………intermittent hypoxia and

………..the water-soluble vitamine E (Trolox) and

………….melatonin, as

…………….antioxidants and inhibitors of mitochondrial permeability transition pore protect dopaminergic cells from cytotoxic effect of 6-OHDA. ………….It is supposed that mitochondrial permeability transition pore plays an important role in apoptosis of neurons in the brain.


Lavialle et al 2008

Abstract – France


Several studies suggest that (n-3) PUFA [(n-3) polyunsaturated fatty acid] may play a role in the regulation of cognitive functions, locomotor and exploratory activity, and affective disorders. Additionally, (n-3) PUFA affect pineal function, which is implicated in the sleep-wake rhythm.

However, no studies to our knowledge have explored the role of PUFA on the circadian system.

We investigated the effect of an (n-3) PUFA-deficient diet on locomotor and pineal melatonin rhythms in Syrian hamsters used as model species in circadian rhythm research.

To assess the possible relationship between voluntary wheel running activity and dopaminergic neurotransmission, we also measured endogenous monoamine concentrations in the striatum.

……….Two-month-old male hamsters, fed either an (n-3) PUFA-deficient or an (n-3) PUFA-adequate diet, were housed individually in cages equipped with run wheels. At 3 mo, cerebral structures were extracted for biochemical and cellular analysis.

In (n-3) PUFA-deficient hamsters, the induced changes in the pineal PUFA membrane phospholipid composition were associated with a reduction in the nocturnal peak level of melatonin that was 52% lower than in control hamsters

The (n-3) PUFA-deficient hamsters also had higher diurnal … and nocturnal …) locomotor activity than the control hamsters, in parallel with activation of striatal dopaminergic function

…….The (n-3) PUFA-deficient hamsters exhibited several symptoms: …chronic locomotor hyperactivity,

….disturbance in melatonin rhythm, a

…..nd striatal hyperdopaminergia.

We suggest that an (n-3) PUFA-deficient diet lessens the melatonin rhythm, weakens endogenous functioning of the circadian clock, and plays a role in nocturnal sleep disturbances as described in attention deficit/hyperactivity disorder.



Hau 2007

Abstract – Ecology and Evolutionary Biology, Guyot Hall, Princeton University, Princeton, NJ 08544, USA. hau@princeton.edu

Regulation of male traits by testosterone: implications for the evolution of vertebrate life histories.

The negative co-variation of life-history traits such as fecundity and lifespan across species suggests the existence of ubiquitous trade-offs.

Mechanistically, trade-offs result from the need to differentially allocate limited resources to traits like reproduction versus self-maintenance, with selection favoring the evolution of optimal allocation mechanism.

Here I discuss the physiological (endocrine) mechanisms that underlie optimal allocation rules and how such rules evolve.

The hormone


may mediate life-history trade-offs due to its pleiotropic actions in male vertebrates.

the ‘evolutionary potential hypothesis’

proposes that testosterone signaling mechanisms and male traits

evolve independently.

In the latter scenario, the linkage between hormone and traits itself can be shaped by selection, leading to variation in trade-off functions. I will review recent case studies supporting the evolutionary potential hypothesis and suggest micro-evolutionary experiments to unravel the

mechanistic basis of life-history evolution.


Roff, Heibo & Vellestad 2006

Abstract – Department of Biology, University of California, Riverside, CA 92521, USA. derek.roff@ucr.edu

The importance of growth and mortality costs in the evolution of the optimal life history.

A central assumption of life history theory

is that the evolution of the component traits

is determined in part by trade-offs between these traits.

