*Endocannabinoid System, Fear and Anxiety

Fear

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[NOTE:  These articles do not directly concern our endocannabinoid system, but does describe more about human fear]

Martinez et al 2007b

Abstract – Instituto de Neurociências & Comportamento-INeC, Campus USP, 14040-901, Ribeirão Preto, SP, Brazil.

Eur Neuropsychopharmacol. 2007 Nov;17(11):717-24. Epub 2007 Mar 29.

Links

Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray.

Martinez RC, Ribeiro de Oliveira A, Brandão ML.

The amygdala is an important filter

for unconditioned and conditioned aversive information.

The amygdala synthesizes the stimuli input

from the environment and then signals the degree of threat

that they represent

to the dorsal periaqueductal gray (dPAG),

which would be in charge of

selecting, organizing and executing

the appropriate defense reaction.

In this study, we examined the influence of fluoxetine microinjections (1.75 and 3.5 nmol/0.2 microL) into the lateral (LaA) and basolateral (BLA) amygdaloid nuclei on the freezing and escape responses induced by electrical stimulation of the dPAG. Freezing behavior was also measured after the interruption of the electrical stimulation of the dPAG. On the following day, these rats were also submitted to a contextual fear paradigm to examine whether these microinjections would affect the conditioned freezing to contextual cues previously associated with foot shocks. Fluoxetine injections into both amygdaloid nuclei did not change the freezing and escape thresholds, but disrupted the dPAG-post-stimulation freezing. Moreover, the conditioned freezing was enhanced by fluoxetine.

Whereas 5-HT mechanisms in the amygdala

facilitate the acquisition of conditioned fear

they inhibit the dPAG-post-stimulation freezing.

However, the unconditioned fear triggered by activation of the dPAG is produced downstream of the amygdala. These findings have important implications for the understanding of the neurochemical substrates that underlie panic and generalized anxiety disorders.

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Moreira & Lutz 2008

Addict Biol. 2008 Jun;13(2):196-212. Epub 2008 Apr 16.

Links

The endocannabinoid system: emotion, learning and addiction.

Moreira FA, Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 6, 55099 Mainz, Germany. moreira@uni-mainz.de

The identification of the cannabinoid receptor type 1 (CB1 receptor) was the milestone discovery in the elucidation of the behavioural and emotional responses induced by the Cannabis sativa constituent Delta(9)-tetrahydrocannabinol. The subsequent years have established the existence of the endocannabinoid system. The early view relating this system to emotional responses is reflected by the fact that N-arachidonoyl ethanolamine, the pioneer endocannabinoid, was named

anandamide after the Sanskrit word ‘ananda’, meaning ‘bliss’.

However, the emotional responses to cannabinoids are not always pleasant and delightful. Rather, anxiety and panic may also occur after activation of CB1 receptors. The present review discusses

three properties of the endocannabinoid system as an attempt to understand these diverse effects.

….First, this system typically functions ‘on-demand’, depending on environmental stimuli and on the emotional state of the organism.

….Second, it has a wide neuro-anatomical distribution, modulating brain regions with different functions in responses to aversive stimuli.

….Third, endocannabinoids regulate the release of other neurotransmitters that may have even opposing functions, such as GABA and glutamate.

Further understanding of the temporal, spatial and functional characteristics of this system is necessary to clarify its role in emotional responses and will promote advances in its therapeutic exploitation.

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Martinez et al 2007b

Eur Neuropsychopharmacol. 2007 Nov;17(11):717-24. Epub 2007 Mar 29.

Links

Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray.

Martinez RC, Ribeiro de Oliveira A, Brandão ML.

Instituto de Neurociências & Comportamento-INeC, Campus USP, 14040-901, Ribeirão Preto, SP, Brazil.

unconditioned fear triggered by activation of the dorsal periaqueductal gray dPAG is produced

downstream of the amygdala.

The amygdala is an important filter for unconditioned and conditioned aversive information.

The amygdala synthesizes the stimuli input from the environment

…..and then signals the degree of threat that they represent

…..to the dorsal periaqueductal gray (dPAG),

.which would be in charge of selecting, organizing and executing the appropriate defense reaction.

In this study, we examined the influence of fluoxetine microinjections (1.75 and 3.5 nmol/0.2 microL) into the lateral (LaA) and basolateral (BLA) amygdaloid nuclei

on the freezing and escape responses

induced by electrical stimulation of the dPAG. Freezing behavior was also measured after the interruption of the electrical stimulation of the dPAG. On the following day, these rats were also submitted to a contextual fear paradigm to examine whether these microinjections would affect the conditioned freezing to contextual cues previously associated with foot shocks. Fluoxetine injections into both amygdaloid nuclei did not change the freezing and escape thresholds, but disrupted the dorsal periaqueductal gray (dPAG) -post-stimulation freezing.

Moreover, the conditioned freezing was enhanced by fluoxetine.

Whereas 5-HT [serotonin] mechanisms in the amygdala facilitate the acquisition of conditioned fear

they inhibit the dPAG-post-stimulation freezing.

However, the unconditioned fear triggered by activation of the dPAG is produced

downstream of the amygdala.

These findings have important implications for the

understanding of the neurochemical substrates

that underlie panic and generalized anxiety disorders.

Linda note:  Yes – and this is what I have been looking for, though I don’t fully understand how this is so important.  Perhaps in the area of attachment, this system is what sticks our “insides” together, keeps us attached on our insides so that in our lives we can be attached on the “outside” to others of our species and to the world we live in.

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Neuroscience. 2003;120(4):1157-70.

Links

The rodent amygdala contributes to the production of cannabinoid-induced antinociception.

Manning BH, Martin WJ, Meng ID.

Department of Neuroscience, Merck Research Laboratories, 770 Sumneytown Pike WP46-300, West Point, PA 19486-0004, USA. barton_manning@merck.com

Neuropharmacology. 2008 Jan;54(1):141-50. Epub 2007 Jul 19.

Links

Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.

Moreira FA, Kaiser N, Monory K, Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany.

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Niyuhire et al 2007

Psychopharmacology (Berl). 2007 Apr;191(2):223-31. Epub 2007 Jan 9.

Links

The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific.

Niyuhire F, Varvel SA, Thorpe AJ, Stokes RJ, Wiley JL, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.

RATIONALE: Disruption of CB(1) receptor signaling through the use of CB(1) (-/-) mice or the CB(1) receptor antagonist rimonabant (SR141716)

…..has been demonstrated to

……impair extinction of learned responses in conditioned fear and Morris water maze tasks.

In contrast, CB(1) (-/-) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task. OBJECTIVES: The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks. MATERIALS AND METHODS: Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement.

After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session. RESULTS: Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks

………but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions.

Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task. CONCLUSIONS: These results support the hypothesis that

the CB(1) receptor plays a vital role in the extinction of aversive memories

This is a PTSD issue

……but is not essential for extinction of learned responses in appetitively motivated tasks.

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Finger et al 2008

Neuroimage. 2008 Dec;43(4):748-55. Epub 2008 Aug 28.

Links

Dissociable roles of medial orbitofrontal cortex in human operant extinction learning.

Finger EC, Mitchell DG, Jones M, Blair RJ.

Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. Elizabeth.Finger@lhsc.on.ca

Operant extinction, which features

modification of instrumental responses to stimuli following a change in associated reinforcement,

is an important form of learning for organisms in dynamic environments.

Animal studies have highlighted orbital and medial prefrontal cortex and amygdala as mediators of operant extinction. Yet little is known about the neural mediators of operant extinction learning in humans. Using a novel fMRI paradigm, we report dissociable functional responses in distinct regions of medial orbitofrontal cortex (mOFC) during successful appetitive and aversive based operant extinction.

During successful operant extinction, increased activity was observed in frontopolar OFC, while decreased activity was observed in caudal mOFC and rostral anterior cingulate cortex (rACC) relative to both (i) successful control trials where the reinforcement associated with the stimulus does not change; and (ii) successful acquisition trials during initial learning of the stimulus-reinforcement associations.

Functional connectivity analysis demonstrated inverse connectivity between frontopolar OFC and both rACC and the amygdala. These data support animal models suggesting the

importance of mOFC-amygdala interaction

during operant extinction

and expand our knowledge of the neural systems in humans. These findings suggest that in humans, frontopolar OFC modulates activity in caudal mOFC, rACC and amygdala during successful operant extinction learning.

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Egner, Jamieson & Gruzelier 2005

Neuroimage. 2005 Oct 1;27(4):969-78.

Links

Hypnosis decouples cognitive control from conflict monitoring processes of the frontal lobe.

Egner T, Jamieson G, Gruzelier J.

Functional MRI Research Center, Columbia University, Neurological Institute Box 108, 710 West 168th Street, New York, NY 10032, USA. te2111@columbia.edu

Hypnosis can profoundly alter sensory awareness and cognitive processing. While the cognitive and behavioral phenomena associated with hypnosis have long been thought to relate to attentional processes, the neural mechanisms underlying susceptibility to hypnotic induction and the hypnotic condition are poorly understood.

Here, we tested the proposal that highly hypnotizable individuals are particularly adept at focusing attention at baseline, but that their attentional control is compromised following hypnosis due to a decoupling between conflict monitoring and cognitive control processes of the frontal lobe.

Employing event-related fMRI and EEG coherence measures, we compared conflict-related neural activity in the anterior cingulate cortex (ACC) and control-related activity in the lateral frontal cortex (LFC) during Stroop task performance between participants of low and high hypnotic susceptibility, at baseline and after hypnotic induction. The fMRI data revealed that conflict-related ACC activity interacted with hypnosis and hypnotic susceptibility, in that highly susceptible participants displayed increased conflict-related neural activity in the hypnosis condition compared to baseline, as well as with respect to subjects with low susceptibility.

Cognitive-control-related LFC activity, on the other hand, did not differ between groups and conditions. These data were complemented by a decrease in functional connectivity (EEG gamma band coherence) between frontal midline and left lateral scalp sites in highly susceptible subjects after hypnosis.

These results suggest that individual differences in hypnotic susceptibility are linked with the efficiency of the frontal attention system, and that the hypnotized condition is characterized by a

functional dissociation

of conflict monitoring and cognitive control processes.

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Hewig et al 2006

Biol Psychol. 2006 Jan;71(1):42-53. Epub 2005 Mar 17.

Links

The relation of cortical activity and BIS/BAS on the trait level.

Hewig J, Hagemann D, Seifert J, Naumann E, Bartussek D.

Department of Biological and Clinical Psychology, Friedrich-Schiller-Universität Jena, Am Steiger 3, Haus 1, D-07743 Jena, Germany. hewig@biopsy.uni-jena.de

The behavioral activation system (BAS) and the behavioral inhibition system (BIS) have been proposed to be related to anterior asymmetry in the BIS/BAS model of anterior asymmetry. As an alternative, it may be suggested that

behavioral activation comprises approach and withdrawal motivation and that the BAS is related to bilateral frontal trait activity. The aim of the present study was an empirical investigation on the relation between cortical trait activity, BIS and BAS. Data of 59 subjects on four occasions were analyzed. On each occasion, cortical activity was evaluated with resting EEG, and the BIS and BAS strength was assessed with questionnaires. Subjects with greater bilateral frontal cortical activity showed higher BAS scores.

The latter result may suggest that

behavioral activation comprises

approach and withdrawal motivation.

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J Pers Soc Psychol. 2004 Dec;87(6):926-39.

Links

On the selective relation of frontal cortical asymmetry and anger-out versus anger-control.

Hewig J, Hagemann D, Seifert J, Naumann E, Bartussek D.

Department of Biological and Clinical Psychology, Friedrich-Schiller-Universität Jena, Jena, Germany. hewig@biopsy.uni-jena.de

The model of anterior asymmetry and emotion proposes an asymmetric representation of approach and withdrawal systems in the left and right anterior brain regions. Within this framework, 3 different concepts have been related to anterior asymmetry: affective valence, motivational direction, and behavioral activation. The aim of the present study was an empirical investigation into the relation between anterior cortical activity and questionnaire measures related to the 3 dimensions positive versus negative affect, approach versus withdrawal motivation, and behavioral activation versus inhibition. Subjects with relative greater left than right frontal cortical activity showed higher anger-out scores and lower anger-control scores. These results support the hypothesis that motivational direction is related to frontal asymmetry (approach-left and withdrawal-right). Furthermore, subjects with greater bilateral (left and right) frontal cortical activity showed higher behavioral activation scores. This finding might suggest that behavioral activation is related to approach and withdrawal motivation. ((c) 2004 APA,

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Amodio et al 2008

Psychophysiology. 2008 Jan;45(1):11-9. Epub 2007 Oct 1.

Links

Neurocognitive components of the behavioral inhibition and activation systems: implications for theories of self-regulation.

Amodio DM, Master SL, Yee CM, Taylor SE.

Department of Psychology, New York University, New York, New York 10003, USA. David.amodio@nyu.edu

We examined the neurocognitive correlates of the Behavioral Inhibition and Behavioral Activation Systems (BIS/BAS) in an effort to clarify ambiguities concerning interpretations of BIS as reflecting inhibition versus avoidance. We hypothesized that

self-reported BIS should relate to neural mechanisms associated with

conflict monitoring, whereas

self-reported BAS should be associated with neural correlates of

approach motivation.

Consistent with these predictions, higher self-reported BIS was uniquely related to the N2 event-related potential on No-Go trials of a Go/No-Go task, linking

BIS with conflict monitoring and sensitivity to No-Go cues.

Higher BAS was uniquely related to greater left-sided baseline frontal cortical asymmetry associated with approach orientation.

Implications for theories of self-regulation involving conflict monitoring, cognitive control, and approach/avoidance motivation are discussed.

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Brain Behav Immun. 2009 Jan;23(1):27-35. Epub 2008 Jun 16.

Links

Neurobiological correlates of coping through emotional approach.

Master SL, Amodio DM, Stanton AL, Yee CM, Hilmert CJ, Taylor SE.

Department of Psychology, University of California, Los Angeles, 1285 Franz Hall, Los Angeles, CA 90095-1563, USA.

This investigation considered possible health-related neurobiological processes associated with “emotional approach coping” (EAC), or intentional efforts to identify, process, and express emotions surrounding stressors.

…. The findings suggest that the salubrious effects of EAC strategies for managing stress may be linked to an approach-oriented neurocognitive profile and to well-regulated proinflammatory cytokine responses to stress.

PMID: 18558470 [PubMed – indexed for MEDLINE

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Rademacher et al 2008

Neuropharmacology. 2008 Jan;54(1):108-16. Epub 2007 Jun 29.

Links

Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice.

Rademacher DJ, Meier SE, Shi L, Ho WS, Jarrahian A, Hillard CJ.

Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Endocannabinoid signaling has been implicated in habituation to repeated stress. The hypothesis that repeated exposures to stress alters endocannabinoid signaling in the limbic circuit was …. These studies are consistent with the hypothesis that

stress exposure

alters endocannabinoid signaling in the brain

and that alterations in endocannabinoid signaling

occur during

habituation to stress.

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receptors in the eyes?  Is this related to our ‘seeing’ facial cues?

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Monk et al 2008

Arch Gen Psychiatry. 2008 May;65(5):568-76.

Links

Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder.

Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro HM, Chen G, McClure-Tone EB, Ernst M, Pine DS.

Department of Psychology, University of Michigan, 530 Church St, Ann Arbor, MI 48109-1043, USA. csmonk@umich.edu

Vigilance for threat is a key feature of generalized anxiety disorder (GAD). The amygdala and the ventrolateral prefrontal cortex

constitute a neural circuit that is responsible for detection of threats. Disturbed interactions between these structures

may underlie pediatric anxiety.

To date, no study has selectively examined responses to briefly presented threats in GAD or in pediatric anxiety. OBJECTIVE: To investigate amygdala and ventrolateral prefrontal cortex activation during processing of briefly presented threats in pediatric GAD. DESIGN: Case-control study. SETTING: Government clinical research institute. PARTICIPANTS: Youth volunteers, 17 with GAD and 12 without a psychiatric diagnosis. MAIN OUTCOME MEASURES: We used functional magnetic resonance imaging to measure blood oxygenation level-dependent signal. During imaging, subjects performed an attention-orienting task with rapidly presented (17 milliseconds) masked emotional (angry or happy) and neutral faces.

RESULTS: When viewing masked angry faces, youth with GAD relative to comparison subjects showed greater right amygdala activation that positively correlated with anxiety disorder severity.

Moreover, in a functional connectivity (psychophysiological interaction) analysis, the

right amygdala and the right ventrolateral prefrontal cortex showed strong negative coupling

specifically to masked angry faces.

This negative coupling tended to be weaker

in youth with GAD than in comparison subjects.

CONCLUSIONS: Youth with GAD have hyperactivation of the amygdala to briefly presented masked threats.

The presence of threat-related

negative connectivity between the right ventrolateral prefrontal cortex and the amygdala

suggests that

the prefrontal cortex modulates the amygdala response to threat.

In pediatric GAD, amygdala hyperresponse occurs in the absence of a compensatory increase in modulation by the ventrolateral prefrontal cortex.

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Biol Psychol. 2008 Oct;79(2):216-22. Epub 2008 May 29.

Links

Relationship between trait anxiety, prefrontal cortex, and attention bias to angry faces in children and adolescents.

Telzer EH, Mogg K, Bradley BP, Mai X, Ernst M, Pine DS, Monk CS.

Department of Psychology, University of California, Los Angeles, CA, USA. ehtelzer@ucla.edu

Using event-related functional magnetic resonance imaging (fMRI) with a visual-probe task that assesses attention to threat, we investigated the cognitive and neurophysiological correlates of trait anxiety in youth. During fMRI acquisition, 16 healthy children and adolescents viewed angry-neutral face pairs and responded to a probe that was on the same (angry-congruent) or opposite (angry-incongruent) side as the angry face. Attention bias scores were calculated by subtracting participants’ mean reaction time for angry-congruent trials from angry-incongruent trials. Trait anxiety was positively associated with attention bias towards angry faces. Neurophysiologically, trait anxiety was positively associated with right dorsolateral prefrontal cortex (PFC) activation on a contrast of trials that reflect the attention bias for angry faces (i.e. angry-incongruent versus angry-congruent trials). Trait anxiety was also positively associated with right ventrolateral PFC activation on trials with face stimuli (vesus baseline), irrespective of their

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Martinez, de Oliveira & Brandao 2006

Abstract – Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.

Neurobiol Learn Mem. 2006 Jan;85(1):58-65. Epub 2005 Sep 28.

Links

Conditioned and unconditioned fear organized in the periaqueductal gray are differentially sensitive to injections of muscimol into amygdaloid nuclei.

Martinez RC, de Oliveira AR, Brandão ML.

Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.

The lateral and basolateral nuclei of the amygdala

(LaA and BLA, respectively)

serve as a filter for unconditioned and conditioned aversive information that ascends to higher structures from the brainstem,

whereas the central nucleus of the amygdala (CeA)

is considered to be the main output for the

defense reaction

It has been shown that the dorsal periaqueductal gray (dPAG)

is activated by threatening stimuli

and has important functional links with the amygdala

through two-way anatomical connections.

In this work, we examined the influence of chemical inactivation of these nuclei of amygdala on the freezing and escape responses induced by electrical stimulation through electrodes implanted in the dPAG of Wistar rats. Each rat also bore a cannula implanted in the LaA, BLA or CeA for injections of muscimol (0.5 microg/0.5 microL) or its vehicle. The duration of freezing behavior that outlasts electrical stimulation of the dPAG was also measured. On the following day, these animals were submitted to a contextual fear-conditioning using foot shocks as unconditioned stimulus. Conditioned freezing to contextual cues previously associated with foot shocks was also inhibited by injections of muscimol into these amygdaloid nuclei.

The contextual conditioned freezing behavior

is generated in the neural circuits of conditioned fear

in the amygdala.

The data obtained also show that injections of muscimol into the three amygdaloid nuclei did not change the aversive threshold of freezing, but disrupted the dPAG post-stimulation freezing. Previous findings that the latter freezing results directly from dPAG stimulation and that it is not sensitive to a context shift suggest that it is unconditioned in nature.

Thus, the amygdala can affect some, but not all, aspects of unconditioned freezing. Post-stimulation freezing may reflect the process of transferring aversive information from dPAG to higher brain structures.

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Oliveira et al 2004

Abstract – Laboratório de Psicobiologia, Faculdade Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP) 14040-901, Ribeirão Preto, Brazil.

Neuroreport. 2004 Oct 5;15(14):2281-5.

Links

Role of amygdala in conditioned and unconditioned fear generated in the periaqueductal gray.

Oliveira LC, Nobre MJ, Brandão ML, Landeira-Fernandez J.

The amygdala and ventral portion of the periaqueductal gray (vPAG) are crucial for the expression of the contextual freezing behavior. However, it is still unclear whether the amygdala also plays a role in defensive behaviors induced by electrical stimulation of the dorsal periaqueductal gray (dPAG). In the present study, rats were implanted with electrodes into dPAG for determination of the thresholds for freezing and escape responses before and after sham or electrolytic lesions in the amygdala. Animals were then submitted to a context fear conditioning procedure. Amygdala lesions disrupted contextual freezing but did not affect defensive behaviors induced by dPAG electrical stimulation. These results indicate that

contextual and unconditioned freezing behaviors

are mediated by independent neural circuits

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See also:

Neuropsychopharmacology. 2007 May;32(5):1032-41. Epub 2006 Oct 18.

Links

Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task.

Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.

Neuropharmacology. 2008 Jan;54(1):141-50. Epub 2007 Jul 19.

Links

Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.

Moreira FA, Kaiser N, Monory K, Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany.

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Chhatwal et al 2008

Neuropsychopharmacology. 2009 Jan;34(2):509-21. Epub 2008 Jun 25.

Links

Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning.

Chhatwal JP, Gutman AR, Maguschak KA, Bowser ME, Yang Y, Davis M, Ressler KJ.

Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.

The endocannabinoid system

and the cannabinoid type 1 receptor (CB1R)

are required for the

extinction of conditioned fear.

CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation.

We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that

interactions between the endocannabinoid and

CCKergic transmitter systems

may underlie the process of extinction of conditioned fear.

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Mol Neurobiol. 2007 Aug;36(1):92-101. Epub 2007 Aug 17.

Links

The endocannabinoid system and extinction learning.

Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany. blutz@uni-mainz.de

Pharmacol Res. 2007 Nov;56(5):367-81. Epub 2007 Sep 8.

Links

The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction.

Lafenêtre P, Chaouloff F, Marsicano G.

Research Centre INSERM U862, AVENIR Team Molecular Mechanisms of Behavioural Adaptation, 146 rue Léo Saignat, 33700 Bordeaux, France.

Varvel, Anum & Lichtman 2005

Psychopharmacology (Berl). 2005 Jun;179(4):863-72. Epub 2004 Dec 24.

Links

Disruption of CB(1) receptor signaling impairs extinction of spatial memory in mice.

Varvel SA, Anum EA, Lichtman AH.

Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA.

RATIONALE: A growing body of in vitro and in vivo evidence indicates that

a central endocannabinoid system,

…….consisting of CB(1) receptors and endogenous cannabinoids,

……. modulates specific aspects of mnemonic [memory aid] processes.

Previous research has demonstrated that either permanent or drug-induced

………disruption of CB(1) receptor signaling

………interferes with the extinction of a conditioned fear response.

OBJECTIVES: In the present study, we evaluated whether the endocannabinoid system also plays a role in extinguishing learned escape behavior in a Morris water maze task. METHODS: CB(1) (-/-) mice and mice repeatedly treated with 3 mg/kg of the CB(1) receptor antagonist SR 141716 (Rimonabant) were trained to locate a hidden platform in the Morris water maze. Following acquisition, the platform was removed and subjects were assigned to either a massed (i.e., five consecutive sessions consisting of four 2-min trials/session) or a spaced (a single, 1-min trial every 2-4 weeks) extinction protocol. RESULTS: Strikingly, both 3 mg/kg SR 141716-treated mice and CB(1) (-/-) mice continued to return to the target location across all five trials in the spaced extinction procedure, while the control mice underwent extinction by the third or fourth trial. In contrast, both the 3-mg/kg SR 141716-treated and CB(1) (-/-) mice exhibited extinction in the massed extinction trial procedure. CONCLUSIONS: These findings indicate that disruption of CB(1) receptor signaling impairs extinction processes in the Morris water maze, thus lending further support to the hypothesis that

the endocannabinoid system plays an integral role in the suppression of non-reinforced learned behaviors.

I don’t understand how this is non-reinforced learning – if they don’t find the hidden platform they will eventually tire out and drown.  Isn’t that intrinsic reward enough to reinforce the memory of where the platform is?

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Hofmann 2008

Clin Psychol Rev. 2008 Feb;28(2):199-210. Epub 2007 May 3.

Links

Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders.

Hofmann SG.

Department of Psychology, Boston University, 648 Beacon Street, 6th Floor, Boston, MA 02215-2002, United States. shofmann@bu.edu

Anxiety disorders are highly prevalent. Fear conditioning and extinction learning in animals often serve as simple models of fear acquisition and exposure therapy of anxiety disorders in humans. This article reviews the empirical and theoretical literature on cognitive processes in fear acquisition, extinction, and exposure therapy. It is concluded that exposure therapy is a form of cognitive intervention that specifically changes the expectancy of harm. Implications for therapy research are discussed.  Do they use the word “cognitive” in relation to animal models?

See also:

Clin Psychol Rev. 2001 Jul;21(5):751-70.

Links

Information processing in social phobia: a critical review.

Heinrichs N, Hofmann SG.

Boston University, USA.

Eur J Pharmacol. 2005 Mar 7;510(1-2):69-74.

Links

Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task.

Hölter SM, Kallnik M, Wurst W, Marsicano G, Lutz B, Wotjak CT.

Max-Planck-Institut für Psychiatrie, AG Neuronale Plastizität/Mausverhalten, Kraepelinstr. 2, D-80804 München, Germany. Nature. 2002 Aug

1;418(6897):530-4.

Links

Comment in:

Nature. 2002 Aug 1;418(6897):488-9.

The endogenous cannabinoid system controls extinction of aversive memories.

Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B.

Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.

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Blair et al 2008

Am J Psychiatry. 2008 Sep;165(9):1193-202. Epub 2008 May 15.

Links

Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders.

Blair K, Shaywitz J, Smith BW, Rhodes R, Geraci M, Jones M, McCaffrey D, Vythilingam M, Finger E, Mondillo K, Jacobs M, Charney DS, Blair RJ, Drevets WC, Pine DS.

Mood and Anxiety Program, NIMH, NIH, 15K North Dr., MSC 2670, Bethesda, MD 20892, USA.

Generalized social phobia involves fear/avoidance, specifically of social situations, whereas

generalized anxiety disorder involves intrusive worry about diverse circumstances.

It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder. METHOD: Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N=17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment. RESULTS:

The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder.

In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder. CONCLUSIONS: These results suggest that

neural circuitry dysfunctions differ

in generalized social phobia and

generalized anxiety disorder.

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Alvarez et al 2008

Abstract – Mood and Anxiety Disorders Program, National Institute of Mental Health-National Institutes of Health, Bethesda, Maryland 20892, USA. alvarezr@mail.nih.gov

J Neurosci. 2008 Jun 11;28(24):6211-9.

Links

Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions.

Alvarez RP, Biggs A, Chen G, Pine DS, Grillon C.

Functional imaging studies of cued fear conditioning in humans have mostly confirmed findings in animals, but it is unclear whether the brain mechanisms that underlie contextual fear conditioning in animals are also preserved in humans. We investigated this issue using functional magnetic resonance imaging and virtual reality contexts. Subjects underwent differential context conditioning in which they were repeatedly exposed to two contexts (CXT+ and CXT-) in semirandom order, with contexts counterbalanced across participants. An unsignaled footshock was consistently paired with the CXT+, and no shock was ever delivered in the CXT-. Evidence for context conditioning was established using skin conductance and anxiety ratings.

Consistent with animal models centrally implicating the

hippocampus and amygdala in a network supporting context conditioning, CXT+ compared with CXT- significantly activated

right anterior hippocampus and

bilateral amygdala.

In addition, context conditioning was associated with activation in posterior orbitofrontal cortex,

medial dorsal thalamus,

anterior insula,

subgenual anterior cingulate, and

parahippocampal,

inferior frontal, and

parietal cortices.

Structural equation modeling was used to assess interactions among the core brain regions mediating context conditioning. The derived model indicated that

++++ medial amygdala ++++

was the source of key efferent and afferent connections including input from orbitofrontal cortex.

These results provide evidence that similar brain mechanisms may underlie contextual fear conditioning across species.

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Samson & Pare 2005

J Neurosci. 2005 Feb 16;25(7):1847-55.

Links

Activity-dependent synaptic plasticity in the central nucleus of the amygdala.

Samson RD, Paré D.

Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, New Jersey 07102, USA.

.

Much evidence indicates that

fear conditioning involves potentiation of some thalamic inputs to the lateral amygdala (LA)

In turn, the lateral amygdala (LA)

would excite more neurons in the central nucleus (CE),

leading to the generation of fear responses

via their brainstem and hypothalamic projections.

However, the posterior thalamus

not only projects to lateral amygdala (LA)

but also to the medial sector of CE (CEm),

suggesting that CEm might also be a site of plasticity.

To test whether CEm also exhibits activity-dependent synaptic plasticity, we performed whole-cell recordings of CEm neurons in amygdala slices and stimulated thalamic axons coursing through the internal capsule and, as a control, the basolateral (BL) nucleus. High-frequency stimulation of thalamic inputs led to a long-lasting potentiation of thalamic responses, whereas BL-evoked responses remained unchanged. This thalamic long-term potentiation (LTP) developed even when slices were prepared with a cut severing the connections between the LA and CEm but was greatly reduced when an NMDA receptor antagonist was added to the perfusate shortly before and during LTP induction. Yet, intracellular dialysis with the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate did not prevent induction of the thalamic LTP, suggesting that presynaptic NMDA receptors are required for its induction. Consistent with this, the thalamic LTP also developed when the cells were dialyzed with a calcium chelator or kept hyperpolarized during induction. Finally, this thalamic LTP was associated with reduced amounts of paired-pulse facilitation, suggesting that it is expressed presynaptically. These results are consistent with the idea that the CEm plays an active role in fear conditioning.

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Royer & Pare 2002

Neuroscience. 2002;115(2):455-62.

Links

Bidirectional synaptic plasticity in intercalated amygdala neurons and the extinction of conditioned fear responses.

Royer S, Paré D.

Center for Molecular and Behavioral Neuroscience, Rutgers State University, 197 University Avenue, Newark, NJ 07102, USA.

Classical fear conditioning

is believed to result from

potentiation of conditioned synaptic inputs

in the basolateral amygdala.

That is, the conditioned stimulus

would excite more neurons in the central nucleus and,

via their projections to the brainstem and hypothalamus,

evoke fear responses.

However, much data suggests that extinction of fear responses

does not depend on the reversal of these changes

but on a parallel

NMDA-dependent learning

that competes with the first one.

Because they control impulse traffic

from the basolateral amygdala

to the central nucleus,

GABAergic neurons of the intercalated cell masses are ideally located to implement this second learning.

Consistent with this hypothesis, the present study shows that low- and high-frequency stimulation of basolateral afferents respectively induce long-term depression (LTD) and potentiation (LTP) of responses in intercalated cells. Moreover, induction of LTP and LTD is prevented by application of an NMDA antagonist. To determine how these activity-dependent changes are expressed, we tested whether LTD and LTP induction are associated with modifications in paired-pulse facilitation, an index of transmitter release probability. Only LTP induction was associated with a change in paired-pulse facilitation. Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that

LTP is associated with presynaptic alterations, but that

LTD and depotentiation depend on postsynaptic changes.

Taken together, our results suggest that

basolateral synapses

onto intercalated neurons

can express NMDA-dependent LTP and LTD,

consistent with the possibility that

intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses.

Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.

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Lopez de Armentia & Sah 2007

J Physiol. 2007 Jun 15;581(Pt 3):961-70. Epub 2007 Mar 22.

Links

Bidirectional synaptic plasticity at nociceptive afferents in the rat central amygdala.

López de Armentia M, Sah P.

Queensland Brain Institute, University of Queensland, QLD 4072 Australia.

Glutamatergic inputs arising from the parabrachial nucleus to neurons in the lateral sector of the central amygdala were studied in vitro. Tetanic stimulation of these inputs led to LTP that did not require activation of NMDA receptors or a rise of postsynaptic calcium. LTP was accompanied by a reduction in the paired-pulse ratio, indicating that LTP results from an increase in transmitter release probability. Activation of adenylyl cyclase with forskolin potentiated these inputs with a similar reduction in paired-pulse facilitation and occluded LTP induction. LTP was inhibited by the protein kinase A blocker H89. Low-frequency stimulation led to LTD that required activation of postsynaptic NMDA receptors and a rise in postsynaptic calcium. There was no change in paired-pulse facilitation with LTD. LTD was blocked by protein phosphatase blockers calyculin and okadaic acid. We conclude that parabrachial inputs to the lateral sector of the central amygdala show presynaptic LTP that requires activation of a presynaptic protein kinase A via a calcium-dependent adenylyl cyclase while LTD at the same synapses is postsynaptic and requires a rise in postsynaptic calcium and activation of protein phosphatase.

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Schroeder & Shinnick-Gallagher 2004

Eur J Neurosci. 2004 Jul;20(2):549-56.

Links

Fear memories induce a switch in stimulus response and signaling mechanisms for long-term potentiation in the lateral amygdala.

Schroeder BW, Shinnick-Gallagher P.

Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Blvd., Galveston, Texas, 77555-1031, USA. bwschroe@utmb.edu

Activity-dependent modification of synapses

is fundamental for information storage in the brain

and underlies behavioral learning.

Fear conditioning

is a model of emotional memory and anxiety

that is expressed as an enduring increase in synaptic strength

in the lateral amygdala (LA).

Here we analyzed synaptic plasticity in the rat cortico-LA pathway during maintenance of fear memory. We show for the first time that the

stimulus frequency for synaptic potentiation

is switched

during maintenance of fear memory,

and the underlying signaling mechanisms

are altered in the cortico-LA pathway.

In slices from fear-conditioned animals, high-frequency stimulation-induced (HFS) long-term potentiation (LTP) was attenuated, whereas low-frequency stimulation (LFS) elicited a long-lasting potentiation. HFS generates robust LTP that is dependent on N-methyl-d-aspartate receptor (NMDAR) and L-type voltage-gated calcium channel (VGCC) activation in control animals, whereas in fear-conditioned animals HFS LTP is NMDAR- and VGCC-independent. LFS-LTP is partially NMDAR-dependent, but VGCCs are necessary for potentiation in fear memory. Collectively, these results show that

during maintenance of fear memory

the stimulus requirements for amygdala afferents

and critical signaling mechanisms

for amygdala synaptic potentiation are altered,

suggesting that cue-engaged synaptic mechanisms

in the amygdala

are dramatically affected as a result of emotional learning.

++++

See also:

Eur J Neurosci. 2005 Oct;22(7):1775-83.

Links

Fear learning induces persistent facilitation of amygdala synaptic transmission.

Schroeder BW, Shinnick-Gallagher P.

Department of Pharmacology and Toxicology, Neuroscience Graduate Program, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1031, USA.

Brain Res. 2007 Jan 5;1127(1):36-44. Epub 2006 Nov 17.

Links

Cannabinoid receptors are localized to noradrenergic axon terminals in the rat frontal cortex.

Oropeza VC, Mackie K, Van Bockstaele EJ.

Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, 900 Walnut St., Suite 400, Philadelphia, PA 19107, USA.

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Azad et al 2004

J Neurosci. 2004 Nov 3;24(44):9953-61.

Links

Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling.

Azad SC, Monory K, Marsicano G, Cravatt BF, Lutz B, Zieglgänsberger W, Rammes G.

Clinical Neuropharmacology, Max-Planck-Institute of Psychiatry, 80804 Munich, Germany. azad@mpipsykl.mpg.de

Endocannabinoids are crucial for the extinction of aversive memories, a process that considerably involves the amygdala. And their formation … extinction being the formation of replacement memories that do not erase the original ones

Here, we show that low-frequency stimulation of afferents in the lateral amygdala with 100 pulses at 1 Hz releases endocannabinoids postsynaptically from neurons of the basolateral amygdala of mice in vitro and thereby induces a long-term depression of inhibitory GABAergic synaptic transmission (LTDi) via a presynaptic mechanism.

…..Lowering inhibitory synaptic transmission significantly increases the amplitude of excitatory synaptic currents in principal neurons of the central nucleus, which is the main output site of the amygdala.

LTDi involves a selective mGluR1 (metabotropic glutamate receptor 1)-mediated calcium-independent mechanism and the activation of the adenylyl cyclase-protein kinase A pathway. LTDi is abolished by the cannabinoid type 1 (CB1) receptor antagonist SR141716A and cannot be evoked in CB1 receptor-deficient animals. LTDi is significantly enhanced in mice lacking the anandamide-degrading enzyme fatty acid amide hydrolase. The present findings show for the first time that mGluR activation induces a retrograde endocannabinoid signaling via activation of the adenylyl cyclase-protein kinase A pathway and the release of anandamide. Furthermore, the results indicate that

anandamide

decreases the activity of inhibitory interneurons in the amygdala. This disinhibition increases the activity of common output neurons

and could provide a prerequisite for

extinction

by formation of new memory.

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Egan et al 2003

Cell. 2003 Jan 24;112(2):257-69.

Links

The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.

Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR.

Clinical Brain Disorders Branch, National Institute of Mental Health, Room 4s-235, 10 Center Drive, Bethesda, MD 20892, USA.

Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a

valine (val) to methionine (met) substitution in the 5′ pro-region of the human BDNF protein.

In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation …and lower hippocampal n-acetyl aspartate (NAA), …. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a

role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF

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See also related to memory:

Hariri et al 2003

J Neurosci. 2003 Jul 30;23(17):6690-4.

Links

Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance.

Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR.

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.

Hashimoto et al 2008

Neurosci Res. 2008 Aug;61(4):360-7. Epub 2008 Apr 20.

Links

Dose-dependent effect of the Val66Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity.

Hashimoto R, Moriguchi Y, Yamashita F, Mori T, Nemoto K, Okada T, Hori H, Noguchi H, Kunugi H, Ohnishi T.

The Osaka-Hamamatsu Joint Research Center For Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. hashimor@psy.med.osaka-u.ac.jp

Genes Brain Behav. 2009 Feb;8(1):43-52. Epub 2008 Sep 11.

Links

Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer’s disease.

Hashimoto R, Hirata Y, Asada T, Yamashita F, Nemoto K, Mori T, Moriguchi Y, Kunugi H, Arima K, Ohnishi T.

Department of Clinical Disorder Research, The Osaka-Hamamatsu Joint Research Center For Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. hashimor@psy.med.osaka-u.ac.jp

Arch Gen Psychiatry. 2006 Jul;63(7):731-40.

Links

Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers.

Ho BC, Milev P, O’Leary DS, Librant A, Andreasen NC, Wassink TH.

Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA.

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Frodl et al 2007

Arch Gen Psychiatry. 2007 Apr;64(4):410-6.

Links

Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression.

Frodl T, Schüle C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM.

Department of Psychiatry and Psychotherapy and Radiology, Ludwig-Maximilians University, Munich, Germany. Thomas.Frodl@med.uni-muenchen.de

CONTEXT: Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity, which is believed to be altered in patients with major depression. OBJECTIVE: To examine the effect of the BDNF Val66Met polymorphism on hippocampal and amygdala volumes in patients with major depression and in healthy control subjects. DESIGN: Cross-sectional comparison between patients and controls. SETTING: Inpatients with major depression from the Department of Psychiatry and Psychotherapy and healthy controls from the community were recruited. PARTICIPANTS: The study population of 120 subjects included 60 patients with major depression and 60 healthy controls. MAIN OUTCOME MEASURES: Using a combined strategy, hippocampal and amygdala volumes were estimated on high-resolution magnetic resonance images, and genotyping was performed for the BDNF Val66Met polymorphism. RESULTS: Patients had significantly smaller hippocampal volumes compared with controls (P = .02).

Significantly smaller hippocampal volumes were observed for patients and for controls carrying the Met-BDNF allele compared with subjects homozygous for the Val-BDNF allele (P = .006)

. With respect to amygdala volumes, no significant differences between patients and controls and no significant main effects for the BDNF Val66Met polymorphism were observed. CONCLUSIONS: These

genotype-related alterations suggest that Met-BDNF allele carriers might be at risk to develop smaller hippocampal volumes and may be susceptible to major depression.

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Bueller et al 2006

Biol Psychiatry. 2006 May 1;59(9):812-5. Epub 2006 Jan 25.

Links

BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects.

Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK.

Mental Health Research Institute, The University of Michigan, Ann Arbor, Michigan, USA.