Whereas the existence of such trade-offs has been well demonstrated, the relative importance of these remains unclear. In this paper we use optimality theory to test the hypothesis that the trade-off between present and future fecundity [the intellectual productivity of a creative imagination; The quality or power of producing abundantly; fruitfulness or fertility] induced by the costs of continued growth is a sufficient explanation for the optimal age at first reproduction, alpha, and the optimal allocation to reproduction, G, in 38 populations of perch and Arctic char. This hypothesis is rejected for both traits and we conclude that this trade-off, by itself, is an insufficient explanation for the observed values of alpha and G. Similarly, a fitness function that assumes a mortality cost to reproduction but no growth cost cannot account for the observed values of alpha. In contrast, under the assumption that fitness is maximized, the observed life histories can be accounted for by the joint action of trade-offs between growth and reproductive allocation and between mortality and reproductive allocation (Individual Juvenile Mortality model). Although the ability of the growth/mortality model to fit the data does not prove that this is the mechanism driving the evolution of the optimal age at first reproduction and allocation to reproduction, the fit does demonstrate that the hypothesis is consistent with the data and hence cannot at this time be rejected. We also examine two simpler versions of this model, one in which adult mortality is a constant proportion of juvenile mortality [Proportional Juvenile Mortality (PJM) model] and one in which the proportionality is constant within but not necessarily between species [Specific Juvenile Mortality (SSJM) model]. We find that the PJM model is unacceptable but that the SSJM model produces fits suggesting that, within the two species studied, juvenile mortality is proportional to adult mortality but the value differs between the two species.


Larke & Crews 2006

Abstract – Kent State University, USA.

Parental investment, late reproduction, and increased reserve capacity are associated with longevity in humans.

Throughout the living world trade-offs between reproductive success and longevity have been observed.

In general, two extremes of life history patterning are reported, r- and K-selected species.

The latter tend toward larger body sizes, few offspring from any one pregnancy, few offspring over the female reproductive span, longer life spans, and greater parental investment (PI: all efforts and expenses associated with the production, gestation, post-natal care, feeding, and protection of young) (e.g., whales, elephants, hominids).

r-selected species tend toward smaller body size, multiple births/litters per pregnancy, female production of many gametes and offspring over the life span, and low levels of PI (e.g., most plants, insects, mice).

These differences have significant influences on physiological variation among human populations.

Across human samples, reproductive success (RS: the number of offspring successfully birthed and reared to reproductive age) has been reported to vary positively, negatively, and not at all with longevity of women.

This complexity may be in part due to the fact that both early-life and late-life fecundity are associated with longevity in women, while total parity seems a poor gauge of female longevity in humankind.

Large variations in associations of RS with longevity in women suggest that multiple factors may confound this association. One confounding factor is that among women, reproductive success (RS is largely determined not by fecundity, but by the quality of PI available to offspring.

As I discover that mental health genes are probably tied to reproductive success aspects, the more I realize that poor parenting quality creates such a toxic interaction with the world that the mental health adaptations the offspring make lessen their own reproductive fitness on many levels and in many ways.  How we turn out as adults is not only a result of our parenting as it is built into our bodies, brains, nervous systems, immune systems – but also signals potential mates (and others in our social network as a species) not only of our own fitness, but signals about the safety or toxicity of the world we live in.

We are losing the ability to read these signals or to understand them.

When Panksepp’s monkeys stick together according to brain damage, they are reading one another’s signals – including reproductive ones.

Among modern humans, PI is more complex, longer lasting (both relatively and absolutely), and extensive than for any other mammal.

This suggests that modern human life history is a reflection of the co-evolution of longevity and extensive PI as part of our species’ biocultural evolution.

The need for long-term PI has greatly shaped human physiological variation and patterns of longevity.


Crews & Gerber 2003

Abstract – Department of Anthropology, School of Public Health, Ohio State University, Columbus, Ohio, USA.

Reconstructing life history of hominids and humans.

Aspects of life history, such as processes and timing of development, age at maturation, and life span are consistently associated with one another across the animal kingdom.

Species that develop rapidly tend to mature and reproduce early, have many offspring, and exhibit shorter life spans (r-selection) than

those that develop slowly, have extended periods of premature growth, mature later in life, reproduce later and less frequently, have few offspring and/or single births, and exhibit extended life spans (K-selection).

In general, primates are among the most K-selected of species.

A suite of highly derived life history traits characterizes humans.

Among these are physically immature neonates, slowed somatic development both in utero and post-natally, late attainment of reproductive maturity and first birth, and extended post-mature survival.

Exactly when, why, and through what types of evolutionary interactions this suite arose is currently the subject of much conjecture and debate.