BACKGROUND: A frequent polymorphism of the brain-derived neurotrophic factor (BDNF) gene (val(66)met) has been suggested to modulate hippocampal neuronal plasticity and has been associated with individual variations in emotional reactivity traits and episodic memory. METHODS: The hippocampal formation was outlined in high-resolution anatomical magnetic resonance imaging (MRI) data in a sample of 36 healthy volunteers and compared between individuals as a function of the presence of the met-BDNF allele. Both whole-brain volume corrected and uncorrected data were tested for effects of genotype, sex, and age. RESULTS: The met-BDNF allele was associated with an 11% reduction in the volume of the hippocampal formation. CONCLUSIONS: In spite of a relatively small sample size, the presence of the met-BDNF allele was found associated with a reduced volume of the hippocampal formation in healthy volunteers and may represent a vulnerability factor for the development of disease processes associated with the dysfunction of this brain region.

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See also:

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4888-93. Epub 2009 Mar 2.

Links

Comment in:

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4579-80.

Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory.

Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL, Cuomo V.

Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy. patrizia.campolongo@uniroma1.it

J Neuroendocrinol. 2008 May;20 Suppl 1:35-8.

Links

The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity.

Cota D.

Department of Psychiatry, Obesity Research Center, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu

The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease. For example, the ECS not only represents the biological substrate of marijuana’s effects, but also is known to modulate several neuroendocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis. Although previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids. Studies using mice lacking cannabinoid receptor CB(1) have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity. Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems. Endocannabinoids have been found to mediate the nongenomic glucocorticoid-induced inhibition of the release of corticotrophin-releasing factor within the paraventricular nucleus of the hypothalamus. Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of stress-related diseases, including anxiety, depression and obesity.

PMID: 18426497 [PubMed – indexed for MEDLINE]

++++++++++

Wust et al 2004

J Clin Endocrinol Metab. 2004 Feb;89(2):565-73.

Links

Comment in:

J Clin Endocrinol Metab. 2004 Feb;89(2):563-4.

Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress.

Wüst S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH.

Department of Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany. wuest@uni-trier.de

Chronic dysregulation of hypothalamus-pituitary-adrenal [HPA] axis activity is related to several stress-related disorders.

Evidence suggests that polymorphisms in the glucocorticoid receptor (GR) gene may have an impact on this neuroendocrine system. In the present investigation, 112 healthy males were studied to estimate the impact of

three GR gene polymorphisms (BclI RFLP, N363S, ER22/23EK) on cortisol and ACTH responses to psychosocial stress (

Trier Social Stress Test) and pharmacological stimulation (1 microg ACTH(1-24), 0.5 mg dexamethasone). Because only four ER22/23EK heterozygotes were identified, these subjects were not statistically analyzed. Compared with subjects with the wild-type GR genotype (n = 36),

363S allele carriers (n = 10) showed significantly increased salivary cortisol responses to stress, whereas the BclI genotype GG (n = 18) was associated with a diminished cortisol response. BclI heterozygotes and homozygotes (GG) exhibited a trend toward lower ACTH responses, compared with wild-type subjects and 363S carriers.

The cortisol response to ACTH(1-24) administration was not significantly different between genotypes. After dexamethasone ingestion, 363S carriers showed a trend toward an enhanced cortisol suppression. This is the first report documenting an impact of GR gene polymorphisms on cortisol (and perhaps ACTH) responses to psychosocial stress. These variants may contribute to the individual vulnerability for hypothalamus-pituitary-adrenal-related disorders.

See also:

A psychobiological perspective on genetic determinants of hypothalamus-pituitary-adrenal axis activity.

Wüst S, Federenko IS, van Rossum EF, Koper JW, Kumsta R, Entringer S, Hellhammer DH.

Ann N Y Acad Sci. 2004 Dec;1032:52-62. Review.

Habituation of cortisol responses to repeated psychosocial stress-further characterization and impact of genetic factors.

Wüst S, Federenko IS, van Rossum EF, Koper JW, Hellhammer DH.

Psychoneuroendocrinology. 2005 Feb;30(2):199-211.

PMID: 15471617 [PubMed – indexed for MEDLINE]

Related Articles

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Hippocampus. 2008;18(2):221-6.

Links

Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus.

Hill MN, Carrier EJ, Ho WS, Shi L, Patel S, Gorzalka BB, Hillard CJ.

Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.

Experimental studies indicate a bidirectional, functional relationship between glucocorticoids and the endocannabinoid system; however, the effects of repeated glucocorticoid treatment on the endocannabinoid system have not been examined. In this study, we treated male rats with either a single dose or a 21-day course of treatment with corticosterone (20 mg/kg) and measured hippocampal cannabinoid CB(1) receptor expression and endocannabinoid content. The 21-day, but not the single, administration of corticosterone significantly reduced both the binding site density and amount of protein of the hippocampal cannabinoid CB(1) receptor without affecting affinity for the CB(1) receptor agonist, [(3)H]CP55940. With regard to hippocampal endocannabinoid content, acute corticosterone treatment resulted in a significant reduction in anandamide but did not affect 2-arachidonylglycerol, while repeated corticosterone treatment did not alter content of either anandamide or 2-arachidonylglycerol. These data support the hypothesis that the cannabinoid CB(1) receptor is under negative regulation by glucocorticoids in the hippocampus, and suggest that hippocampal cannabinoid CB(1) receptor signaling could be reduced under conditions associated with hypersecretion of glucocorticoids, such as chronic stress. (c) 2007 Wiley-Liss, Inc.

PMID: 18058925 [PubMed – indexed for MEDLINE

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We don’t think about it this way, but feeling fear is painful

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Das et al 2005

Neuroimage. 2005 May 15;26(1):141-8.

Links

Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems.

Das P, Kemp AH, Liddell BJ, Brown KJ, Olivieri G, Peduto A, Gordon E, Williams LM.

Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), Darlinghurst, NSW, Australia. prithad@psych.usyd.edu.au

Effective perception of fear signals is crucial for human survival and the importance of the amygdala in this process is well documented. Animal, lesion and neuroimaging studies indicate that

incoming sensory signals of fear

travel from thalamus to amygdala

via two neural pathways:

a direct subcortical route and

an indirect pathway via the sensory cortex.

Other lines of research have demonstrated prefrontal modulation of the amygdala. However, no study to date has examined the prefrontal modulation of the thalamo-cortico-amygdala pathways in vivo.

We used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamus, amygdala and sensory (inferior occipital, fusiform) cortices, and the

modulation of these networks

by the anterior cingulate cortex (ACC).

Functional magnetic resonance imaging (fMRI) data were acquired for 28 healthy control subjects during a fear perception task, with neutral as the ‘baseline’ control condition. Main effect analysis, using a region of interest (ROI) approach, confirmed that these regions are part of a distributed neural system for fear perception. Psychophysiological interactions revealed

an inverse functional connectivity

between occipito-temporal visual regions

and the left amygdala,

but a positive connectivity between these visual region and the right amygdala, suggesting that there is

a hemispheric specialization in the transfer of fear signals

from sensory cortices to amygdala.

Physiophysiological interactions revealed a dorsal-ventral division in ACC modulation of the thalamus-sensory cortex pathway. While the dorsal ACC showed a positive modulation of this pathway, the ventral ACC exhibited an inverse relationship.

In addition, both the dorsal and ventral ACC showed an inverse interaction with the direct thalamus-amygdala pathway. These findings suggest that thalamo-amygdala and cortical regions are involved in a dynamic interplay, with functional differentiation in both lateralized and ventral/dorsal gradients. Breakdowns in these interactions may give rise to affect-related symptoms seen in a range of neuropsychiatric disorders.

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Liddell et al 2005

Neuroimage. 2005 Jan 1;24(1):235-43.

Links

A direct brainstem-amygdala-cortical ‘alarm’ system for subliminal signals of fear.

Liddell BJ, Brown KJ, Kemp AH, Barton MJ, Das P, Peduto A, Gordon E, Williams LM.

School of Psychology, University of Sydney, NSW 2006, Australia. belindal@psych.usyd.edu.au

We examined whether consciously undetected fear signals engage a collateral brainstem pathway to the amygdala and prefrontal cortex in the intact human brain, using functional neuroimaging. ‘Blindsight’ lesion patients can respond to visual fear signals independently from conscious experience, suggesting that these signals reach the amygdala via a direct pathway that bypasses the primary visual cortex. Electrophysiological evidence points to concomitant involvement of prefrontal regions in automatic orienting to subliminal signals of fear, which may reflect innervation arising from brainstem arousal systems. To approximate blindsight in 22 healthy subjects, facial signals of fear were presented briefly (16.7 ms) and masked such that conscious detection was prevented. Results revealed that

subliminal fear signals

elicited activity in the brainstem region encompassing the superior colliculus and locus coeruleus, pulvinar and amygdala, and in fronto-temporal regions associated with orienting.

These findings suggest that crude sensory input from the superior colliculo-pulvinar visual pathway to the amygdala may allow for sufficient appraisal of fear signals to innervate the locus coeruleus.

The engagement of the locus coeruleus could explain the observation of diffuse fronto-temporal cortical activity, given its role in evoking collateral ascending noradrenergic efferents to the subcortical amygdala and prefrontal cortex.

This network may represent an

evolutionary adaptive neural ‘alarm’ system

for rapid alerting to sources of threat,

without the need for conscious appraisal.

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Williams et al 2006

Hum Brain Mapp. 2006 Aug;27(8):652-61.

Links

Amygdala-prefrontal dissociation of subliminal and supraliminal fear.

Williams LM, Liddell BJ, Kemp AH, Bryant RA, Meares RA, Peduto AS, Gordon E.

Brain Dynamics Centre, Westmead Hospital, Westmead Sydney, NSW, Australia. lea@psych.usyd.edu.au

Facial expressions of fear are universally recognized signals of potential threat. Humans may have evolved specialized neural systems for responding to fear in the absence of conscious stimulus detection. We used functional neuroimaging to establish whether the amygdala and the medial prefrontal regions to which it projects are engaged by subliminal fearful faces and whether responses to subliminal fear are distinguished from those to supraliminal fear. We also examined the time course of amygdala-medial prefrontal responses to supraliminal and subliminal fear. Stimuli were fearful and neutral baseline faces, presented under subliminal (16.7 ms and masked) or supraliminal (500 ms) conditions. Skin conductance responses (SCRs) were recorded simultaneously as an objective index of fear perception. SPM2 was used to undertake search region-of-interest (ROI) analyses for the amygdala and medial prefrontal (including anterior cingulate) cortex, and complementary whole-brain analyses. Time series data were extracted from ROIs to examine activity across early versus late phases of the experiment. SCRs and amygdala activity were enhanced in response to both subliminal and supraliminal fear perception.

Time series analysis showed a trend toward greater right amygdala responses to subliminal fear,

but left-sided responses to supraliminal fear.

Cortically, subliminal fear was distinguished by right ventral anterior cingulate activity and

supraliminal fear by dorsal anterior cingulate and medial prefrontal activity.

Although subcortical amygdala activity was relatively persistent for subliminal fear, supraliminal fear showed more sustained cortical activity.

The findings suggest that preverbal processing of fear may occur via a direct rostral-ventral amygdala pathway without the need for conscious surveillance,

whereas elaboration of consciously attended signals of fear may rely on higher-order processing within a dorsal cortico-amygdala pathway.

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Being scared is painful.  When it comes to stress reactions in the body, how stress “drives” the body reactions – that stress can be from fear or from pain – how does the brain tell them apart?  Or is the experience of this emotional pain after being terrified still a “secondary” reaction??

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Reilly et al 2008

Neurosci Lett. 2008 May 30;437(2):135-8. Epub 2008 Mar 30.

Links

Novel candidate genes identified in the brain during nociception in common carp (Cyprinus carpio) and rainbow trout (Oncorhynchus mykiss).

Reilly SC, Quinn JP, Cossins AR, Sneddon LU.

University of Liverpool, School of Biological Sciences, The BioScience Building, Liverpool L69 7ZB, UK.

Recent studies have demonstrated that teleost fish possess nociceptors that detect potentially painful stimuli and that the physiological properties of these fibers are markedly similar to those found in mammals. This finding led to suggestions of possible pain perception in fish, contrary to the view that the sensory response in these animals is limited to the spinal cord and hindbrain and as such is reflexive.

Therefore, the aim of this study was to determine if the brain is active at the molecular level by using a microarray analysis of gene expression in the forebrain, midbrain and hindbrain of two fish species. A comparison between the two species at different time points showed that

many genes

were differentially regulated

in response to a noxious stimulus

compared with controls.

A number of genes

that are involved in mammalian nociception,

such as brain-derived neurotrophic factor (BDNF)

and the cannabinoid CB1 receptor

were regulated in the fish brain after a nociceptive event.

Novel candidates that showed significant regulation in both species were also identified. In particular,

the Van Gogh-like 2 gene,

was regulated in both carp and trout and should be pursued to establish its precise role in nociception.

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Pickel et al 2006

Neuroscience. 2006 Oct 27;142(3):671-90. Epub 2006 Aug 14.

Links

Dopamine D1 receptors co-distribute with N-methyl-D-aspartic acid type-1 subunits and modulate synaptically-evoked N-methyl-D-aspartic acid currents in rat basolateral amygdala.

Pickel VM, Colago EE, Mania I, Molosh AI, Rainnie DG.

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 411 East 69th Street, Room KB-410, New York, NY 10021, USA. vpickel@med.cornell.edu

Activation of dopamine D1 or glutamate [the most common excitatory neurotransmitter in the brain], N-methyl-d-aspartic acid (NMDA) receptors [a sub-type of glutamate receptors that are activated by NMDA] in the basolateral amygdala (BLA) can potently influence

…………………..affective behaviors and associative learning.

Physical protein-protein interactions also can occur between C-terminal peptides of D1 receptors and the NMDA-receptor subunit-1 (NR1),

……….suggesting intracellular associations of direct relevance to dopaminergic modulation of NMDA currents.

In vitro analysis of physiologically characterized projection neurons revealed an excitatory response to bath application of either dopamine or the preferential D1 receptor agonist, dihydrexidine.

…………. In these neurons, dopamine also selectively reduced stimulation-evoked isolated NMDA receptor-mediated currents, but not isolated non-NMDA receptor-mediated currents or the response to exogenous NMDA application. ………….The selective reduction of the NMDA receptor-mediated currents suggests that this effect occurs at a postsynaptic locus.

……………..Moreover, both D1 and NR1 were localized to postsynaptic surfaces of biocytin-filled and physiologically characterized projection neurons.

Our results provide ultrastructural evidence for D1/NR1 endomembrane associations that may dynamically contribute to the attenuation of NMDA receptor-mediated currents following prior activation of D1 receptors in BLA projection neurons.

………….The potential for postsynaptic cross-talk between D1 and NMDA receptors

in BLA [basolateral nucleus of the amygdala] projection neurons as well as a similar interaction in presynaptic terminals

………could have important implications for the formation and extinction of affective memories.

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LoPresti et al 2008

J Neurosci. 2008 Apr 2;28(14):3718-28.

Links

Working memory for social cues recruits orbitofrontal cortex and amygdala: a functional magnetic resonance imaging study of delayed matching to sample for emotional expressions.

LoPresti ML, Schon K, Tricarico MD, Swisher JD, Celone KA, Stern CE.

Center for Memory and Brain, Boston University, Boston, Massachusetts 02215, USA. mattlo@bu.edu

During everyday interactions, we continuously monitor and maintain information about different individuals and their changing emotions in memory. Yet to date, working memory (WM) studies have primarily focused on mechanisms for maintaining face identity, but not emotional expression, and studies investigating the neural basis of emotion have focused on transient activity, not delay related activity. The goal of this functional magnetic resonance imaging study was to investigate WM for two critical social cues: identity and emotion. Subjects performed a delayed match-to-sample task that required them to match either the emotional expression or the identity of a face after a 10 s delay. Neuroanatomically, our predictions focused on the orbitofrontal cortex (OFC) and the amygdala, as these regions have previously been implicated in emotional processing and long-term memory, and studies have demonstrated sustained OFC and medial temporal lobe activity during visual WM.

Consistent with previous studies, transient activity during the sample period representing emotion and identity was found in the superior temporal sulcus and inferior occipital cortex, respectively. Sustained delay-period activity was evident in OFC, amygdala, and hippocampus, for both emotion and identity trials.

These results suggest that, although initial processing of emotion and identity is accomplished in anatomically segregated temporal and occipital regions,

sustained delay related memory for these two critical features is held by the OFC, amygdala and hippocampus. These regions share rich connections, and have been shown previously to be necessary for binding features together in long-term memory. Our results suggest a role for these regions in active maintenance as well.

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see also:

Marchalant et al 2008

Neurobiol Aging. 2008 Dec;29(12):1894-901. Epub 2007 Jun 11.

Links

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats.

Marchalant Y, Cerbai F, Brothers HM, Wenk GL.

Department of Psychology, Psychology Building, Ohio State University, Columbus, OH 43210, USA. marchalant.1@osu.edu

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Choi et al 2008b

Abstract – Neuroscience Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

Endocrinology. 2008 Feb;149(2):818-26. Epub 2007 Nov 26.

Links

The anteroventral bed nucleus of the stria terminalis differentially regulates hypothalamic-pituitary-adrenocortical axis responses to acute and chronic stress.

Choi DC, Evanson NK, Furay AR, Ulrich-Lai YM, Ostrander MM, Herman JP.

The anteroventral region of the bed nucleus of the stria terminalis (BST)

stimulates

hypothalamic-pituitary-adrenocortical (HPA) axis

responses to acute stress.

So activation of the HPA axis is same thing as it being in drive!?

However, the role of the anterior BST nuclei in chronic drive of the HPA axis has yet to be established. Therefore, this study tests the role of the anteroventral BST in physiological responses to chronic drive, using a chronic variable stress (CVS) model. Male Sprague-Dawley rats received either bilateral ibotenate lesions, targeting the anteroventral BST, or vehicle injection into the same region. Half of the lesion and control rats were exposed to a 14-d CVS paradigm consisting of twice-daily exposure to unpredictable, alternating stressors. The remaining rats were nonhandled control animals that remained in home cages. On the morning after the end of CVS exposure, all rats were exposed to a novel restraint stress challenge. CVS induced attenuated body weight gain, adrenal hypertrophy, thymic involution, and enhanced CRH mRNA in hypophysiotrophic neurons of the hypothalamic paraventricular nucleus, none of which were affected by anteroventral BST lesions. In the absence of CVS, lesions attenuated the plasma corticosterone and paraventricular nucleus c-fos mRNA responses to the acute restraint stress. In contrast, lesions of the anteroventral BST elevated plasma ACTH and corticosterone responses to novel restraint in the rats previously exposed to CVS. These data suggest that the

anterior anteroventral region of the bed nucleus of the stria terminalis (BST) plays very different roles

in integrating acute stimulation

and chronic drive of the HPA axis,

perhaps mediated by chronic stress-induced recruitment of distinct anteroventral region of the bed nucleus of the stria terminalis (BST) cell groups or functional reorganization of stress-integrative circuits.

See also:

Br J Pharmacol. 2001 Nov;134(6):1319-27.

Links

Effects of cannabinoids on adrenaline release from adrenal medullary cells.

Niederhoffer N, Hansen HH, Fernandez-Ruiz JJ, Szabo B.

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg i. Br., Germany. niederho@uni-freiburg.de

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Bradley et al 2008

Arch Gen Psychiatry. 2008 Feb;65(2):190-200.

Links

Comment in:

Arch Gen Psychiatry. 2008 Nov;65(11):1336-7; author reply 1337-9.

Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene.

Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W, Gillespie CF, Berg T, Evces M, Newport DJ, Stowe ZN, Heim CM, Nemeroff CB, Schwartz A, Cubells JF, Ressler KJ.

Atlanta VA Medical Center, Georgia, USA.

CONTEXT: Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults.

Child abuse and trauma

alter the endogenous stress response,

principally corticotropin-releasing hormone [CRH]

and its downstream effectors,

suggesting that a gene x environment interaction

at this locus may be important in depression.

OBJECTIVE: To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene. DESIGN: Association study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms. SETTING: General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia. PARTICIPANTS: The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished). MAIN OUTCOME MEASURES: Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders. RESULTS: Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199).

CONCLUSIONS: These data support the

corticotropin-releasing hormone hypothesis of depression

and suggest that a gene x environment interaction

is important for the expression of depressive symptoms

in adults with CRHR1 risk or protective alleles

who have a history of child abuse.