Humankind’s biocultural adaptations have helped to structure human life history evolution in unique ways not seen in other animal species.

Among all species,

life history traits may respond rapidly

to alterations in selective pressures

through hormonal processes.

Selective pressures on life history likely varied widely among hominids and humans over their evolutionary history.

This suggests that current patterns of human growth, development, maturation, reproduction, and post-mature survival may be of recent genesis, rather then long-standing adaptations.

Thus, life history patterns observed among contemporary human and chimpanzee populations may provide little insight to those that existed earlier in hominid/human evolution.

We can still come to understand the process and apply logic – epigenetics included


Romanovskii 2002

Abstract – article in Russian – Department of General Ecology, Biological Faculty, M.V. Lomonosov Moscow State University, Moscow 119899, Russia.

[Life-history variation within a taxon: a comparative analysis of birds and mammals]

Most studies on life-history evolution discuss the necessity of distinguishing between extrinsic and intrinsic sources of variability in life-history traits.

I use log/log plots of yearly neonate production in daughters (b) versus adult mortality (Ma) for 75 bird species and 88 mammal species to compare graphically life-history “fields” arranged by these selective forces along a “slow-fast continuum”. Under the assumptions of steady-state and linear relationship between adult mortality and reproductive effort, as well as between juvenile survival and relative neonate weight, it is possible to place additional axes in the two-dimensional plot, and to predict covariations among demographic and individual growth traits. The functional regression analysis shows, that the assumptions are completely fulfilled, at least for birds, but

mammals show nonlinear relationship between adult mortality and reproductive effort.

This can be explained by peculiarities of metabolism and parental care in small mammals with high reproductive output.

Hence, for birds the axis of relative neonate weight approximately coincides in direction with the juvenile survivorship axis, but this is not a case for mammals.

In both taxa, the relative neonate weight is an invariant in relation to fecundity and adult mortality (but not in relation to adult body weight). This important feature, together with other intrinsic (energetic and phylogenetic) constraints, explains well-documented close covariations among traits, even when the effect of body size is factored out.

It is argued that life-history and body size variations in birds and mammals mainly depend on a pattern of temporal resource deficiency, although this impact cannot be separated from that of extrinsic juvenile mortality.

I survived my mother’s treatment of me because there were enough other resources available to me to offset her treatment and the damage it did to me as I developed.  This might not have been so in a less developed cultural environment – but then parenting was a tribally shared obligation and her treatment of me would not have been allowed – “back then” as it has been in our recent history.

Single couple parenting is only possible because we have enough other resources available to us for this form of parenting to exist.  There has to be enough resources to balance the equation for anybody to survive past childhood to the child bearing years.  When the equation is not balanced – all things being considered – survival does not happen.  If there is a cost for survival in terms of internal adaptations that have to be made by the individual in conjunction with stress from the environment and genetic alterations, we pay that price, also.


Sinervo et al 2008

Abstract – Department of Ecology and Evolutionary Biology, University of California, Santa Cruz, CA 95064, USA. sinervo@biology.ucsc.edu

The role of pleiotropy vs signaller-receiver gene epistasis in life history trade-offs: dissecting the genomic architecture of organismal design in social systems.

Traditional life history theory ignores trade-offs

due to social interactions,

yet social systems expand the set of possible trade-offs affecting a species evolution—

by introducing asymmetric interactions between the sexes, age classes and invasion of alternative strategies.

Which themselves no doubt evolved related to food and protection – division of labor

We outline principles for understanding gene epistasis

due to signaller-receiver dynamics,

gene interactions between individuals,

and impacts on life history trade-offs.

Signaller-receiver epistasis create trade-offs among multiple correlated traits that affect fitness, and generate multiple fitness optima conditional on frequency of alternative strategies.

In such cases, fitness epistasis [The masking of the effects of one gene by the action of another, example: widow’s peak masked by the baldness gene] generated by selection can maintain linkage disequilibrium, even among physically unlinked loci.

In reviewing genetic methods for studying life history trade-offs, we conclude that current artificial selection or gene manipulation experiments focus on pleiotropy.