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Rossi et al 2008

J Neurosci. 2008 Jul 16;28(29):7284-92.

Links

Chronic psychoemotional stress impairs cannabinoid-receptor-mediated control of GABA transmission in the striatum.

Rossi S, De Chiara V, Musella A, Kusayanagi H, Mataluni G, Bernardi G, Usiello A, Centonze D.

Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.

Exposure to stressful events

has a myriad of consequences in animals and in humans,

and triggers synaptic adaptations in many brain areas.

Stress might also alter cannabinoid-receptor-mediated transmission in the brain,

but no physiological study has addressed this issue so far. In the present study, we found that

social defeat stress,

induced in mice by exposure to aggression,

altered cannabinoid CB(1)-receptor-mediated control

of synaptic transmission in the striatum.

In fact, the presynaptic inhibition of GABAergic IPSCs induced by the cannabinoid CB(1) receptor agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol] was reduced after a single stressful episode and fully abolished after 3 and 7 d of stress exposure. Repeated psychoemotional stress also impaired the sensitivity of GABA synapses to endocannabinoids mobilized by group I metabotropic glutamate receptor stimulation, whereas the cannabinoid CB(1)-mediated control of glutamate transmission was unaffected by repeated exposure to an aggressor.

Corticosteroids released in response to the activation of the hypothalamic-pituitary-adrenal axis played a major role in the synaptic defects observed in stressed animals, because these alterations were fully prevented by pharmacological blockade of glucocorticoid receptors and were mimicked by corticosterone injections. The recovery of stress-induced synaptic defects was favored when stressed mice were given access to a running wheel or to sucrose consumption, which function as potent natural rewards.

A similar rescuing effect was obtained by a single injection of cocaine, a psychostimulant with strong rewarding properties.

Targeting cannabinoid CB(1) receptors or endocannabinoid metabolism might be a valuable option to treat stress-associated neuropsychiatric conditions.

Linda note:  Does this rescue effect involve dopamine or serotonin release?  Or is this implicating the cannabinoid reward system itself?  I’m not clear here – hard without the articles to READ!

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Psychoneuroendocrinology. 2008 Jun;33(5):659-69. Epub 2008 Apr 2.

Links

The role of the posterior medial bed nucleus of the stria terminalis in modulating hypothalamic-pituitary-adrenocortical axis responsiveness to acute and chronic stress.

Choi DC, Furay AR, Evanson NK, Ulrich-Lai YM, Nguyen MM, Ostrander MM, Herman JP.

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Veenema et al 2005

Psychoneuroendocrinology. 2005 Jul;30(6):550-7.

Links

The stress response to sensory contact in mice: genotype effect of the stimulus animal.

Veenema AH, Sijtsma B, Koolhaas JM, de Kloet ER.

Department of Animal Physiology, Center for Behavioral and Cognitive Neurosciences, University of Groningen, Groningen, The Netherlands. alexa.veenema@biologie.uni-regensburg.de

Male wild house mice selectively bred for long and short attack latency (LAL and SAL, respectively) What genes did they manipulate, vasopressin? were previously shown to respond differently to chronic sensory contact stress with another SAL male. In the present study, it was investigated whether the genotype of the opponent played a role in the differential stress response of LAL and SAL mice. To this end, a LAL or SAL male was housed either under standard conditions (i.e. with a female), single, or in sensory contact with another LAL or SAL male for a period of 5 days. This period was chosen in order to study stress response adaptations. Although social isolation (singly housed) already induced changes in some physiological markers, in particular in LAL mice, the highest number of stress-induced changes was observed in LAL and SAL males living opposite a male of the other genotype. This was indicated in LAL mice by higher corticosterone levels, adrenal hypertrophy, and reduced seminal vesicle weight, and in SAL mice by higher ACTH levels and adrenal hypertrophy. Some mechanisms through which LAL and SAL mice could perceive each other as being different are proposed in the discussion, but it remains unclear why these

mice show a differential stress response depending on the genotype of the opponent.

Linda note:  They must give off signals that are understood and trigger reactions and responses in both In conclusion, it was demonstrated that a psychosocial stressor triggered line-specific changes in LAL and SAL mice, which were shown to be determined by the genotype of the stressor. These results open a new avenue to investigate mechanisms underlying genotypic-dependent stress responses.

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Llorente et al 2007

Abstract – Departamento de Fisiología (Fisiología Animal II), Facultad de Ciencias Biológicas, Universidad Complutense, Ciudad Universitaria, C/ Jose Antonio Novais, 2; 28040 Madrid, Spain.

Maternal deprivation [24h on postnatal day 9]

might represent an animal model of schizophrenia

and behavioural and neurochemical alterations observed in adulthood

may be mediated by hippocampal impairments

induced by abnormally increased glucocorticoids due to neonatal stress.

We aimed to provide new data for psychoimmunoendocrine characterization of this animal model by evaluating its effects in adolescent rats of both genders. In previous studies we found that cannabinoid compounds counteracted the enhanced impulsivity of maternally deprived animals and that the cannabinoid receptor agonist WIN 55,212-2 showed neuroprotective properties in neonatal rats. So, we hypothesized that this compound could counteract at least some of the detrimental effects that we expected to find in maternally deprived animals. Accordingly, the drug was administered immediately after the maternal deprivation period. Maternally deprived males showed significantly decreased motor activity in the holeboard and the plus-maze. The cannabinoid agonist induced, exclusively in males, a significant anxiogenic-like effect, which was reversed by maternal deprivation. In the forced swimming test, both treatments independently induced depressive-like responses.

Maternal deprivation reduced immunological function whereas the drug exerted tissue-dependent effects on the immune parameters analyzed.

Maternally deprived females showed reduced corticosterone levels whereas the cannabinoid agonist increased hormone concentration in all groups

. In general, the results show detrimental effects of both treatments as well as intriguing interactions,

notably in relation to emotional behavior

and certain immunological responses.

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Llorente et al 2007

Psychoneuroendocrinology. 2007 Jul;32(6):636-50. Epub 2007 Jun 5.

Links

Early maternal deprivation and neonatal single administration with a cannabinoid agonist induce long-term sex-dependent psychoimmunoendocrine effects in adolescent rats.

Llorente R, Arranz L, Marco EM, Moreno E, Puerto M, Guaza C, De la Fuente M, Viveros MP.

Departamento de Fisiología (Fisiología Animal II), Facultad de Ciencias Biológicas, Universidad Complutense, Ciudad Universitaria, C/ Jose Antonio Novais, 2; 28040 Madrid, Spain.

Maternal deprivation [24h on postnatal day 9]

might represent an animal model of schizophrenia

and behavioural and neurochemical alterations observed in adulthood

may be mediated by hippocampal impairments

induced by abnormally increased glucocorticoids due to neonatal stress.

We aimed to provide new data for

psychoimmunoendocrine characterization

of this animal model by evaluating its effects in adolescent rats of both genders. In previous studies we found that cannabinoid compounds counteracted the enhanced impulsivity of maternally deprived animals and that the cannabinoid receptor agonist WIN 55,212-2 showed neuroprotective properties in neonatal rats. So, we hypothesized that this compound could counteract at least some of the detrimental effects that we expected to find in maternally deprived animals. Accordingly, the drug was administered immediately after the maternal deprivation period. Maternally deprived males showed significantly decreased motor activity in the holeboard and the plus-maze. The cannabinoid agonist induced, exclusively in males, a significant anxiogenic-like effect, which was reversed by maternal deprivation. In the forced swimming test, both treatments independently induced depressive-like responses.

Maternal deprivation reduced immunological function whereas the drug exerted tissue-dependent effects on the immune parameters analyzed.

Maternally deprived females showed reduced corticosterone levels whereas the cannabinoid agonist increased hormone concentration in all groups

. In general, the results show detrimental effects of both treatments as well as intriguing interactions,

notably in relation to emotional behavior

and certain immunological responses.

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Lopez-Gallardo et al 2008

Dev Neurobiol. 2008 Sep 15;68(11):1334-47.

Links

Gender-dependent cellular and biochemical effects of maternal deprivation on the hippocampus of neonatal rats: a possible role for the endocannabinoid system.

Llorente R, Llorente-Berzal A, Petrosino S, Marco EM, Guaza C, Prada C, López-Gallardo M, Di Marzo V, Viveros MP.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, Madrid, Spain.

Adult animals submitted to a single prolonged episode of maternal deprivation (MD) [24 h, postnatal days (PND) 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia.

These behavioral impairments may be related to neuronal loss in the hippocampus triggered by elevated glucocorticoids. Furthermore, our previous data suggested functional relationships between MD stress and the endocannabinoid system. In this study, we addressed the effects of MD on hippocampal glial cells and the possible relationship with changes in plasma corticosterone (CORT) levels. In addition, we investigated the putative involvement of the endocannabinoid system by evaluating (a) the effects of MD on hippocampal levels of endocannabinoids (b)

The modulation of MD effects

by two inhibitors of

endocannabinoids inactivation,

the fatty acid amide hydrolase inhibitor N-arachidonoyl-serotonin (AA-5-HT),

and the endocannabinoid reuptake inhibitor, OMDM-2.

Drug treatments were administered once daily from PND 7 to PND 12 at a dose of 5 mg/kg, and the animals were sacrificed at PND 13.

MD induced increased CORT levels in both genders.

MD males also showed an increased number of astrocytes in CA1 and CA3 areas and a significant increase in hippocampal 2-arachidonoylglycerol.

The cannabinoid compounds

reversed the endocrine and cellular effects

of maternal deprivation.

We provide direct evidence for gender-dependent cellular and biochemical effects of MD on developmental hippocampus, including changes in the endocannabinoid system.

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Llorente et al 2008

Dev Neurobiol. 2008 Sep 15;68(11):1334-47.

Links

Gender-dependent cellular and biochemical effects of maternal deprivation on the hippocampus of neonatal rats: a possible role for the endocannabinoid system.

Llorente R, Llorente-Berzal A, Petrosino S, Marco EM, Guaza C, Prada C, López-Gallardo M, Di Marzo V, Viveros MP.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, Madrid, Spain.

Adult animals submitted to a single prolonged episode of maternal deprivation (MD) [24 h, postnatal days (PND) 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. These

behavioral impairments may be related to neuronal loss in the hippocampus triggered by elevated glucocorticoids.

Furthermore, our previous data suggested functional relationships between MD [maternal deprivation] stress and the endocannabinoid system.

In this study, we addressed the effects of MD on

hippocampal glial cells and the possible relationship with changes in plasma corticosterone (CORT) levels. In addition, we investigated the putative involvement of the endocannabinoid system by evaluating (a) the effects of MD on hippocampal levels of endocannabinoids (b) The modulation of MD effects by two inhibitors of endocannabinoids inactivation, the fatty acid amide hydrolase inhibitor N-arachidonoyl-serotonin (AA-5-HT), and the endocannabinoid reuptake inhibitor, OMDM-2.

Drug treatments were administered once daily from PND 7 to PND 12 at a dose of 5 mg/kg, and the animals were sacrificed at PND 13.

MD induced increased CORT levels in both genders.

MD males also showed an increased number of astrocytes in CA1 and CA3 areas and a significant increase in hippocampal 2-arachidonoylglycerol.

The cannabinoid compounds reversed the endocrine and cellular effects of maternal deprivation. We provide

direct evidence for gender-dependent cellular and biochemical effects of MD on developmental hippocampus, including changes in the endocannabinoid system.

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IMPORTANT

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Marco et al 2008

Neurosci Biobehav Rev. 2009 Apr;33(4):498-507. Epub 2008 Apr 3.

Links

Detrimental psychophysiological effects of early maternal deprivation in adolescent and adult rodents: altered responses to cannabinoid exposure.

Marco EM, Adriani W, Llorente R, Laviola G, Viveros MP.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Spain.

Environmental rearing conditions during the neonatal period are critical for the establishment of neurobiological factors controlling behavior and stress responsiveness.

Early maternal deprivation (MD), consisting of a single 24-h maternal deprivation episode during early neonatal life, has been proposed as an animal model for certain psychopathologies including anxiety, depression and schizophrenic-related disorders.

Despite first onset of mental disorders usually occur during adolescence, characterization of MD has been mostly developed in adult animals. We review here a series of experiments that were conducted on rats and mice, in which we analyzed the psychoimmunoendocrine outcomes of MD at both adolescence and adulthood. As a whole our results indicate that

MD might promote a depressive-like trait that may be present from adolescence to maturity.

Maternally deprived adolescent animals

also displayed altered locomotor responses,

a reduced interest for social investigation

and seemed prone for impulsive behavior.

Therefore, MD in rodents is further confirmed as a suitable animal model for the study of neuropsychiatric disorders that might become evident during adolescence.

Given the increasing consumption of cannabis derivatives among the juvenile population and the reported comorbidity of neuropsychiatric symptoms with cannabis abuse, we also discuss our

results indicating altered responses

of maternally deprived adolescent animals

to cannabinoid compounds.

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Viveros et al 2007

Neural Plast. 2007;2007:52908.

Links

Endocannabinoid system and synaptic plasticity: implications for emotional responses.

Viveros MP, Marco EM, Llorente R, López-Gallardo M.

Departamento de Fisiología Fisiología Animal II, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain. pazviver@bio.ucm.es

The endocannabinoid system has been involved

in the regulation of anxiety, and proposed as an

inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli.

Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic [anxious] and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity,

whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects.

Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories.

Thus, the endocannabinoid system

appears to play a pivotal role in the regulation of emotional states.

Endocannabinoids have emerged

as mediators of short- and long-term synaptic plasticity in diverse brain structures.

Despite the fact that most of the studies on this field have been performed using in vitro models,

endocannabinoid-mediated plasticity

might be considered as a plausible candidate

underlying some of the diverse physiological functions

of the endogenous cannabinoid system,

including developmental, affective and cognitive processes.

In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn,

enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

[Is there no other way to heal this system other than taking drugs?  ]

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Viveros et al 2007b

Behav Pharmacol. 2007 Sep;18(5-6):375-89.

Links

The role of the hippocampus in mediating emotional responses to nicotine and cannabinoids: a possible neural substrate for functional interactions.

Viveros MP, Marco EM, Llorente R, Lamota L.

Faculty of Biology, Department of Physiology (Animal physiology II), Complutense University, Madrid, Spain. pazviver@bio.ucm.es

The endocannabinoid system is involved in the regulation of behavioral and physiological stress-related responses. Nicotine exerts complex effects on emotional behavior, and its withdrawal may result in depressive and anxiogenic-like symptoms. Cannabinoid receptor agonists and nicotine induce biphasic effects in diverse tests of unconditioned anxiety, alter adrenocortical activity and affect hippocampus-dependent contextual fear conditioning. Upon exposure to stressful stimuli, central endocannabinoid and cholinergic systems appear to be activated in key limbic areas such as hippocampus and amygdala, which might contribute to adaptive cognitive and emotional strategies to cope with aversive situations.

Numerous studies indicate the existence of functional interactions between nicotine and cannabinoids, particularly in relation to anxiety-related processes.

An overlapping distribution of CB1 and nicotinic acetylcholine receptors in the hippocampus is observed and the endocannabinoid system exerts a modulatory role over the hippocampal cholinergic system. In this review, we point to the hippocampus as a relevant neural substrate for cannabinoid-nicotine interactions, notably as regards emotional responses.

After a general description of the cannabinoid and nicotinic systems, we review their implications in unconditioned anxiety, depressive-like behavior and fear conditioning. Then we discuss the role of both systems in modulating stress-induced changes at cellular, endocrine and behavioural levels and their possible involvement in hippocampal neurogenesis. Although we mainly focus on animal data, some relevant human studies are also discussed.

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Veenema et al 2003

J Neuroendocrinol. 2003 Mar;15(3):256-67.

Links

Genetic selection for coping style predicts stressor susceptibility.

Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM.

Department of Animal Physiology, Centre for Behavioural and Cognitive Neuroscience, University of Groningen, The Netherlands. a.h.veenema@biol.rug.nl

Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which

show distinctly different coping styles,

also display a differential regulation

of the hypothalamic-pituitary-adrenal axis [HPA]

after exposure to an acute stressor.

To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls.

The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated [nonaggressive] LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behavior in the forced swimming test than LAL controls.

Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated [more aggressive] SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyze the role of genetic factors in the individual differences in stress-related psychopathology.

Refer to the doves and hawks information – still need to know what genes they are manipulating re aggression levels!

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See also:

Horm Behav. 2003 Jan;43(1):197-204.

Links

Differences in basal and stress-induced HPA regulation of wild house mice selected for high and low aggression.

Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM, Bohus BG.

Department of Animal Physiology, Center for Behavioral and Cognitive Neuroscience, University of Groningen, Haren, The Netherlands. A.H.Veenema@biol.rug.nl

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This following article is in the cannabinoid section on PAIN KILLERS

Pharmacol Res. 2007 Nov;56(5):367-81. Epub 2007 Sep 8.

Links

The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction.

Lafenêtre P, Chaouloff F, Marsicano G.

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see also from cannabinoid section on PAIN KILLERS:

Lutz 2007

Abstract – Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany. blutz@uni-mainz.de

The endocannabinoid system and extinction learning.

Lutz B.

Mol Neurobiol. 2007 Aug;36(1):92-101. Epub 2007 Aug 17. Review.

PMID: 17952654 [PubMed – indexed for MEDLINE]

Related Articles

The endogenous cannabinoid system controls extinction of aversive memories.

Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B.

Nature. 2002 Aug 1;418(6897):530-4.

PMID: 12152079 [PubMed – indexed for MEDLINE]

Related Articles

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Marschner et al 2008

Abstract – NeuroImage Nord, Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany. a.marschner@uke.uni-hamburg.de

J Neurosci. 2008 Sep 3;28(36):9030-6.

Links

Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning.

Marschner A, Kalisch R, Vervliet B, Vansteenwegen D, Büchel C.

Lesion studies in animals have identified a critical role of the hippocampus in context fear conditioning. To extend these findings to human volunteers, we used functional magnetic resonance imaging to investigate neural responses associated with context fear conditioning in humans. Our novel conditioning paradigm consisted of aversive electrical shocks (unconditioned stimulus) that were delivered either cue or context related.

Differential evoked responses,

related to the conditioned stimulus (CS),

were found in the

anterior cingulate cortex and the

bilateral insular cortices,

regions that have been implicated in

anticipatory anxiety.

In case of context conditioning, a similar pattern was observed during the presentation of the entire context. In line with previous conditioning studies,

differential responses in the amygdala showed a time by stimulus interaction, suggesting rapid adaptation of CS-specific responses. More importantly, a

similar differential decay of activation

was observed during context conditioning in the

hippocampus, in agreement with a

role of the hippocampus in the

acquisition phase of human

context fear conditioning.

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See also:

J Neural Transm. 2007;114(8):1055-63. Epub 2007 Mar 19.

Links

Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression.

Koethe D, Llenos IC, Dulay JR, Hoyer C, Torrey EF, Leweke FM, Weis S.

Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. koethe@ecnp.net

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Anxiolysis

An anxiolytic is a drug prescribed for the treatment of symptoms of anxiety

See also about anxiety:

Neuropsychopharmacology. 2009 Feb;34(3):593-606. Epub 2008 Jun 25.

Links

Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels.

Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di Marzo V.

Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy.

Neuropharmacology. 2008 Jan;54(1):151-60. Epub 2007 Jul 6.

Links

Erratum in:

Neuropharmacology. 2008 Aug;55(2):247.

CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour.

Rubino T, Guidali C, Vigano D, Realini N, Valenti M, Massi P, Parolaro D.

DBSF, Pharmacology Section and Center of Neuroscience, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy.

Cereb Cortex. 2008 Jun;18(6):1292-301. Epub 2007 Oct 5.

Links

Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex.

Rubino T, Realini N, Castiglioni C, Guidali C, Viganó D, Marras E, Petrosino S, Perletti G, Maccarrone M, Di Marzo V, Parolaro D.

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SEE ALSO:

The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice.

Mikics E, Dombi T, Barsvári B, Varga B, Ledent C, Freund TF, Haller J.

Behav Pharmacol. 2006 May;17(3):223-30.

PMID: 16572000 [PubMed – indexed for MEDLINE]

Related Articles

Cannabinoid CB1 receptor dependent effects of the NMDA antagonist phencyclidine in the social withdrawal model of schizophrenia.

Haller J, Szirmai M, Varga B, Ledent C, Freund TF.

Behav Pharmacol. 2005 Sep;16(5-6):415-22.

PMID: 16148446 [PubMed – indexed for MEDLINE]

Related Articles

CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents.