Multi-trait selection experiments,

multi-gene engineering methods

or multiple endocrine manipulations

can test for epistasis and circumvent these limitations.

In nature, gene mapping in field pedigrees is required to study social gene epistasis and associated trade-offs.

Moreover, analyses of correlational selection and frequency-dependent selection are necessary to study epistatic social system trade-offs, which can be achieved with group-structured versions of Price’s (1970) equation.


Kirk 2005

Abstract – Department of Biology, Washington University, Campus box 1229, St. Louis, MO 63130, USA. kirk@biology.wustl.edu

A twelve-step program for evolving multicellularity and a division of labor

The volvocine algae provide an unrivalled opportunity to explore details of an evolutionary pathway leading from a unicellular ancestor to multicellular organisms with a division of labor between different cell types.

Members of this monophyletic group of green flagellates range in complexity from unicellular Chlamydomonas through a series of extant organisms of intermediate size and complexity to Volvox, a genus of spherical organisms that have thousands of cells and a germ-soma division of labor.

It is estimated that these organisms all shared a common ancestor about 50 +/- 20 MYA. Here we outline twelve important ways in which the developmental repertoire of an ancestral unicell similar to modern C. reinhardtii was modified to produce first a small colonial organism like Gonium that was capable of swimming directionally, then a sequence of larger organisms … in which there was an increasing tendency to differentiate two cell types, and eventually Volvox carteri with its complete germ-soma division of labor.

OK, so it’s a long way to human societies’ division of labor – but it’s a related process!  That’s why we have the sensitivity spectrum


Michod et al 2006

Abstract – Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, USA. michod@u.arizona.edu

Life-history evolution and the origin of multicellularity.

The fitness of an evolutionary individual

can be understood in terms of its two basic components: survival and reproduction.

Actually, nature only cares about the reproduction part of this equation – that’s what survival is all about

As embodied in current theory, trade-offs between these fitness components drive the evolution of life-history traits in extant multicellular organisms.

Here, we argue that the evolution of germ-soma specialization and the emergence of individuality at a new higher level during the transition from unicellular to multicellular organisms are also consequences of trade-offs between the two components of fitness-survival and reproduction.

The models presented here explore fitness trade-offs at both the cell and group levels during the unicellular-multicellular transition.

When the two components of fitness negatively covary at the lower level there is an enhanced fitness at the group level equal to the covariance of components at the lower level.

We show that the group fitness trade-offs are initially determined by the cell level trade-offs.

However, as the transition proceeds to multicellularity, the group level trade-offs depart from the cell level ones, because certain fitness advantages of cell specialization may be realized only by the group.

The curvature of the trade-off between fitness components is a basic issue in life-history theory and we predict that this curvature is concave in single-celled organisms but becomes increasingly convex as group size increases in multicellular organisms.

We argue that the increasingly convex curvature of the trade-off function

is driven by the initial cost

of reproduction to survival

which increases as group size increases.

To illustrate the principles and conclusions of the model, we consider aspects of the biology of the volvocine green algae, which contain both unicellular and multicellular members.


Miller 2002

Abstract – Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA. stmiller@umbc.edu

Taming the fierce roller: an “enhanced” understanding of cellular differentiation in Volvox.

Few organisms offer a better opportunity to explore the mechanisms of cellular differentiation, and their origins, than Volvox.

Volvox consists of just two cell types, germ and soma, and is the most complex member of a family of green algae that includes unicellular and multicellular relatives.

At the heart of the cell-fate determination program

of Volvox carteri is the regA gene,

which encodes a putative transcriptional repressor

that prevents somatic cells from expressing

reproductive functions.

Stark et al. have dissected the regA gene to determine how its expression is restricted to somatic cells.

Their results suggest that regA expression is controlled by multiple enhancers, the most important of which prevents transcription in reproductive cells.

While these findings shed light on Volvox development, they also raise a new set of questions about the mechanisms that control the germ-soma dichotomy in this organism.

This is getting closer to the level of explaining epigenetic possibilities, I suppose.

Solari et al 2006

Abstract – Department of Ecology and Evolutionary Biology, Program in Applied Mathematics, University of Arizona, Tucson, AZ 85721, USA.

Multicellularity and the functional interdependence of motility and molecular transport.

Benefits, costs, and requirements accompany the transition from motile totipotent [A class of stem cells that can develop into the full organism from which the stem cell was derived] unicellular organisms to multicellular organisms having cells specialized into reproductive (germ) and vegetative (sterile soma) functions such as motility [spontaneous motion].


Kirk 2001

Abstract – Department of Biology, Washington University, St. Louis, Missouri 63130, USA. kirk@biology.wustl.edu

Germ-soma differentiation in volvox.

Volvox carteri is a spherical green alga with a predominantly asexual mode of reproduction and a complete germ-soma division of labor.

Its somatic cells are specialized for motility, incapable of dividing, and programmed to die when only a few days old, whereas its gonidia (asexual reproductive cells) are nonmotile, specialized for growth and reproduction, and potentially immortal.

When a gonidium is less than 2 days old it divides to produce a juvenile spheroid containing all of the somatic cells and gonidia that will be present in an adult of the next generation.

The first visible step in germ-soma differentiation is a set of asymmetric cleavage divisions in the embryo that set apart small somatic initials from their large gonidial-initial sister cells.

Three types of genes have been found to play key roles in germ-soma specification.

First a set of gls genes act in the embryos to shift cell-division planes, resulting in the asymmetric divisions that set apart the large-small sister-cell pairs.

Then a set of lag genes act in the large cells to prevent somatic differentiation, while the regA gene acts in the small cells to prevent reproductive development.

An inducible transposon was used to tag and recover some of these and other developmentally important genes. The glsA gene encodes a chaperone-like protein that, like another chaperone that is one of its putative binding partners, is associated with the cell division apparatus, although how this leads to asymmetric division remains to be elucidated.

The regA gene encodes a somatic-cell-specific nuclear protein that appears to function by repressing genes required for chloroplast biogenesis, thereby preventing somatic cells from growing enough to reproduce.

Somatic-cell-specific expression of regA is controlled by three intronic enhancers.


The following abstracts put this whole fitness for reproductive success reality into perspective with the larger picture of the success of our species throughout our evolution.

Steve called my book’s genre forensic autobiography.  It’s now turning into forensic archeological evolutionary autobiography.


Wood & Lonergan 2008

Abstract – The George Washington University, Department of Anthropology, Center for the Advanced Study of Hominid Paleobiology, Washington, DC 20052, USA. bernardwood@gmail.com

The hominin fossil record: taxa, grades and clades.

This paper begins by reviewing the fossil evidence for human evolution.

It presents summaries of each of the taxa recognized in a relatively speciose hominin taxonomy.

These taxa are grouped in grades,

namely possible and probable hominins, archaic hominins, megadont archaic hominins, transitional hominins, pre-modern Homo and anatomically modern Homo.

The second part of this contribution considers some of the controversies that surround hominin taxonomy and systematics.

The first is the vexed question of how you tell

an early hominin from an early panin,

or from taxa belonging to an extinct clade closely related to the Pan-Homo clade.

Secondly, we consider how many species should be recognized within the hominin fossil record, and review the philosophies and methods used to identify taxa within the hominin fossil record.

Thirdly, we examine how relationships within the hominin clade are investigated, including descriptions of the methods used to break down an integrated structure into tractable analytical units, and then how cladograms are generated and compared.

We then review the internal structure of the hominin clade, including the problem of how many subclades should be recognized within the hominin clade, and we examine the reliability of hominin cladistic hypotheses. The last part of the paper reviews the concepts of a genus, including the criteria that should be used for

recognizing genera within the hominin clade.


Robson & Wood 2008

Abstract – Department of Anthropology, University of Utah, Salt Lake City, UT 84112, USA. robson@umnh.utah.edu

Hominin life history: reconstruction and evolution.

In this review we attempt to reconstruct the evolutionary history of hominin life history from extant and fossil evidence.

We utilize demographic life history theory and distinguish

life history variables, traits such as weaning, age at sexual maturity, and life span, from

life history-related variables such as body mass, brain growth, and dental development.