Haller J, Varga B, Ledent C, Freund TF.

Behav Pharmacol. 2004 Jul;15(4):299-304.

PMID: 15252281 [PubMed – indexed for MEDLINE]

Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice.

Haller J, Varga B, Ledent C, Barna I, Freund TF.

Eur J Neurosci. 2004 Apr;19(7):1906-12.

PMID: 15078564 [PubMed – indexed for MEDLINE]

Related Articles

Cereb Cortex. 2009 Jan;19(1):165-75. Epub 2008 May 13.

Links

The role of prefrontal cortex CB1 receptors in the modulation of fear memory.

Lin HC, Mao SC, Su CL, Gean PW.

Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Tainan 701, Taiwan

Learn Mem. 2006 May-Jun;13(3):316-21. Epub 2006 May 16.

Links

Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle.

Lin HC, Mao SC, Gean PW.

Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan. bailu@mail.nih.gov

Learn Mem. 2008 Dec 2;15(12):876-84. Print 2008.

Links

Chronic cannabinoid administration in vivo compromises extinction of fear memory.

Lin HC, Mao SC, Chen PS, Gean PW.

Institute of Basic Medical Sciences and Department of Pharmacology, Center for Gene Regulation and Signal Transduction Research, National Cheng-Kung University, Tainan, Taiwan.

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Machado et al 2008

Behav Neurosci. 2008 Apr;122(2):251-66.

Links

Bilateral neurotoxic amygdala lesions in rhesus monkeys (Macaca mulatta): consistent pattern of behavior across different social contexts.

Machado CJ, Emery NJ, Capitanio JP, Mason WA, Mendoza SP, Amaral DG.

Department of Psychiatry and Behavioral Sciences, The M.I.N.D. Institute, University of California, Davis, Sacramento, CA 95817, USA.

Although the amygdala has been repeatedly implicated in normal primate social behavior, great variability exists in the specific social and nonsocial behavioral changes observed in nonhuman primates with bilateral amygdala lesions. One plausible explanation pertains to differences in social context. This study measured the social behavior of amygdala-lesioned and unoperated rhesus monkeys (Macaca mulatta) in 2 contexts. Monkeys interacted in 4-member social groups over 32 test days.

Across the 2 contexts, amygdala lesions produced a highly consistent pattern of social behavior. …………Operated monkeys engaged in more affiliative social interactions with control partners than did controls.

………..In the course of their interactions, amygdala-lesioned monkeys also displayed an earlier decrease in nervous and fearful personality qualities than did controls.

…………..The increased exploration and sexual behavior recorded for amygdala-lesioned monkeys in pairs was not found in the 4-member groups.

The authors concluded that the amygdala contributes to social inhibition

….and that this function transcends various social contexts.

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Emery et al 2001

Behav Neurosci. 2001 Jun;115(3):515-44.

Links

The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta).

Emery NJ, Capitanio JP, Mason WA, Machado CJ, Mendoza SP, Amaral DG.

University of California, Davis, USA.

The role of the amygdala in dyadic social interactions

…..of adult rhesus monkeys (Macaca mulatta) was assessed after bilateral ibotenic acid lesions. …….Social, nonsocial, and spatial behaviors of amygdalectomized and control monkeys were assessed in 3 dyadic experiments: constrained, unconstrained, and round robin.

……Lesions produced extensive bilateral damage to the amygdala.

Across all experiments, the amygdalectomized monkeys demonstrated increased social affiliation, decreased anxiety, and increased confidence compared with control monkeys, particularly during early encounters.

…………Normal subjects also demonstrated increased social affiliation toward the amygdalectomized subjects.

These results indicate that amygdala lesions in adult monkeys

………lead to a decrease in the species-normal

……..reluctance to immediately engage a novel conspecific in social behavior.

The altered behavior of the amygdalectomized monkeys may have induced the increased social interactions from their normal companions.

This is contrary to the idea that amygdalectomy produces a decrease in social interaction and increased aggression from conspecifics.

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COMPLEX INFORMATION HERE ABOUT HOW ENDOCANNABINOIDS WORK WITH OUR NEUROTRANSMITTERS IN THE BRAIN:

de Lago et al 2007

Life Sci. 2007 Feb 13;80(10):979-88. Epub 2006 Nov 23.

Links

Neurochemical effects of the endocannabinoid uptake inhibitor UCM707 in various rat brain regions.

de Lago E, Ortega-Gutiérrez S, Ramos JA, López Rodríguez ML, Fernández-Ruiz J.

To date, UCM707, (5Z,8Z,11Z,14Z)-N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide,

……has the highest potency and selectivity in vitro and in vivo

….as inhibitor of the endocannabinoid uptake.

Linda note:  So these results suggest that there is an “over abundance” of AEA creating these brain changes noted here?

Its biochemical, pharmacological and therapeutic properties have been intensely studied recently, but the information on its capability to modify neurotransmitter activity, which obviously underlies the above properties, is still limited.

In the present study, we conducted a time-course experiment in rats aimed at examining the neurochemical effects of UCM707 in several brain regions following a subchronic administration (5 injections during 2.5 days) of this inhibitor in a dose of 5 mg/kg weight.

….In the hypothalamus, the administration of UCM707 did not modify GABA contents but reduced norepinephrine levels at 5 h after administration, followed by an increase at 12 h. …..Similar trends were observed for dopamine,

……whereas serotonin content remained elevated at 1 and, in particular, 5 and 12 h after administration.

In the case of the basal ganglia, UCM707 reduced GABA content in the substantia nigra but only at longer (5 or 12 h) times after administration.

………There were no changes in serotonin content,

………but a marked reduction in its metabolite 5HIAA was recorded in the substantia nigra.

…..The same pattern was found for dopamine, contents of which were not altered by UCM707 in the caudate-putamen,

………but its major metabolite DOPAC exhibited a marked decrease at 5 h.

In the cerebellum,

…….UCM707 reduced GABA, serotonin and norepinephrine content, but only the reduction found for norepinephrine at 5 h reached statistical significance.

The administration of UCM707 did not modify the contents of these neurotransmitters in the hippocampus and the frontal cortex.

Lastly, in the case of limbic structures, the administration of UCM707

……markedly reduced dopamine content in the nucleus accumbens at 5 h,

…..whereas GABA content remained unchanged in this structure

….and also in the ventral-tegmental area and the amygdala.

By contrast, norepinephrine and serotonin content increased at 5 h in the nucleus accumbens, but not in the other two limbic structures.

In summary, UCM707 administered subchronically modified the contents of serotonin, GABA, dopamine and/or norepinephrine with a pattern strongly different in each brain region. So, changes in GABA transmission (decrease) were restricted to the substantia nigra, but did not appear in other regions, whereas dopamine transmission was also altered in the caudate-putamen and the nucleus accumbens.

By contrast, norepinephrine and serotonin were altered by UCM707 in the

…..hypothalamus,

….cerebellum (only norepinephrine), and

……nucleus accumbens,

………….exhibiting biphasic effects in some cases

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Linda note:  In some ways this exploratory search I am doing is like drilling a well, or finding the bottom of it – to get a clear clean stream so that I can come up to the surface in my own way to make sense of what happened to me – the interaction of my body, brain, mind, self with the torture and abuse I experienced throughout my 18 years of development – so I can determine the best I can what the impact of that was on me and in me.  Going to the source – the smallest increment of knowledge I can possibly understand – putting it all together from there – again, the best that I can.

Looking in all directions, above and below me, to the left and to the right of me, within me —  I do this with a fierce determination – the best that I can muster, knowing that this cancer I fight might remove me from this job at any time.  Research demonstrates that strong social support mitigates and modulates the impact of traumas of all kinds for the better – though nobody seems to be able to say exactly what happens – with or without this strong and adequate social support.

The WHAT of this has to happen in a “where of this” – I trust that the awareness is inside of me – what I know personally – and that it will resonate with the truth as I find it.  Going to the bottom of the well – perhaps in that dream I had as I hung onto that rope, dangling there, rope fraying to nothing as I remained, eyes shut, suspended between terror and faith – perhaps my feet were only a few inches above safe ground.  I don’t know.  In the dream I did not look.  I am looking now!

The interaction of attachment, strong or terrible social interaction – cannot possibly be a mysterious and unknowable event.  We are designed by and limited to the extremes by our genetic code and the processes that it contains as it manifests and operates within us.  Social support and the impact it has on our being has to be modulated within a genetic matrix.

There is something about the endocannabinoid system that seems to be pivotal, key and central, to the expanding consequences of experience as it moves from the particular to the general and back again within the potentialities of being a human in a human form.  If I am careful enough, thorough enough, and move in the right direction, the arrow of my intelligence needs to encounter the truth as I can understand it, and then explain it to others – assuming that there is a single damn important and relevant factor contained in this whole mess!  And assuming that I can find it.

I want to change what the little people know and how they know it.  I want to empower them to be enlightened just a little bit more about their life in their body – a sort of tour guide – presenting something useful, awesome, fascinating, empowering – as we move forward into a more complicated and difficult world, as we evolve, and as we get lost along the way.

From the bottom up, if I can only find simple and clear ways to explain the basics of interactions, internally and externally, that shed light on how we get along inside and outside, with others and when alone – going below ground to the roots, following up and out to the tips of the branches, straightening some bent developmental trajectories.  Why are there so many hurting people?  So many with mental illness, addictions included, alone without support, wandering the streets, struggling so hard?  They are still all our brethren (is there a feminine version of this word?).  They are still connected to this huge tree of our species as long as they breath, in and out, in and out.

Can I present something clear and simple, like a transparency, x-ray super vision – supervision – so we can look within and without from a slightly more compassionate place based on – informed compassion – in-formed compassion.  To see at the center of the matrix where everything shifts from the center out depending on attachment systems….  A sort of simple hands-on every day physiological-psychological Haiku – or coup – taking our power into the people – to interact on equal ground with the professionals we turn to – in clinics or on street corners – or in the grocery stores – for our chemical dependencies of every sort – to modulate our beings in the absence of what we were designed by evolution to optimally need for our optimal state of balance and well-being – attachment within our species – being fully operational components of a species-wide system that needed us.  With 7 billion and growing, the rules have all changed – and how does that feel to us personally?  Collectively?  For these are growing pains….

How do I know, or why do I think, that the center of the operational matrix within us might be at the cannabinoid system of operation?  Because it is there at our conception, and guides our development from that point onward – being key and central, I suspect, in its influence on all the other “axis” operations in our bodies.

Like people with their arms waving, with lights in their hands, directing the flow of air traffic on the ground, on the runways – this system may well be the one that directs the signaling in our bodies as we journey through life in these bodies.

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Page, Oropeza & Van Bockstaele 2008

Neurosci Lett. 2008 Jan 24;431(1):1-5. Epub 2007 Nov 9.

Links

Local administration of a cannabinoid agonist alters norepinephrine efflux in the rat frontal cortex.

Page ME, Oropeza VC, Van Bockstaele EJ.

Thomas Jefferson University, Department of Neurosurgery, Farber Institute for Neurosciences, 900 Walnut Street, Suite 400, Philadelphia, PA 19107, United States.

Delta(9)-tetrahydrocannabinol, the main psychoactive ingredient in marijuana, activates specific cannabinoid (CB) receptors to exert complex actions on modulatory neurotransmitters involved in attention and cognition.

Previous research has demonstrated that systemic administration of the synthetic cannabinoid agonist, WIN 55,212-2, increases norepinephrine efflux in the frontal cortex.

…..The distribution of CB1 receptors on noradrenergic fibers in the frontal cortex

…..suggests this may be one potential site for the regulation of norepinephrine release.

In the present study, we first examined the ability of a CB1 antagonist, applied locally in the frontal cortex of adult male Sprague-Dawley rats, to block the actions of systemic WIN 55,212-2. Pretreatment with SR 141716A (300 microM) significantly attenuated the excitatory effects of WIN 55,212-2 (15 mg/kg, i.p.). Next, the impact of direct perfusion of WIN 55,212-2 into the frontal cortex on extracellular norepinephrine efflux was measured. Direct application of WIN 55,212-2 (100 microM) into the frontal cortex elicited a significant increase in extracellular norepinephrine efflux suggesting that activation of cortical cannabinoid receptors contributes to alterations in norepinephrine levels in this brain region.

Finally, local administration of SR 141716A followed by local administration of WIN 55,212-2 revealed a paradoxical inhibition of norepinephrine efflux.

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Gabbott, Warner & Busby 2006

Neuroscience. 2006;139(3):1039-48. Epub 2006 Mar 9.

Links

Amygdala input monosynaptically innervates parvalbumin immunoreactive local circuit neurons in rat medial prefrontal cortex.

Gabbott PL, Warner TA, Busby SJ.

Department of Biological Sciences, The Open University, Milton Keynes MK7 6AA, UK. p.l.gabbott@open.ac.uk

‘feed-forward’ inhibitory mechanisms

The projection from the basolateral nucleus of the amygdala (BLA) conveys information about the affective significance of sensory stimuli to the medial prefrontal cortex (mPFC).

parvalbumin immunopositive (PV+) neurons.

………The results indicate that labeled BLA afferents predominantly contact the spiny processes of presumed pyramidal cells and also provide a direct and specific innervation to a sub-population of local circuit neurons in mPFC containing PV. Since PV+ cells include two significant classes of fast-spiking GABAergic inhibitory interneuron (basket and axo-axonic cells), these novel observations indicate that

the amygdalocortical pathway in the rat

has the ability to directly influence functionally strategic ‘feed-forward’ inhibitory mechanisms

at the first stage of processing amygdalocortical information.

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EMOTIONAL MEMORY

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Follow this link to pubmed and do a search for ‘cannabinoid and emotional memory’ to find 65 articles about the cannabinoid system and emotional memory.

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Rainnie et al 2006

J Comp Neurol. 2006 Sep 1;498(1):142-61.

Links

Physiological and morphological characterization of parvalbumin-containing interneurons of the rat basolateral amygdala.

Rainnie DG, Mania I, Mascagni F, McDonald AJ.

Department of Psychiatry and Center for Behavioral Neuroscience, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA. drainni@emory.edu

The basolateral amygdala (BLA) is critical for the generation of emotional behavior and the

……………………..formation of emotional memory.

Understanding the neuronal mechanisms that contribute to emotional information processing in the BLA will ultimately require knowledge of the anatomy and physiology of its constituent neurons. Two major cell classes exist in the BLA, pyramidal projection neurons and nonpyramidal interneurons. Although the properties of projection neurons have been studied in detail, little is known about the properties of BLA interneurons.

Here, we report [rat study] that BLA interneurons can be differentiated into four electrophysiologically distinct subtypes based on their intrinsic membrane properties and their response to afferent synaptic input.

………..Interneuron subtypes were named according to their characteristic firing pattern generated in response to transient depolarizing current injection and were grouped as follows:

….. 1) burst-firing interneurons (n = 13),

………2) regular-firing interneurons (n = 11),

………..3) fast-firing interneurons (n = 10), and

………4) stutter-firing interneurons (n = 14).

…………..Post hoc histochemical visualization confirmed that all 48 recorded neurons had morphological properties consistent with their being local circuit interneurons. Moreover…we further demonstrated that over 60% of burst-firing and stutter-firing interneurons also expressed the calcium-binding protein parvalbumin (PV(+)).

……….These data demonstrate that interneurons of the BLA show both physiological and neurochemical diversity. Moreover, we demonstrate that the burst- and stutter-firing patterns positively correlate with PV(+) immunoreactivity, suggesting that these neurons may represent functionally distinct subpopulations.

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Woodruff & Sah 2007

J Neurosci. 2007 Jan 17;27(3):553-63.

Links

Networks of parvalbumin-positive interneurons in the basolateral amygdala.

Woodruff AR, Sah P.

Queensland Brain Institute and School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.

The amygdala is a temporal lobe structure that is required for processing emotional information.

…….Polymodal sensory information enters the amygdala at the level of the basolateral amygdala (BLA)

…………and undergoes local processing,

………….after which the behavioral and autonomic responses that accompany emotions are initiated.

Two main neuron types are present in the BLA, pyramidal-like principal neurons that use glutamate as their transmitter, and local circuit interneurons that use GABA as their transmitter. Although the properties of principal neurons are known in some detail, very little is known about the properties of BLA interneurons or the local circuits in which they are involved. Using mice in which EGFP (enhanced green fluorescent protein) is expressed under the control of the parvalbumin promoter, we characterized the properties of parvalbumin-positive interneurons in the BLA.

………… we analyzed the intrinsic circuitry of the BLA.

…….We show that parvalbumin-positive interneurons can be divided into four subtypes as defined by their firing properties.

………..Interneurons are electrically coupled in subtype-specific networks and exhibit subtype-specific heterogeneities in their synaptic dynamics and patterns of connectivity.

………….We propose that these properties allow networks of parvalbumin-expressing neurons to perform an array of information-processing tasks within the BLA.

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Yang et al 2007

Neuropsychopharmacology. 2007 Feb;32(2):332-42. Epub 2006 Mar 22.

Links

Extract of Ginkgo biloba EGb761 facilitates extinction of conditioned fear measured by fear-potentiated startle.

Yang YL, Su YW, Ng MC, Chao PK, Tung LC, Lu KT.

Department of Molecular Biology and Biochemistry, Institute of Biotechnology, National Chia-Yi University, Chia-Yi, Taiwan.

A standard extract of Ginkgo biloba (EGb761) has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention, or vigilance.

We demonstrated that acute systemic administration of EGb761 facilitated the acquisition of conditioned fear.

Many studies suggest the neural mechanism underlies extinction is similar to the acquisition. This raises a possibility that EGb761 may modulate and accelerate the fear extinction process. We tested this possibility by using fear-potentiated startle (FPS) on laboratory rats. …, acute EGb761 administration modulated extinction of conditioned fear by activating ERK1/2.

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Paganelli, Benetoli & Milani 2006

Behav Brain Res. 2006 Nov 1;174(1):70-7. Epub 2006 Aug 24.

Links

Sustained neuroprotection and facilitation of behavioral recovery by the Ginkgo biloba extract, EGb 761, after transient forebrain ischemia in rats.

Paganelli RA, Benetoli A, Milani H.

Department of Pharmacy and Pharmacology, Health Science Center, Pharmaceutical Sciences Post-Graduation Program, State University of Maringá, Av. Colombo 5790, CEP 87020-900 Maringá, Paraná, Brazil

The effects of the Ginkgo biloba extract, EGb 761, on ischemia-induced learning/memory impairments and hippocampal damage were evaluated …EGb 761 reduced the extent of hippocampal CA1 cell lossan effect sustained at least up to 40 days after ischemia.

These findings show that EGb 761 is effective in reducing, at least partially, both the cognitive impairments and hippocampal damage after TGCI in rats, and suggest that its effect on behavioral recovery may be dissociated from the neuroprotective effect on the hippocampus.

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Yang, Chao & Lu 2006

Neuropsychopharmacology. 2006 May;31(5):912-24.

Links

Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear.

Yang YL, Chao PK, Lu KT.

Department of Molecular Biology and Biochemistry, Institute of Biotechnology, National Chia-Yi University, Chia-Yi, Taiwan.

We examined the effect of glucocorticoid agonists on the extinction of conditioned fear in rats by using fear-potentiated startle….

All results suggested that

amygdaloid glucocorticoid receptors

were involved in the extinction of conditioned fear.

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Bishop 2007

Trends Cogn Sci. 2007 Jul;11(7):307-16. Epub 2007 Jun 5.

Links

Neurocognitive mechanisms of anxiety: an integrative account.

Bishop SJ.

Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, UK. sb445@cam.ac.uk

Anxiety can be hugely disruptive to everyday life. Anxious individuals show increased attentional capture by potential signs of danger, and interpret expressions, comments and events in a negative manner. Do not neglect the role of oxytocin and vasopressin in these states and conditions

These cognitive biases [it is a stretch, I believe, to call them “cognitive processes” when they lie in our very genetic interactions and composition have been widely explored in human anxiety research. By contrast, animal models have focused upon the mechanisms underlying acquisition and extinction of conditioned fear, guiding exposure-based therapies for anxiety disorders. Recent neuroimaging studies of

conditioned fear,

attention to threat and

interpretation of emotionally ambiguous stimuli

indicate common amygdala-prefrontal circuitry

underlying these processes, and

suggest that the balance of activity within this circuitry is altered in anxiety,

creating a bias towards threat-related responses.

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See also:

Trends Cogn Sci. 2007 Jul;11(7):307-16. Epub 2007 Jun 5.

Links

Neurocognitive mechanisms of anxiety: an integrative account.

Bishop SJ.

Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, UK. sb445@cam.ac.uk

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Patel et al 2004

Endocrinology. 2004 Dec;145(12):5431-8. Epub 2004 Aug 26.

Links

Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis.

Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for the adaptation and survival of animals upon exposure to stressful stimuli,

and data suggest that endocannabinoid (eCB) signaling modulates neuroendocrine function.

These data indicate that eCB signaling negatively modulates HPA axis function in a context-dependent manner and suggest that pharmacological augmentation of eCB signaling could serve as a novel approach to the treatment of anxiety-related disorders.

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Wenger, Ledent & Tramu 2003

Neuroendocrinology. 2003 Dec;78(6):294-300.

Links

The endogenous cannabinoid, anandamide, activates the hypothalamo-pituitary-adrenal axis in CB1 cannabinoid receptor knockout mice.

Wenger T, Ledent C, Tramu G.

Department of Human Morphology and Developmental Embryology, Semmelweis University, Budapest, Hungary. wenger@ana2.sote.hu

The purpose of this study was to investigate the effects of the endogenous cannabinoid arachidonoyl-ethanolamide, anandamide (AEA), on the activity of the hypothalamo-pituitary-adrenal (HPA) axis in cannabinoid receptor (CB(1) receptor) inactivated (KO) mice.

A low dose (0.01 mg/kg i.p.) of AEA significantly increased plasma corticotropin (ACTH) and corticosterone concentrations in both wild-type (+/+) and in mutant (-/-) animals.

In each case, hormone levels reached their peaks at 90 min after AEA administration. In a parallel experiment, AEA administration was preceded by the injection of SR 141716A (1.0 mg/kg), a selective and potent CB(1) receptor antagonist, or of capsazepine (5.0 mg/kg), a potent vanilloid receptor of type 1 (VR1) antagonist. The latter drugs did not prevent the effects of AEA on the HPA axis. Using Fos protein immunohistochemistry, we observed that the parvocellular part of the hypothalamic paraventricular nucleus (PVN) was activated as early as 45 min after AEA injection and reached peak levels after 60 min in both +/+ and -/- mice. Furthermore, the CB(1) and VR1 receptor antagonists did not block the effects of AEA on Fos immunoreactivity. The results strongly support the view

that activation of the HPA axis produced by AEA

possibly occurs via a currently unknown (CB(x)) cannabinoid receptor present in PVN

++++++++++++++++++++++

Barna et al 2004

Life Sci. 2004 Oct 29;75(24):2959-70.

Links

The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation: in vivo and in vitro studies in CB1 receptor knockout mice.

Barna I, Zelena D, Arszovszki AC, Ledent C.

Institute of Experimental Medicine, 1083 Budapest, P.O. Box 67, Hungary. barna@koki.hu

Exogenous cannabinoids affect multiple hormonal systems including the hypothalamo-pituitary-adrenocortical (HPA) axis.

These data suggest that endogenous cannabinoids are also involved in the HPA control;

however, the mechanisms underlying this control are poorly understood. We assessed the role of endogenous cannabinoids in the regulation of the HPA-axis by studying CB1 receptor knockout (KO) and wild type (WT) mice. Basal and novelty stress-induced plasma levels of adrenocorticotropin (ACTH) and corticosterone were higher in CB1-KO than in WT mice. We investigated the involvement of the pituitary in the hormonal effects of CB1 gene disruption by studying the in vitro release of ACTH from anterior pituitary fragments using a perifusion system. Both the basal and corticotropin releasing hormone (CRH)-induced ACTH secretion were similar in CB1-KO and WT mice. The synthetic glucocorticoid, dexamethasone suppressed the CRH-induced ACTH secretion in both genotypes; thus, the negative feedback of ACTH secretion was not affected by CB1 gene disruption. The cannabinoid agonist, WIN 55,212-2 had no effects on basal and CRH-stimulated ACTH secretion by anterior pituitary slices.

In our hands, the

disruption of the CB1 gene lead to HPA axis hyperactivity,

but the pituitary seems not to be involved in this effect.

Our data are consistent with the assumption that endogenous cannabinoids inhibit the HPA-axis via centrally located CB1 receptors, however the understanding of the exact underlying mechanism needs further investigation.

++++++++++++++++++++++

Hill et al 2006b

Eur J Neurosci. 2006 Oct;24(7):1845-9.

Links

Endocannabinoids modulate stress-induced suppression of hippocampal cell proliferation and activation of defensive behaviours.

Hill MN, Kambo JS, Sun JC, Gorzalka BB, Galea LA.

Department of Psychology and the Brain Research Centre, University of British Columbia, Vancouver, BC, Canada V6T1Z4.

The endocannabinoid system has been shown to regulate

both the hypothalamic-pituitary-adrenal (HPA) axis

and emotionality.

The present experiment was designed to examine whether pharmacological modulation of the endocannabinoid system would affect the suppression of hippocampal cell proliferation and increase in defensive behaviours seen following exposure to predator odour (trimethylthiazoline; TMT) stress. Rats were administered either an endocannabinoid uptake inhibitor (AM404; 2 mg/kg) or a cannabinoid CB1 receptor antagonist (AM251; 5 mg/kg) 30 min prior to exposure to TMT. Exposure to TMT reduced cell proliferation in the dentate gyrus and increased the expression of defensive burying. Administration of AM404 significantly inhibited defensive burying, and attenuated the reduction in cell proliferation in response to TMT exposure. Administration of AM251 alone significantly increased cell proliferation; however, pretreatment with AM251 prevented neither the stress-induced suppression of cell proliferation nor the stress-induced increase in behavioural responses.

These results support previous research demonstrating

that augmentation of endocannabinoid signalling

can suppress stress-responsive systems.

They also suggest that endocannabinoids

may play a complex role

in the regulation of neurogenesis

via cell proliferation in the hippocampus.

++++++++++++++++++++++++

Cota et al 2007

Endocrinology. 2007 Apr;148(4):1574-81. Epub 2006 Dec 28.

Links

Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.

Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grübler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, Pagotto U.

Group of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.

The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the

hypothalamus-pituitary-adrenal (HPA) axis.

However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis.

Although

circadian HPA axis responsiveness

is preserved,

CB1-/- mice are characterized by an enhanced circadian drive

on the HPA axis,

resulting in elevated plasma corticosterone concentrations at the onset of the

dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/–derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice.

Both CBL-/- and CB1+/+ mice

…. properly respond to a high-dose dexamethasone test,

….but response to low-dose dexamethasone is influenced by genotype.

In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized…

Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus.

Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas.

In conclusion, our findings indicate that

CB1 deficiency enhances the

circadian HPA axis

activity peak

and leads to central impairment of glucocorticoid feedback,

thus further outlining the essential role of the endocannabinoid system

in the modulation of neuroendocrine functions.

++++++++++++++++++++++++

See also, from regulation file:

Cota 2008

J Neuroendocrinol. 2008 May;20 Suppl 1:35-8.

Links

The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity.

Cota D.

Department of Psychiatry, Obesity Research Center, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu

Steiner & Wotjak 2008

Prog Brain Res. 2008;170:397-432.

Links

Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis.

Steiner MA, Wotjak CT.

Max Planck Institute of Psychiatry, Neuroplasticity Group, Kraepelinstrasse, Munich, Germany.

++++++++++++++++

IMPORTANT

+++++++

Phan et al 2008

J Neurosci. 2008 Mar 5;28(10):2313-9.

Links

Cannabinoid modulation of amygdala reactivity to social signals of threat in humans.

Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, de Wit H.

Department of Psychiatry, University of Michigan and Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan 48109, USA. luan@umich.edu

The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of delta(9)-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of

CB(1) receptors localized within the basolateral amygdala,

a critical brain region for

threat perception.

This must be a crucially active area for “doves” in a different way than for “hawks”

However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that

THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

Tied to the attachment system, I would say, and the process of feeling safe and securely attached

++++++++++++++++++++++++

J Neurosci. 2005 Dec 7;25(49):11489-93.

Links

Oxytocin modulates neural circuitry for social cognition and fear in humans.

Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A.

Cognitive Neuroscience Group, Center for Psychiatry and Psychotherapy, Justus-Liebig University, D-35385 Giessen, Germany.

In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.

PMID: 16339042 [PubMed – indexed for MEDLINE]

See also:

Pubmed database search for “oxytocin cannabinoid” brings up 17 articles.

Including:

J Neurosci. 2007 Feb 7;27(6):1325-33.

Links

Retrograde regulation of GABA transmission by the tonic release of oxytocin and endocannabinoids governs postsynaptic firing.

Oliet SH, Baimoukhametova DV, Piet R, Bains JS.

Institut National de la Santé et de la Recherche Médicale, Unité 862, Université Victor Segalen Bordeaux 2, Bordeaux 33077, France.

+++++++++++++++++++++++

Yang et al 2007b

Neuropsychopharmacology. 2007 May;32(5):1042-51. Epub 2006 Oct 18.

Links

Glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats.

Yang YL, Chao PK, Ro LS, Wo YY, Lu KT.

Institute of Biotechnology, National Chia-Yi University, Chia-Yi, Taiwan

Recent results show that brain glucocorticoids are involved in the dysregulation of fear memory extinction in post-traumatic stress disorder patients.

The present study was aimed to elucidate the possible mechanism of glucocorticoids on the conditioned fear extinction….

These results suggest that glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction.

+++++++++++++++++

Flint, Valentine & Papandrea 2007

Neuroscience. 2007 Sep 21;148(4):833-44. Epub 2007 Jul 20.

Links

Reconsolidation of a long-term spatial memory is impaired by cycloheximide when reactivated with a contextual latent learning trial in male and female rats.

Flint RW Jr, Valentine S, Papandrea D Jr.

Department of Psychology, The College of Saint Rose, 432 Western Avenue, Albany, NY 12203-1490, USA. flintr@strose.edu

Reconsolidation of long-term memory has become a topic of great interest in recent years, and has the potential to provide important information regarding memory processes and the treatment of memory-related disorders. The present study examined the role of systemic protein synthesis inhibition in reconsolidation of a long-term spatial memory reactivated by a contextual latent learning trial in male and female rats. Using the Morris water maze, we demonstrate that: 1) a contextual latent reactivation treatment enhances memory, 2) systemic protein synthesis inhibition selectively impairs test performance when administered in conjunction with a memory reactivation treatment, and 3) that these effects are more pronounced in female rats.

These findings indicate a role for protein synthesis in the reconsolidation of a contextually reactivated long-term spatial memory using the water maze, and a potential differential effect of sex in this apparatus. The role of the strength of the memory trace is discussed and the relevance of these findings to theories of reconsolidation and therapeutic treatment of post-traumatic stress disorder is discussed.

++++

Rodriguez-Ortiz et al 2008

Neurobiol Learn Mem. 2008 Mar;89(3):352-9. Epub 2007 Nov 28.

Links

Intrahippocampal anisomycin infusions disrupt previously consolidated spatial memory only when memory is updated.

Rodriguez-Ortiz CJ, Garcia-DeLaTorre P, Benavidez E, Ballesteros MA, Bermudez-Rattoni F.

Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F. 04510, Mexico.

Reconsolidation has proven to be a common phenomenon relevant to memory processing. However, the functional significance of this process is still a matter of debate. Previous work has shown that

reconsolidation is indeed a process

by which updated information is integrated,

through the synthesis of proteins,

to a memory trace.

To further analyze the role that updated information plays in retrieved spatial memory susceptibility to disruption, we injected anisomycin bilaterally in the dorsal hippocampus of Wistar rats. Implanted animals were trained for 5 days on the Morris water maze (MWM) task and injected with anisomycin before the third or fifth training session. When memory was assessed a week later, only animals injected on the third training session showed disruption of long-term memory. Furthermore, when animals were trained for either 3 (middle-trained) or 5 (well-trained) days and a week later anisomycin was infused before a reminder session, only middle-trained rats infused with anisomycin showed reduced performance when tested for long-term memory. Finally, animals trained for 5 days and injected with anisomycin 7 days later on an extinction session showed impaired long-term extinction when tested. These results suggest that for spatial memory tasks acquisition of updated information is a necessary feature to undergo this process. We propose that

reconsolidation is not an accurate term

because it implies that consolidation happens again.

This conception does not fit with the evidence;

hence, we suggest that

updating consolidation is a more descriptive term

to refer to this process.

++++

Antion et al 2008

Learn Mem. 2008 Jan 3;15(1):29-38. Print 2008 Jan.

Links

Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity.

Antion MD, Merhav M, Hoeffer CA, Reis G, Kozma SC, Thomas G, Schuman EM, Rosenblum K, Klann E.

Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.

FEAR MEMORY AND PROTEIN SYNTHESIS

Protein synthesis is required for the expression of enduring memories and long-lasting synaptic plasticity.

During cellular proliferation and growth, S6 kinases (S6Ks) are activated and coordinate the synthesis of de novo proteins. We hypothesized that protein synthesis mediated by S6Ks is critical for the manifestation of learning, memory, and synaptic plasticity. We have tested this hypothesis with genetically engineered mice deficient for either S6K1 or S6K2. We have found that

S6K1-deficient mice express an early-onset contextual fear memory deficit within one hour of training, a deficit in conditioned taste aversion (CTA), impaired Morris water maze acquisition, and hypoactive exploratory behavior. In contrast,

S6K2-deficient mice exhibit decreased contextual fear memory

seven days after training, a

reduction in latent inhibition of CTA,

and normal spatial learning in the Morris water maze.

Surprisingly, neither S6K1- nor S6K2-deficient mice exhibited alterations in protein synthesis-dependent late-phase long-term potentiation (L-LTP). However, removal of S6K1, but not S6K2, compromised early-phase LTP expression. Furthermore, we observed that S6K1-deficient mice have elevated basal levels of Akt phosphorylation, which is further elevated following induction of L-LTP. Taken together, our findings demonstrate that removal of S6K1 leads to a distinct array of behavioral and synaptic plasticity phenotypes that are not mirrored by the removal of S6K2. Our observations suggest that neither gene by itself is required for L-LTP but instead may be required for other types of synaptic plasticity required for cognitive processing.

++++

Artinian et al 2007

Hippocampus. 2007;17(3):181-91.

Links

Reactivation with a simple exposure to the experimental environment is sufficient to induce reconsolidation requiring protein synthesis in the hippocampal CA3 region in mice.

Artinian J, De Jaeger X, Fellini L, de Saint Blanquat P, Roullet P.

Centre de Recherches sur la Cognition Animale, CNRS 5169, Université Paul Sabatier, Toulouse, France.

Our understanding of the memory reconsolidation process is at an earlier stage than that of consolidation. For example, it is unclear if, as for memory consolidation, reconsolidation of a memory trace necessitates protein synthesis. In fact, conflicting results appear in the literature and this discrepancy may be due to differences in the experimental reactivation procedure. Here, we addressed the question of whether protein synthesis in the CA3 hippocampal region is crucial in memory consolidation and reconsolidation of allocentric knowledge after reactivation in different experimental conditions in the Morris water maze.

We showed (1) that an injection of the protein synthesis inhibitor anisomycin in the CA3 region during consolidation or after a single reactivation trial disrupted performance and (2) that protein synthesis is required even after a simple contextual reactivation without any learning trial and independently of the presence of the reinforcement.

This work demonstrates that a simple

exposure to the spatial environment is sufficient

to reactivate the memory trace,

to make it labile,

and that reconsolidation of this trace

requires de novo protein synthesis. Is this the same as CONTEXT?

++++

Artinian et al 2008

Eur J Neurosci. 2008 Jun;27(11):3009-19.

Links

Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation.

Artinian J, McGauran AM, De Jaeger X, Mouledous L, Frances B, Roullet P.

Centre de Recherches sur la Cognition Animale, CNRS 5169, Université Paul Sabatier, Toulouse, France.

The formation of long-term memory requires protein synthesis, particularly during initial memory consolidation. This process also seems to be dependant upon protein degradation, particularly degradation by the ubiquitin-proteasome system.

The aim of this study was to investigate the temporal requirement of protein synthesis and degradation during the initial consolidation of allocentric spatial learning. As

memory returns to a labile state during reactivation,

we also focus on the role of protein synthesis and degradation during memory reconsolidation of this spatial learning. Male CD1 mice were submitted to massed training in the spatial version of the Morris water maze. At various time intervals after initial acquisition or after a reactivation trial taking place 24 h after acquisition, mice received an injection of either the protein synthesis inhibitor anisomycin or the protein degradation inhibitor lactacystin. This injection was performed into the hippocampal CA3 region, which is specifically implicated in the processing of spatial information.

Results show that, in the CA3 hippocampal region, consolidation of an allocentric spatial learning task requires two waves of protein synthesis taking place immediately and 4 h after acquisition, whereas reconsolidation requires only the first wave.

However, for protein degradation, both consolidation and reconsolidation require only one wave, taking place immediately after acquisition or reactivation, respectively. These findings suggest that

protein degradation is a key step for memory reconsolidation, as for consolidation. Moreover, as

protein synthesis-dependent reconsolidation

occurred faster than consolidation,

reconsolidation did not consist of a simple repetition

of the initial consolidation.

So the newest information is that reconsolidation is something different from what they have been considering it to be – is actually a separate process that operates differently from consolidation of the first memory.

++++

Kleppisch et al 2003

J Neurosci. 2003 Jul 9;23(14):6005-12.

Links

Hippocampal cGMP-dependent protein kinase I supports an age- and protein synthesis-dependent component of long-term potentiation but is not essential for spatial reference and contextual memory.

Kleppisch T, Wolfsgruber W, Feil S, Allmann R, Wotjak CT, Goebbels S, Nave KA, Hofmann F, Feil R.

Institut für Pharmakologie und Toxikologie, 80802 München, Germany, Max-Planck-Institut für Psychiatrie, 80804 München, Germany. kleppisch@ipt.med.tu-muenchen.de

cGMP-dependent protein kinase I (cGKI) is expressed in the hippocampus, but its role in hippocampal long-term potentiation (LTP) is controversial. In addition, whether cGKI is involved in spatial learning has not been investigated. To address these issues, we generated mice with a hippocampus-specific deletion of cGKI (cGKIhko mice). Unlike conventional cGKI knock-out mice, cGKIhko mice lack gastrointestinal and cardiovascular phenotypes and have a normal life expectancy, which enables us to analyze hippocampal synaptic plasticity and learning in young and adult animals. Hippocampal LTP after repetitive episodes of theta burst stimulation was impaired in adult (12-14 weeks of age) but not in juvenile (3-4 weeks of age) cGKIhko mice. The difference in LTP between adult control and cGKIhko mice was abolished by the protein synthesis inhibitor anisomycin, suggesting that the impairment of LTP in adult cGKIhko mice reflects a defect in late-phase LTP. Despite their deficit in LTP, adult cGKIhko mutants showed normal performance in a discriminatory water maze and had intact contextual fear conditioning.

These results suggest that hippocampal cGMP-dependent protein kinase I (cGKI)

supports an age- and protein synthesis-dependent form

of hippocampal LTP, whereas

it is dispensable for hippocampus-dependent spatial reference and contextual memory.

+++++++++++++++++

Garakani, Mathew & Charney 2006

Mt Sinai J Med. 2006 Nov;73(7):941-9.

Links

Neurobiology of anxiety disorders and implications for treatment.

Garakani A, Mathew SJ, Charney DS.

Mount Sinai School of Medicine, New York, NY, USA.

The neurobiology of the anxiety disorders, which include panic disorder, post-traumatic stress disorder (PTSD), and specific phobias, among others, has been clarified by advances in the field of classical or Pavlovian conditioning, and in our understanding of basic mechanisms of memory and learning. Fear conditioning occurs when a neutral conditioned stimulus (such as a tone) is paired with an aversive, or unconditioned stimulus (such as a footshock), and then in the absence of the unconditioned stimulus, causes a conditioned fear response. Preclinical studies have shown that the amygdala plays a key role in fear circuitry, and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Drugs such as glutamate N-methyl-D-aspartate (NMDA) antagonists, and blockers of voltage-gated calcium channels, in the amygdala, may block these effects. There is also preliminary evidence for the use of centrally acting beta-adrenergic antagonists, like propranolol, to inhibit consolidation of traumatic memories in PTSD. Finally, fear extinction, which entails new learning of fear inhibition, is central to the mechanism of effective anti-anxiety treatments. Several pharmacological manipulations, such as D-cycloserine, a partial NMDA agonist, have been found to facilitate extinction. Combining these medication approaches with psychotherapies that promote extinction, such as cognitive behavioral therapy (CBT), may offer patients with anxiety disorders a rapid and robust treatment with good durability of effect.