The latter are either linked with, or can be used to make inferences about, life history, thus providing an opportunity for estimating life history parameters in fossil taxa.

We compare the life history variables of modern great apes

and identify traits that are likely to be shared by the last common ancestor of Pan-Homo and those likely to be derived in hominins.

All great apes exhibit slow life histories and we infer this to be true of the last common ancestor of

Pan-Homo and the stem hominin.

Modern human life histories are even slower, exhibiting distinctively long post-menopausal life spans and later ages at maturity[this is currently changing in our country!], pointing to a reduction in adult mortality since the Pan-Homo split.

We suggest that lower adult mortality, distinctively short interbirth intervals, and early weaning characteristic of modern humans are derived features resulting from cooperative breeding.

That is what we have in an interconnected, cooperative society!

We evaluate the fidelity of three life history-related variables, body mass, brain growth and dental development, with the life history parameters of living great apes. We found that body mass is the best predictor of great ape life history events.

Brain growth trajectories and dental development and eruption

are weakly related proxies

and inferences from them should be made with caution.

We evaluate the evidence of life history-related variables available for extinct species and find that

prior to the transitional hominins

there is no evidence of any hominin taxon possessing a body size, brain size or aspects of dental development

much different from what we assume to be the primitive life history pattern for the Pan-Homo clade.

Data for life history-related variables among the transitional hominin grade are consistent and

none agrees with a modern human pattern.

Aside from mean body mass,

adult brain size, crown and root formation times,

and the timing and sequence of dental eruption of Homo erectus

are inconsistent with that of modern humans.

Homo antecessor fossil material suggests a brain size similar to that of Homo erectus s. s., and crown formation times that are not yet modern, though there is some evidence of modern human-like timing of tooth formation and eruption.

The body sizes, brain sizes, and dental development of Homo heidelbergensis and Homo neanderthalensis are consistent with a modern human life history but samples are too small to be certain that they have life histories within the modern human range.

As more life history-related variable information for hominin species accumulates we are discovering that they can also have distinctive life histories that do not conform to any living model.

At least one extinct hominin subclade, Paranthropus,

has a pattern of dental life history-related variables

that most likely set it apart from the life histories

of both modern humans and chimpanzees.


Cameron 2003

Abstract – School of Archaeology & Anthropology, Australian National University, Canberra, ACT, Australia 0200. dwc@anatomy.usyd.edu.au

Early hominin speciation at the Plio/Pleistocene transition.

Over the last half-decade or so,

there has been an explosion in the recognition of

hominin genera and species.

We now have the

late Miocene genera Orrorin and Sahelanthropus,

the mid Pliocene genus Kenyanthropus,

three new Pliocene species of Australopithecus (A. anamensis, A. garhi and A. bahrelghazali)

and a sub species of Ardipithecus (Ar. r. kadabba)

to contend with.

Excepting also the more traditional species allocated to Paranthropus, Australopithecus and early Homo

we are approaching around

15 species over 5 million years

(excluding hominin evolution over the last one million years).

Can such a large number of hominin species be justified?

An examination of extant hominid

(Gorilla gorilla, Pan troglodytes, and Pan paniscus)

anatomical variability indicates that the range of fossil hominin variability supports the recognition of this large number of fossil species.

It is also shown that not all hominins are directly related to the emergence of early Homo and as such have become extinct.

Indeed the traditional australopithecine species ‘A’. anamensis, ‘A’. afarensis and ‘A’. garhi are considered here to belong to a distinct genus Praeanthropus. They are also argued not be hominins, but rather an as yet undefined hominid group from which the more derived hominins evolved.

The first hominin is represented by A. africanus or a hominin very much like it.

The Paranthropus clade is defined by a derived heterochronic condition of peramorphosis, associated with sequential progenesis (contraction of successive growth stages) in brain and dental development, but a mixture of peramorphic and paedomorphic features in its craniofacial anatomy.

Conversely, Kenyanthropus and Homo both share a pattern of peramorphosis, associated with sequential hypermorphosis (prolongation of successive growth stages) in brain development, and paedomorphosis processes in cranial, facial and dental development.