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Domschke et al 2008c

Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):510-6.

Links

Chromosome 4q31-34 panic disorder risk locus: association of neuropeptide Y Y5 receptor variants.

Domschke K, Hohoff C, Jacob C, Maier W, Fritze J, Bandelow B, Krakowitzky P, Kästner F, Rothermundt M, Arolt V, Deckert J.

Department of Psychiatry, University of Muenster, Muenster, Germany. katharina.domschke@ukmuenster.de

There is strong evidence for a genetic contribution to the pathogenesis of panic disorder, with a recent linkage study pointing toward a risk locus on chromosome 4q31-q34 [Kaabi et al., 2006].

Since the neuropeptide Y (NPY) system

has been reported to be involved in the pathophysiology of anxiety

and in particular panic disorder

and the

genes coding for NPY Y1, Y2, and Y5 receptors are located in the suggested risk region (4q31-q32), variants in the NPY, NPY Y1, Y2, and Y5 genes were investigated for association with panic disorder in a sample of 230 German patients with panic disorder and matched healthy controls.

A synonymous (Gly-426-Gly) NPY Y5 coding variant (rs11946004) as well as haplotypes including rs11946004 and an intronic NPY Y5 variant (rs11724320) were significantly associated with panic disorder (P = 0.027), with the effect originating from the subgroup of female patients (P = 0.030), particularly with concurrent agoraphobia (P = 0.002-0.019). No association was observed for any variants located in the genes coding for NPY, NPY Y1, or Y2.

The present results provide preliminary support for an influence of NPY Y5 receptor variants on the etiology of panic disorder in a potentially gender-specific manner further strengthening the evidence for a

risk locus on chromosome 4q31-q34 in anxiety disorders.

However, in order to allow for conclusive evaluation of the present finding and to exclude a false positive result, further studies in larger, independent, preferably family based samples are warranted.

See also:

J Neural Transm. 2008 Sep 2. [Epub ahead of print]

Links

Association analysis of Rgs7 variants with panic disorder.

Hohoff C, Neumann A, Domschke K, Jacob C, Maier W, Fritze J, Bandelow B, Krakowitzky P, Rothermundt M, Arolt V, Deckert J.

Department of Psychiatry, University of Muenster, Albert-Schweitzer-Strasse 11, 48149, Muenster, Germany, hohoffch@uni-muenster.de.

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Erhardt et al 2006

Neuropsychopharmacology. 2006 Nov;31(11):2515-22. Epub 2006 Jul 12.

Links

Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder.

Erhardt A, Ising M, Unschuld PG, Kern N, Lucae S, Pütz B, Uhr M, Binder EB, Holsboer F, Keck ME.

Max Planck Institute of Psychiatry, Munich, Germany.

Anxiety and depressive disorders are among the most common psychiatric disorders with a high number of hospital admissions and a lifetime prevalence of up to 25%.

So far, the pathophysiological mechanisms for anxiety disorders remain to be found. Preclinical studies suggest that changes in hypothalamic-pituitary-adrenocortical (HPA) system function are causally related to the expression of anxiety-related behavior. The findings on HPA system function in patients with anxiety disorders are, however, heterogeneous. Both hypo- and hyperresponsiveness of HPA response in various anxiety disorders under different experimental conditions were found.

…. This finding further underlines the hypothesis that both, depression and panic disorder, share impaired HPA system regulation, supporting the notion that the impairment is involved in the pathophysiology of these clinical conditions.

However, differences in the suppression effects

and psychopathological correlation patterns

between depressed and panic patients

suggest different biological mechanisms of HPA system dysregulation in both disorders.

+++++++++++++++++++++

Ginsberg et al 2003

J Neuroendocrinol. 2003 Nov;15(11):1075-83.

Links

Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus.

Ginsberg AB, Campeau S, Day HE, Spencer RL.

University of Colorado at Boulder, Department of Psychology and Center for Neurosciences, Boulder, CO 80309, USA. abby@psych.colorado.edu

Corticosterone

regulates both basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity

in a negative-feedback fashion.

However, the cellular and molecular mechanisms of this negative feedback have yet to be explicitly characterized. By comparing stress-induced c-fos and corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus (PVN), we may be able to determine

whether acute glucocorticoid treatment affects the net neural excitatory input to the PVN (represented primarily by c-fos mRNA expression) or directly affects the ability of cells in the PVN to respond to that input (represented primarily by CRH hnRNA expression).

In the following studies, we observed the effect of acute glucocorticoid (RU28362) treatment on subsequent HPA axis reactivity by measuring

stress-induced plasma hormone concentration

[corticosterone and adrenocorticotropic hormone (ACTH)]

and gene expression (c-fos and CRH) in the PVN.

First, we examined the dose-response relationship between systemically administered RU28362 (1-150 microg/kg, i.p) and suppression of the stress-induced corticosterone response. We then confirmed central nervous system access of the maximally suppressive dose of RU28362 (150 microg/kg) by an ex vivo radioligand binding assay. RU28362 selectively occupied the majority of glucocorticoid receptors in the hippocampus and hypothalamus while having no effect on mineralocorticoid receptors. In separate studies, RU28362 (150 microg/kg) and corticosterone (5 mg/kg) were injected i.p. 1 h before restraint stress. Compared to vehicle-treated controls, rats treated with RU28362 and corticosterone had substantially blunted stress-induced corticosterone and ACTH production, respectively. Furthermore, treatment with RU28362 significantly blunted stress-induced CRH hnRNA expression in the PVN. By contrast, neither RU28362 nor corticosterone treatment had an effect on stress-induced neuronal activation as measured by c-fos mRNA and its protein product in the PVN.

This dissociation between c-fos and CRH gene expression

suggests that glucocorticoid suppression of HPA activity within this time-frame

is not a result of decreased excitatory neural input to the PVN,

but instead depends on some direct effect of RU28362

on cells intrinsic to the HPA axis.

++++++++++++++++++++

Hill et al 2006

Neuropsychopharmacology. 2006 Dec;31(12):2591-9. Epub 2006 May 10.

Links

Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis.

Hill MN, Ho WS, Sinopoli KJ, Viau V, Hillard CJ, Gorzalka BB.

Department of Psychology, University of British Columbia, Vancouver, BC, Canada.

The efficacy of antidepressants has been linked in part to their ability to reduce activity of the hypothalamic-pituitary-adrenal (HPA) axis;

however, the mechanism by which antidepressants regulate the HPA axis is largely unknown.

Given that recent research has demonstrated that

endocannabinoids can regulate the HPA axis

and exhibit antidepressant potential,

we examined the hypothesis that the endocannabinoid system is regulated by long-term antidepressant treatment.

Three-week administration of the tricyclic antidepressant desipramine (10 mg/kg/day) resulted in a significant increase in the density of the cannabinoid CB(1) receptor in the hippocampus and hypothalamus, without significantly altering endocannabinoid content in any brain structure examined. Furthermore, chronic desipramine treatment resulted in a reduction in both secretion of corticosterone and the induction of the immediate early gene c-fos in the medial dorsal parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following a 5 min exposure to swim stress.

Acute treatment with the CB(1) receptor antagonist, AM251 (1 mg/kg), before exposure to swim stress, completely occluded the ability of desipramine to reduce both corticosterone secretion and induction of c-fos expression in the PVN. Collectively, these data demonstrate

that CB(1) receptor density in the hippocampus and hypothalamus is increased by chronic tricyclic antidepressant treatment,

…..and suggest that this upregulation

could contribute

to the ability of tricyclic antidepressants

to suppress stress-induced activation of the HPA axis.

+++++++++++++++++++++

Dev Neurobiol. 2008 Sep 15;68(11):1334-47.

Links

Gender-dependent cellular and biochemical effects of maternal deprivation on the hippocampus of neonatal rats: a possible role for the endocannabinoid system.

Llorente R, Llorente-Berzal A, Petrosino S, Marco EM, Guaza C, Prada C, López-Gallardo M, Di Marzo V, Viveros MP.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, Madrid, Spain.

Adult animals submitted to a single prolonged episode of maternal deprivation (MD) [24 h, postnatal days (PND) 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. These behavioral impairments may be related to neuronal loss in the hippocampus triggered by elevated glucocorticoids. Furthermore, our previous data suggested functional relationships between MD stress and the endocannabinoid system. In this study, we addressed the effects of MD on hippocampal glial cells and the possible relationship with changes in plasma corticosterone (CORT) levels. In addition, we investigated the putative involvement of the endocannabinoid system by evaluating (a) the effects of MD on hippocampal levels of endocannabinoids (b) The modulation of MD effects by two inhibitors of endocannabinoids inactivation, the fatty acid amide hydrolase inhibitor N-arachidonoyl-serotonin (AA-5-HT), and the endocannabinoid reuptake inhibitor, OMDM-2. Drug treatments were administered once daily from PND 7 to PND 12 at a dose of 5 mg/kg, and the animals were sacrificed at PND 13. MD induced increased CORT levels in both genders. MD males also showed an increased number of astrocytes in CA1 and CA3 areas and a significant increase in hippocampal 2-arachidonoylglycerol. The cannabinoid compounds reversed the endocrine and cellular effects of maternal deprivation. We provide direct evidence for gender-dependent cellular and biochemical effects of MD on developmental hippocampus, including changes in the endocannabinoid system. Copyright (c) 2008 Wiley Periodicals, Inc.

PMID: 18666205 [PubMed – in process]

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Strohle & Holsboer 2003

Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S207-14.

Links

Stress responsive neurohormones in depression and anxiety.

Ströhle A, Holsboer F.

Department of Psychiatry and Psychotherapy, Charité – University Medicine Berlin, Campus Charité-Mitte (CCM), Berlin, Germany. andreas.stroehle@charite.de

Clinical and preclinical studies have gathered substantial evidence that

stress response alterations

play a major role in the development of

major depression,

panic disorder and

posttraumatic stress disorder.

The stress response, the

hypothalamic pituitary adrenocortical (HPA) system

and its modulation by

CRH, corticosteroids and their receptors

as well as the role of natriuretic [an agent that promotes the excretion of sodium in the urine] peptides and neuroactive steroids are described. Exemplarily, we review the role of the HPA system in major depression, panic disorder and posttraumatic stress disorder as well as its possible relevance for treatment.

Impaired glucocorticoid receptor function

in major depression is associated with an excessive release

of neurohormones, like CRH to which a number of signs and symptoms characteristic of depression can be ascribed.

In panic disorder, a role of central CRH in panic attacks has been suggested. Atrial natriuretic peptide (ANP) is causally involved in sodium lactate-induced panic attacks. Furthermore, preclinical and clinical data on its anxiolytic activity suggest that non-peptidergic ANP receptor ligands may be of potential use in the treatment of anxiety disorders. Recent data further suggest a

role of 3alpha-reduced neuroactive steroids in major depression, panic attacks and panic disorder.

Posttraumatic stress disorder is characterized by a peripheral hyporesponsive HPA-system and elevated CRH concentrations in CSF.

This dissociation is probably related to an increased risk for this disorder.

Antidepressants are effective both in depression and anxiety disorders and have major effects on the HPA-system, especially on glucocorticoid and mineralocorticoid receptors.

Normalization of HPA-system abnormalities

is a strong predictor of the clinical course, at least in major depression and panic disorder. CRH-R1 or glucocorticoid receptor antagonists and ANP receptor agonists are currently being studied and may provide future treatment options more closely related to the pathophysiology of the disorders.

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See also:

Endocrinology. 2004 Nov;145(11):5202-9. Epub 2004 Jul 22.

Links

Cocaine- and amphetamine-regulated transcript activates the hypothalamic-pituitary-adrenal axis through a corticotropin-releasing factor receptor-dependent mechanism.

Smith SM, Vaughan JM, Donaldson CJ, Rivier J, Li C, Chen A, Vale WW.

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

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Tsigos & Chrousos 2002

J Psychosom Res. 2002 Oct;53(4):865-71.

Links

Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.

Tsigos C, Chrousos GP.

Hellenic National Diabetes Center, Athens, Greece.

The stress system coordinates the adaptive responses of the organism to stressors of any kind.

The main components of the stress system are the

…..corticotropin-releasing hormone (CRH) and

……locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors,

……the pituitary-adrenal axis,

……and the limbs of the autonomic system.

Not mentioning the immune system!

Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival.

…………….The CRH and LC/NE systems stimulate arousal and attention,

……as well as the mesocorticolimbic dopaminergic system,

….which is involved in anticipatory and reward phenomena,

…..and the hypothalamic beta-endorphin system,

……which suppresses pain sensation and, hence,

….. increases analgesia.   This has to be the opioid receptors

CRH

..inhibits appetite and

…activates thermogenesis [internally generated heat caused by the production of energy]

…..via the catecholaminergic system.

………….Also, reciprocal interactions exist

……between the amygdala and the hippocampus

……and the stress system,

…………….which stimulates these elements and is regulated by them.

CRH plays an important role in inhibiting GnRH secretion during stress,

………while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions.

Interestingly, all three of these functions receive and depend on positive catecholaminergic input.

The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles.

………They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala.

In addition, they [glucocorticoids ]directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5′ deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)),

……contributing further to the suppression of reproductive, growth and thyroid functions.

They [glucocorticoids] also have direct

….as well as insulin-mediated effects

…….on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing “low turnover” osteoporosis.

Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH).

………….CRH antagonists [hyper reactivity] may be useful in human pathologic states,

such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system,

……along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above.

……..Conversely, potentiators of CRH secretion/action [hypo reactivity] may be useful

to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.

How can depression be related to both hypo and hyper-reactivity of the HPA?

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Pharmacol Biochem Behav. 2002 Aug;73(1):147-58.

Links

Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress.

Makino S, Hashimoto K, Gold PW.

Second Department of Internal Medicine, Kochi Medical School, Okoh-cho, Nankoku, Japan. fwjf6671@mb.infoweb.ne.jp

Stress-associated disorders such as melancholic depression are characterized by persistent hypothalamic-pituitary-adrenocortical (HPA) axis activation and intensive anxiety. Corticotropin-releasing hormone (CRH) appears to play an essential role in pathophysiology of such disorders. In an attempt to elucidate possible mechanisms underlying persistent activation of CRH in the central nervous system (CNS), we examined responses of hypothalamic and extrahypothalamic CRH systems to the stressors (immobilization stress or psychological stress) and interactions between these CRH systems and glucocorticoids in rats. We propose multiple feedback loops activating central CRH system: (1) attenuation of glucocorticoid-induced negative feedback on the activity of the hypothalamic and brainstem nuclei during chronic stress, (2) autoregulation of CRH biosynthesis in the hypothalamic paraventricular nucleus (PVN) through up-regulation of Type-1 CRH receptor (CRHR-1), and (3) glucocorticoid-mediated positive effects on the amygdaloid CRH system. Stress initially activates the hypothalamic CRH system, resulting in the hypersecretion of glucocorticoids from the adrenal gland. In addition, the psychological component of the stressor stimulates the amygdaloid CRH system. In the chronic phase of stress, down-regulation of GR in the PVN and other brain structures such as the locus coeruleus (LC) fails to restrain hyperfunction of the HPA axis, and persistent activation of the HPA axis further up-regulates the amygdaloid CRH system. Thus, the hypothalamic and the amygdaloid CRH systems cooperatively constitute stress-responsive, anxiety-producing neurocircuitry during chronic stress, which is responsible for the clinical manifestations of stress-associated disorders. Effects of tricyclic antidepressants (TCAs), which appear to mitigate the above mentioned multiple feedback loop forming the vicious circle to activate central CRH systems, will also be discussed.

PMID: 12076734 [PubMed – indexed for MEDLINE

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Smith & Vale 2006

Dialogues Clin Neurosci. 2006;8(4):383-95.

Links

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress.

Smith SM, Vale WW.

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Animals respond to stress by activating a wide array of behavioral and physiological responses

……that are collectively referred to as the stress response.

Corticotropin-releasing factor (CRF)

……plays a central role in the stress response

……by regulating the hypothalamic-pituitary-adrenal (HPA) axis.

In response to stress, CRF initiates a cascade of events

……that culminate in the release of glucocorticoids from the adrenal cortex.

As a result of the great number of physiological and behavioral effects exerted by glucocorticoids,

…….several mechanisms have evolved to control HPA axis activation and integrate the stress response. Well, I guess these don’t always respond the way we wish they did in our modern world!

Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release.

……………..In addition to glucocorticoid feedback,

…………..the HPA axis is regulated at the level of the hypothalamus

…………by a diverse group of afferent projections from limbic, midbrain, and brain stem nuclei.

The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenomedullary circuits, and parasympathetic systems.

In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli.

See also:

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Malcher-Lopes et al 2006

J Neurosci. 2006 Jun 14;26(24):6643-50.

Links

Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.

Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG, Tasker JG.

Neuroscience Program, Tulane University, New Orleans, Louisiana 70118, USA. malcherlopes@gmail.com

The hypothalamic paraventricular nucleus (PVN)

integrates preautonomic and neuroendocrine

control of energy homeostasis,

fluid balance, and the

stress response.

We recently demonstrated that

glucocorticoids

act via a membrane receptor

to rapidly cause endocannabinoid-mediated suppression of synaptic excitation

in PVN neurosecretory neurons.

Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids.

Here we show that

Glucocorticoids

[Glucocorticoids:  a class of hormones produced by the adrenal gland and simulated by medications such as prednisone]

stimulate endocannabinoid biosynthesis

and release via a Galpha(s)-cAMPprotein kinase A-dependent mechanism and that

leptin blocks glucocorticoid-induced endocannabinoid biosynthesis

and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels.

We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats.

Our findings reveal a

novel hormonal crosstalk

that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.

++++==

Prog Brain Res. 2008;170:379-88.

Links

Rapid synapse-specific regulation of hypothalamic magnocellular neurons by glucocorticoids.

Di S, Tasker JG.

Neurobiology Division, Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, USA.

Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis feed back onto the hypothalamus to rapidly suppress neuroendocrine activation, including oxytocin and vasopressin secretion. Here we provide a brief review focused on our recent findings of a rapid glucocorticoid-induced opposing regulation of glutamate and gamma-aminobutyric acid (GABA) inputs to magnocellular neurons via the release of distinct retrograde messengers. The stress hormone corticosterone and its synthetic analogue dexamethasone elicit the rapid retrograde release of endocannabinoids by activating a novel membrane-associated, G protein-coupled receptor in parvocellular and magnocellular neuroendocrine cells of the hypothalamic paraventricular and supraoptic nuclei. Glucocorticoids also cause the rapid retrograde release of an unknown messenger that facilitates presynaptic GABA release onto magnocellular neuroendocrine cells. These finding suggest that there is a strict synapse-specific segregation of the opposing actions of the two retrogradely released messengers. Thus, the combined actions of glucocorticoids cause a rapid synaptic inhibition of the magnocellular neurons and would be expected, therefore, to mediate a rapid feedback inhibition of the secretion of oxytocin and vasopressin during stress activation of the hypothalamic-pituitary-adrenal axis.

PMID: 18655897 [PubMed – indexed for MEDLINE

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Kohda et al 2007

Links

Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model.

Kohda K, Harada K, Kato K, Hoshino A, Motohashi J, Yamaji T, Morinobu S, Matsuoka N, Kato N.

Department of Neuropsychiatry, Faculty of Medicine, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kkohda@sc.itc.keio.ac.jp

Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experience, and presents with characteristic symptoms, such as intrusive memories, a state of hyperarousal, and avoidance, that endure for years. Single-prolonged stress (SPS) is one of the animal models proposed for PTSD. Rats exposed to SPS showed

enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, which has been reliably reproduced in patients with PTSD, and increased expression of glucocorticoid receptor (GR) in the hippocampus.

In this study, we characterized further neuroendocrinologic, behavioral and electrophysiological alterations in SPS rats. Plasma corticosterone recovered from an initial increase within a week, and gross histological changes and neuronal cell death were not observed in the hippocampus of the SPS rats. Behavioral analyses revealed that the SPS rats presented

enhanced acoustic startle and impaired spatial memory that paralleled the deficits in hippocampal long-term potentiation (LTP) and depression.

Contextual fear memory was enhanced in the rats 1 week after SPS exposure, whereas LTP in the amygdala was blunted. Interestingly, blockade of GR activation by administering 17-beta-hydroxy-11-beta-/4-/[methyl]-[1-methylethyl]aminophenyl/-17-alpha-[prop-1-ynyl]estra-4-9-diene-3-one (RU40555), a GR antagonist, prior to SPS exposure prevented potentiation of fear conditioning and impairment of LTP in the CA1 region. Altogether, SPS caused a number of behavioral changes similar to those described in PTSD, which marks SPS as a putative PTSD model. The

preventive effects of a GR antagonist

suggested that GR activation might play a critical role

in producing the altered behavior and neuronal function

of SPS rats.