This suggests, that these two clades share an important synapomorphy not recognized in the parsimony analyses, suggesting that they may form a sister group relationship to the exclusion of Paranthropus.

This highlights the need to re-interpret phylogenetic results in terms of function and development.

The rapid speciation and extinction as argued here is in keeping with other fossil groups in Africa at the Plio/Pleistocene transition.

This emphasizes that we must approach the

pre-australopithecines and hominins

as part of the endemic African fauna,

and not in isolation to the evolutionary and climatic processes that were operating all around them.


Tocheri et al 2008

Abstract – Human Origins Program, Department of Anthropology, National Museum of Natural History, Smithsonian Institution, Washington DC, USA. tocherim@si.edu

The evolutionary history of the hominin hand since the last common ancestor of Pan and Homo.

Molecular evidence indicates

that the last common ancestor

of the genus Pan and the hominin clade

existed between 8 and 4 million years ago (Ma).

The current fossil record indicates

the Pan-Homo last common ancestor existed

at least 5 Ma and most likely between 6 and 7 Ma.

Together, the molecular and fossil evidence has important consequences for interpreting the evolutionary history of the hand

within the tribe Hominini (hominins).

Firstly, parsimony supports the hypothesis that the hand of the last common ancestor most likely resembled that of an extant great ape overall (Pan, Gorilla, and Pongo), and that of an African ape in particular.

Second, it provides a context for interpreting the derived changes to the hand that have evolved in various hominins.

For example, the Australopithecus afarensis hand is likely derived in comparison with that of the Pan-Homo last common ancestor in having shorter fingers relative to thumb length and more proximo-distally oriented joints between its capitate, second metacarpal, and trapezium.

This evidence suggests that these derived features evolved prior to the intensification of stone tool-related hominin behaviors beginning around 2.5 Ma.

However, a majority of primitive features most likely present in the Pan-Homo last common ancestor are retained in the hands of Australopithecus, Paranthropus/early Homo, and Homo floresiensis.

This evidence suggests that further derived changes

to the hands of other hominins

such as modern humans and Neandertals

did not evolve until after 2.5 Ma and possibly even later than 1.5 Ma, which is currently the earliest evidence of Acheulian technology.

The derived hands of modern humans and Neandertals may indicate a morphological commitment to tool-related manipulative behaviors beyond that observed in other hominins, including those (e.g. H. floresiensis) which may be descended from earlier tool-making species.

The mirror neuron system no doubt developed on a parallel corresponding pathway as there are neurons specific to tool recognition and use.


Crompton, Vereecke & Thorpe 2008

Abstract – School of Biomedical Sciences, The University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, UK. rhcromp@liv.ac.uk

Locomotion and posture from the common hominoid ancestor to fully modern hominins, with special reference to the last common panin/hominin ancestor.

Based on our knowledge of locomotor biomechanics and ecology we predict the locomotion and posture of the last common ancestors of

(a) great and lesser apes and their close fossil relatives (hominoids);

(b) chimpanzees, bonobos and modern humans (hominines); and

(c) modern humans and their fossil relatives (hominins).

We evaluate our propositions against the fossil record in the context of a broader review of evolution of the locomotor system from the earliest hominoids of modern aspect (crown hominoids) to early modern Homo sapiens.

While some early East African stem hominoids were pronograde, it appears that the adaptations which best characterize the crown hominoids are orthogrady and an ability to abduct the arm above the shoulder – rather than, as is often thought, manual suspension sensu stricto.

At 7-9 Ma (not much earlier than the likely 4-8 Ma divergence date for panins and hominins, see Bradley, 2008) there were crown hominoids in southern Europe which were adapted to moving in an orthograde posture, supported primarily on the hindlimb, in an arboreal, and possibly for Oreopithecus, a terrestrial context.

By 7 Ma, Sahelanthropus provides evidence of a Central African hominin, panin or possibly gorilline adapted to orthogrady, and both orthogrady and habitually highly extended postures of the hip are evident in the arboreal East African protohominin Orrorin at 6 Ma.

If the traditional idea that hominins passed through a terrestrial ‘knuckle-walking’ phase is correct, not only does it have to be explained how a quadrupedal gait typified by flexed postures of the hindlimb could have preadapted the body for the hominin acquisition of straight-legged erect bipedality, but we would have to accept a transition from stem-hominoid pronogrady to crown hominoid orthogrady, back again to pronogrady in the African apes and then back to orthogrady in hominins.

Hand-assisted arboreal bipedality, which is part of a continuum of orthograde behaviors, is used by modern orangutans to forage among the small branches at the periphery of trees where the core hominoid dietary resource, ripe fruit, is most often to be found.

Derivation of habitual terrestrial bipedality from arboreal hand-assisted bipedality requires fewer transitions, and is also kinematically and kinetically more parsimonious.


Pickford 2002

Abstract – Collège de France, Laboratoire de Paléontologie, UMR 8569 du CNRS, 8 rue Buffon, 75005 Paris, France.

Palaeoenvironments and hominoid evolution.

One of the key features that separates humans and their closest relatives (extinct species of the genus Homo and Praeanthropus and the australopithecines Australopithecus and Paranthropus) on the one hand, from the other hominoids, on the other, is their obligate bipedal locomotion when on the ground.

This major difference from the generally quadrupedal locomotion practiced by other hominoids (Pan, Gorilla, Pongo and many extinct lineages) is reflected in many parts of the body, including all the major bones in the legs, arms, trunk and cranium.

Locomotion has thus been of major interest to those interested in human origins, evolution, classification and phylogeny.

A major hurdle to studies of the origins of bipedalism concerns the paucity of African hominoid fossils between 15 Ma, when all the adequately known hominoids were quadrupedal (most were pronograde, but at least one lineage was orthograde), and 4.2 Ma by which time fully bipedal hominids were established in Africa.

Examination of Old World geology and palaeontology reveals a great deal about the evolution of palaeoenvironments and faunas during this period, and it is suggested that hominids evolved bipedal locomotion at the same time that there was a fundamental reorganization of faunas towards the end of the Miocene.

This faunal turnover resulted in the establishment of faunal lineages of “modern” aspect in Africa at the expense of “archaic” lineages which either went extinct or suffered a diminution of diversity.

Many of the “modern” lineages were adapted to open country habitats in which grass became a major component of the diet as shown by modifications in the cheek teeth.

Hominoids, in contrast, retained their traditional diet

but were obliged to forage over greater and greater areas

in order to do so, and this tactic led to pressures

to modify the locomotor system rather than the diet.

If bipedal hominids originated during this period, then the family Hominidae (sensu stricto) dates from about 8-7 Ma.


Senut 2002

Abstract – Laboratoire de Paléontologie du Muséum National d’Histoire Naturelle, UMR 8569 et GDR 983 CNRS, 8, rue Buffon, 75005 Paris, France.

From apes to humans: locomotion as a key feature for phylogeny.

If bipedalism has often been considered to be of a crucial interest for understanding hominid evolution, the acceptance of locomotor features to build phylogenies is still far from being a reality in the field.

Especially for hominid evolution, it still seems to be difficult to accept that traits, other than craniodental ones, can be useful for defining the major dichotomies.

The recent discovery of Australopithecus anamensis suggests a challenging view of the major dichotomy between apes and humans.

Whilst it is widely accepted that Ardipithecus ramidus is ancestral to Australopithecus anamensis, which in its turn is ancestral to Australopithecus afarensis and then to later hominids, the postcranial adaptations, which should be taken into account, suggest another branching pattern.

Based on the fact that by 4.0 million years two different locomotor patterns can be identified in hominids, two lineages would appear to be present:

the “Australopithecine” lineage

(with Australopithecus afarensis or Ardipithecus ramidus if the latter is really a hominid sensu stricto)

and the “Hominine” lineage (with Australopithecus anamensis = Praeanthropus africanus).



2 thoughts on “WELL-BEING

    • I have no expertise regarding breastfeeding other than my own personal experience. Sadly, 20 years after my youngest suffered his entire first year with serious ear infections did I finally find out that he was very possibly reacting to something in MY diet. I hope you have access to a good doctor to help you with this choice — does your baby have allergic colitis?

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