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Viveros, Marco & File 2005

Pharmacol Biochem Behav. 2005 Jun;81(2):331-42.

Links

Endocannabinoid system and stress and anxiety responses.

Viveros MP, Marco EM, File SE.

Departmento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain. pazviver@bio.ucm.es

Cannabinoid agonists induce complex

and often contradictory effects on anxiety

in humans and experimental animals. The data from animal tests provide evidence of

dose-dependent bidirectional modulation of anxiety by the cannabinoid system

and the importance of environmental context.

The mechanisms mediating the effects of cannabinoids on anxiety-related responses

appear to involve CB1 and non-CB1 cannabinoid receptors.

In addition, the

CRH,

GABA(A),

cholecystokinin,

opioid and

serotonergic systems

have also been implicated.

Brain regions such as the amygdala, hippocampus and cortex, directly involved in the regulation of emotional behavior, contain high densities of CB1 receptors.

Mutant mice lacking CB1 receptors show anxiogenic-like

and depressive-like phenotypes in several tests, as well as

profound alterations in their adrenocortical activity.

Pharmacological blockade of CB1 receptors induces anxiety in rats, and inhibition of anandamide metabolism produces anxiolytic-like effects. Thus, the

endocannabinoid system appears to play a pivotal role in the regulation of emotional states

and may constitute a novel pharmacological target for anti-anxiety therapy.

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De Kloet & Derijk 2004

Ann N Y Acad Sci. 2004 Dec;1032:14-34.

Links

Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance.

De Kloet ER, Derijk R.

Division of Medical Pharmacology, LACDR/LUMC, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands. e.kloet@lacdr.leidenuniv.nl

Optimal regulation of the stress response is a prerequisite for adaptation, homeostasis, and health.

There are two modes of operation in the stress response.

First, an immediate response mode mediated by corticotrophin-releasing hormone-1 (CRH-1) receptors that organizes the behavioral, sympathetic, and hypothalamic-pituitary-adrenal (HPA) response to a stressor.

Second, a slower mode, which facilitates behavioral adaptation, promotes recovery, and reestablishes homeostasis.

Corticosteroid hormones are implicated in both stress system modes.

On the one hand, cortisol and corticosterone determine the threshold or sensitivity of the fast responding mode, whereas the very same hormones in high concentrations facilitate termination of the stress response.

In the brain, these actions exerted by the corticosteroid hormones are mediated by

two distinct nuclear receptor types, that is,

mineralocorticoid receptors (MRs) and

glucocorticoid receptors (GRs). Whereas

MRs maintain neuronal homeostasis and limit the disturbance by stress,

GRs help to recover after the challenge and to store the experience for coping with future encounters.

Imbalance in MR/GR-mediated actions compromises homeostatic processes in these neurons,

which is thought to underlie maladaptive behavior

and HPA dysregulation that may lead to

aberrant metabolism,

impaired immune function, and

altered cardiovascular control.

The balance in MR/GR-mediated actions depends on bioavailability of corticosteroids,

access to the receptors,

the stoichiometry of co-regulators, and

other proteins as well as

genetic factors, among which single nucleotide polymorphisms (SNPs) of the GRs are extensively documented.

Stress can bias the receptor signaling pathways,

changing “good” corticosteroid actions into “bad” ones.

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Meijer et al 2006

Mol Cell Endocrinol. 2008 Nov 25;295(1-2):59-69. Epub 2008 May 21.

Links

Modulation of transcription parameters in glucocorticoid receptor-mediated repression.

Sun Y, Tao YG, Kagan BL, He Y, Jr SS.

Steroid Hormones Section, NIDDK/CEB, National Institutes of Health, Bethesda, MD, United States.

Glucocorticoid hormones modulate brain function and as such are crucial for responding and adjusting to physical and psychological stressors. Their effects are mediated via mineralo- and glucocorticoid receptors, which in large measure

act as transcription factors to modulate transcription of target genes, in a receptor-, cell-, and state-specific manner.

The nature and magnitude of these transcriptional effects depend on the presence and activity of downstream proteins, such as steroid receptor coactivators and corepressors (together: coregulators), many of which are expressed in the brain.

We address the role of coregulators for mineralo- and glucocorticoid receptor-mediated modulation of gene transcription. We first address evidence from cell lines for the importance of coregulator stoichiometry for steroid signaling. The in vivo importance of coregulators-when possible specifically for glucocorticoid signaling in the brain-is discussed based on knockout mice, transient knockdown of steroid receptor coactivators, and distribution and regulation of coactivator expression in the brain. We conclude that for a better understanding of modulation of brain function by glucocorticoids, it is necessary to take into account the role of coregulators, and to assess their importance relative to changes in hormone levels and receptor expression. Which of course they don’t mention specifically what these coregulators, etc. are, and of course I don’t have the article – which I wouldn’t understand much anyway

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Sun et al 2008

Mol Cell Endocrinol. 2008 Nov 25;295(1-2):59-69. Epub 2008 May 21.

Links

Modulation of transcription parameters in glucocorticoid receptor-mediated repression.

Sun Y, Tao YG, Kagan BL, He Y, Jr SS.

Steroid Hormones Section, NIDDK/CEB, National Institutes of Health, Bethesda, MD, United States.

Glucocorticoid receptors (GRs) affect both gene induction and gene repression. The disparities of receptor binding to DNA and increased vs. decreased gene expression have suggested significant mechanistic differences between GR-mediated induction and repression.

Numerous transcription factors are known to modulate three parameters of gene induction: the total activity (V(max)) and position of the dose-response curve with glucocorticoids (EC(50)) and the percent partial agonist activity with antiglucocorticoids. We have examined the effects on GR-mediated repression of five modulators (coactivators TIF2 [GRIP1, SRC-2] and SRC-1, corepressor SMRT, and comodulators STAMP and Ubc9), a glucocorticoid steroid (deacylcortivazol [DAC]) of very different structure, and an inhibitor of histone deacetylation (trichostatin A [TSA]). These factors interact with different domains of GR and thus are sensitive topological probes of GR action. These agents altered the V(max), EC(50), and percent partial agonist activity of endogenous and exogenous repressed genes similarly to that previously observed for GR-regulated gene induction. Collectively, these results suggest that

GR-mediated induction and repression share many of the same molecular interactions

and that the causes for different levels of gene transcription arise from more distal downstream steps.

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van der Laan & Meijer 2008

Eur J Pharmacol. 2008 May 13;585(2-3):483-91. Epub 2008 Mar 18.

Links

Pharmacology of glucocorticoids: beyond receptors.

van der Laan S, Meijer OC.

Division of Medical Pharmacology, Leiden/Amsterdam Centre for Drug Research (LACDR), PO Box 9502, 2300 RA Leiden, The Netherlands. s.van.der.laan@lacdr.leidenuniv.nl

Glucocorticoid hormones are important regulators of homeostasis. They are used clinically as highly effective anti-inflammatory compounds and have been prescribed for more than fifty years for a variety of conditions. They mediate their genomic actions by binding to two different intracellular receptors in target cells.

The pharmacology of glucocorticoids largely depends on ligand concentration and receptor expression levels in target tissue.

However, their genomic actions also critically depend on coactivators and corepressors recruitment. We discuss how

various non-receptor factors

affect glucocorticoid potency and efficacy

with respect to their genomic effects.

Differential recruitment of coregulators may account for many ligand- and cell-specific effects of glucocorticoids. This is best illustrated by the recent identification of selective glucocorticoid receptor agonists that induce distinct conformational changes to the receptors resulting in altered protein-protein interactions and consequently different regulation of gene expression. We conclude that these new molecular insights will contribute to the design of safer glucocorticoids that retain full pharmacological properties with reduced side-effects.

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Haller, Mikics & Makara 2008

Front Neuroendocrinol. 2008 May;29(2):273-91. Epub 2007 Oct 24.

Links

The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings.

Haller J, Mikics E, Makara GB.

Department of Behavioral Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1083, Hungary.

.

Mounting evidence suggests that—

beyond the well-known genomic effects—

glucocorticoids affect cell function

via non-genomic mechanisms.

Such mechanisms operate in many major systems and organs including the cardiovascular, immune, endocrine and nervous systems, smooth and skeletal muscles, liver, and fat cells.

………..Non-genomic effects are exerted by direct actions on membrane lipids (affecting membrane fluidity), membrane proteins (e.g. ion channels and neurotransmitter receptors), and cytoplasmic proteins (e.g. MAPKs, phospholipases, protein kinases, etc.).

……… These actions are mediated by the glucocorticoids per se or by the proteins dissociated from the liganded glucocorticoid receptor complex.

The MR and GR also activate non-genomic mechanisms in certain cases. Some effects of glucocorticoids are shared by a variety of steroids, whereas others are more selective. Moreover, “ultra-selective” effects-mediated by certain glucocorticoids only-were also shown. Disparate findings suggest that non-genomic mechanisms also show “demand-specificity”, i.e. require the coincidence of two or more processes. Some of the non-genomic mechanisms activated by glucocorticoids are therapeutically relevant; moreover, the “non-genomic specificity” of certain glucocorticoids raises the possibility of therapeutic applications. Despite the large body of evidence, however, the non-genomic mechanisms of glucocorticoids are still poorly understood. Criteria for differentiating genomic and non-genomic mechanisms are often loosely applied; interactions between various mechanisms are unknown, and non-genomic mechanism-specific pharmacological (potentially therapeutic) agents are lacking. Nevertheless, the

discovery of non-genomic mechanisms

is a major breakthrough in stress research,

and further insights into these mechanisms may open novel approaches for the therapy of various diseases.

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Stahn et al 2007

Mol Cell Endocrinol. 2007 Sep 15;275(1-2):71-8. Epub 2007 Jun 2.

Links

Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists.

Stahn C, Löwenberg M, Hommes DW, Buttgereit F.

Department of Rheumatology and Clinical Immunology, Charité University Hospital, Schumannstrasse 20/21, 10117 Berlin, Germany. stahn@drfz.de

Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases.

See also:

Steroids. 2008 Oct;73(9-10):1025-9. Epub 2007 Dec 14.

Links

Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands.

Löwenberg M, Stahn C, Hommes DW, Buttgereit F.

Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. m.lowenberg@amc.uva.nl

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Davis, Walker & Myers 2003

Ann N Y Acad Sci. 2003 Apr;985:218-32.

Links

Role of the amygdala in fear extinction measured with potentiated startle.

Davis M, Walker DL, Myers KM.

Department of Psychiatry, Emory University, Atlanta, Georgia 30322, USA. mdavis4@emory.edu

Although much is now known about the neural basis of excitatory fear conditioning, much less is known about the neural basis of inhibitory conditioning.

One type of inhibitory conditioning is extinction, a process in which stimuli that elicit fear by virtue of previous associations with aversive stimuli such as shock (excitatory fear conditioning) are now presented in the absence of the aversive stimuli (extinction training). As a result, the ability of the conditioned stimulus to elicit fear gradually diminishes. Extinction is different from forgetting and does not reflect an erasure of the original fear memory.

Instead, extinction is an active form of inhibitory learning that competes with excitatory fear conditioning. Infusions into the amygdala (a brain area essential for excitatory fear conditioning) of either NMDA receptor antagonists or inhibitors of the NMDA-receptor-linked mitogen-activated protein kinase cascade block extinction learning. Conversely, the NMDA receptor agonist D-cycloserine facilitates extinction after either systemic administration or intra-amygdala infusion. Because therapeutic interventions based on extinction procedures are commonly used to treat fear disorders, and because D-cycloserine is a widely available and safe compound, D-cycloserine or similar agents might be usefully combined with traditional extinction-based approaches in the treatment of clinical fear.

Title of article has nothing to do with the abstract!  Role of the amygdala in fear extinction measured with potentiated startle.

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Chevaleyre et al 2007

Neuron. 2007 Jun 7;54(5):801-12.

Links

Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha.

Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Castillo PE.

Dominick P. Purpura [corrected] Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Endocannabinoids (eCBs) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (i.e., CB1) coupled to G(i/o) protein, can mediate short-term and long-term synaptic depression (LTD).

While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1alpha as a key mediator of both CB1 receptor effects on the release machinery and eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Furthermore, our results highlight a conserved mechanism of presynaptic plasticity in the brainReferring to evolution, no doubt, and genetics

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Di et al 2003

J Neurosci. 2003 Jun 15;23(12):4850-7.

Links

Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism.

Di S, Malcher-Lopes R, Halmos KC, Tasker JG.

Division of Neurobiology, Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118-5698, USA.

Glucocorticoid negative feedback in the brain

controls stress, feeding, and neural-immune interactions

by regulating the

hypothalamic-pituitary-adrenal axis,

but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-beta-S application, implicating a postsynaptic G-protein-coupled receptor and the release of a retrograde messenger. The glucocorticoid effect was not blocked by the nitric oxide synthesis antagonist N(G)-nitro-L-arginine methyl ester hydrochloride or by hemoglobin but was blocked completely by the CB1 cannabinoid receptor antagonists AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide] and mimicked and occluded by the cannabinoid receptor agonist WIN55,212-2 [(beta)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate], indicating that it was mediated by retrograde endocannabinoid release. Several peptidergic subtypes of parvocellular neuron, identified by single-cell reverse transcription-PCR analysis,

were subject to rapid inhibitory glucocorticoid regulation,

including

corticotropin-releasing hormone-,

thyrotropin-releasing hormone-,

vasopressin-, and

oxytocin-expressing neurons.

Therefore, our findings reveal a

mechanism of rapid glucocorticoid feedback inhibition of hypothalamic hormone secretion via endocannabinoid release in the PVN

and provide a link between the actions of

glucocorticoids and cannabinoids

in the hypothalamus

that regulate stress and energy homeostasis.

See also:

Endocrinology. 2005 Oct;146(10):4292-301. Epub 2005 Jun 30.

Links

Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons.

Di S, Malcher-Lopes R, Marcheselli VL, Bazan NG, Tasker JG.

Division of Neurobiology, Tulane University, New Orleans, Louisiana 70118-5698, USA.

Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis feed back onto the brain to rapidly suppress neuroendocrine activation, including oxytocin and vasopressin secretion.

Here we show using whole-cell patch clamp recordings that glucocorticoids elicit a rapid, opposing action on synaptic glutamate and gamma-aminobutyric acid (GABA) release onto magnocellular neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus, suppressing glutamate release and facilitating GABA release by activating a putative membrane receptor. ….. suggesting that it was mediated by a retrograde messenger acting at an AM251-sensitive, noncannabinoid/nonvanilloid receptor at presynaptic GABA terminals.

The combined, opposing actions of glucocorticoids mediate a rapid inhibition of the magnocellular neuroendocrine cells, which in turn should mediate rapid feedback inhibition of the secretion of oxytocin and vasopressin by glucocorticoids during stress activation of the hypothalamic-pituitary-adrenal axis.

PMID: 15994343 [PubMed – indexed for MEDLINE]

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Di et al 2005

Endocrinology. 2005 Oct;146(10):4292-301. Epub 2005 Jun 30.

Links

Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons.

Di S, Malcher-Lopes R, Marcheselli VL, Bazan NG, Tasker JG.

Division of Neurobiology, Tulane University, New Orleans, Louisiana 70118-5698, USA.

Glucocorticoids secreted in response to stress activation of the hypothalamic-pituitary-adrenal axis

feed back

onto the brain to

rapidly suppress neuroendocrine activation,

including oxytocin and vasopressin secretion.

Here we show using whole-cell patch clamp recordings that glucocorticoids elicit a rapid, opposing action on synaptic glutamate and gamma-aminobutyric acid (GABA) release onto magnocellular neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus, suppressing glutamate release and facilitating GABA release by activating a putative membrane receptor.

The glucocorticoid effect on both glutamate and GABA release was blocked by inhibiting postsynaptic G protein activity, suggesting a dependence on postsynaptic G protein signaling and the involvement of a retrograde messenger. Biochemical analysis of hypothalamic slices treated with dexamethasone revealed a glucocorticoid-induced rapid increase in the levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The glucocorticoid suppression of glutamate release was blocked by the type I cannabinoid receptor cannabinoid receptor antagonist, AM251, and was mimicked and occluded by AEA and 2-AG, suggesting it was mediated by retrograde endocannabinoid release. The glucocorticoid facilitation of GABA release was also blocked by AM251 but was not mimicked by AEA, 2-AG, or a synthetic cannabinoid, WIN 55,212-2, nor was it blocked by vanilloid or ionotropic glutamate receptor antagonists, suggesting that it was mediated by a retrograde messenger acting at an AM251-sensitive, noncannabinoid/nonvanilloid receptor at presynaptic GABA terminals.

The combined, opposing actions of glucocorticoids

mediate a rapid inhibition of the

magnocellular neuroendocrine cells,

which in turn should mediate rapid feedback inhibition

of the secretion of oxytocin and vasopressin

by glucocorticoids

during stress activation of the

hypothalamic-pituitary-adrenal axis.

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Berkowitz et al 2007

Rev Neurosci. 2007;18(3-4):191-207.

Links

The human dimension: how the prefrontal cortex modulates the subcortical fear response.

Berkowitz RL, Coplan JD, Reddy DP, Gorman JM.

Department of Psychiatry, College of Physicians and Surgeons of Columbia University, Brooklyn, NY, USA.

Numerous studies suggest that the amygdala is critical for the acquisition and expression of fear. Conditioned fear in animals has been considered a good model for human anxiety disorders, but animal models of anxiety have several limitations. Conditioned fear in animals can be directed to a specific stressor and is easily extinguished. Furthermore, animals do not seem to be able to develop the capacity to worry excessively about the future. See attachment disorder section where worry is seen as a way to control against feelings, search preoccupied While animal models are useful and can demonstrate psychiatric illnesses, they do not completely mimic the complex cognitive processes that occur in anxious humans. Thus, we hypothesize that human anxiety disorders are caused at least in part by differential activity in the prefrontal cortex, the brain region that most separates us from our nearest genetic neighbors. The prefrontal cortex is in interaction with the amygdala  The human prefrontal cortex has not only been shown to be more developed than that of other mammals, but it also has unique morphology and gene expression.

Neuroimaging studies repeatedly show abnormalities in the prefrontal cortex in anxious individuals.

Thus, we suggest that the very same cortical complexity that allows us to produce a vibrant culture is also the seat of anxiety disorders. Interestingly, preclinical studies have shown that the

prefrontal cortex inhibits the amygdala. There

appears to be a distinction between two classes of anxiety disorders.

Those disorders involving intense fear and panic–panic disorder, post-traumatic stress disorder [PTSD], and phobias–seem to be characterized by an underactivity of the prefrontal cortex, thus disinhibiting the amygdala.

Disorders such as generalized anxiety disorder and obsessive-compulsive disorder, which involve worry and rumination, on the other hand, seem to be characterized by an overactivity of the prefrontal cortex. Studies of prefrontal cortical function in psychiatric illness should be a fruitful method for identifying effective treatment approaches.

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Neuropharmacology. 2004 Jan;46(1):115-25.

Links

Cannabinoids modulate neuronal firing in the rat basolateral amygdala: evidence for CB1- and non-CB1-mediated actions.

Pistis M, Perra S, Pillolla G, Melis M, Gessa GL, Muntoni AL.

B.B. Brodie Department of Neuroscience, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato (CA), Italy. mpistis@unica.it

Recent evidence indicates that the basolateral amygdala (BLA) may be involved in behavioural effects induced by cannabinoids.

High levels of CB1 cannabinoid receptors have been shown in this region, where they modulate excitatory and inhibitory synaptic transmission. However, the neurophysiological effects of these opposing synaptic actions have not been investigated in vivo. To this purpose….

Taken together, our findings indicate that the overall excitability of efferent neurons in the BLA is strongly reduced by WIN in a non-CB1-dependent manner. In this effect, the contribution of a novel cannabinoid-vanilloid-sensitive putative non-CB1 receptors, the existence of which was postulated in recent reports, might play a role.

PMID: 14654103 [PubMed – indexed for MEDLINE

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Eur J Neurosci. 2006 May;23(9):2385-94.

Links

Cannabinoids modulate spontaneous neuronal activity and evoked inhibition of locus coeruleus noradrenergic neurons.

Muntoni AL, Pillolla G, Melis M, Perra S, Gessa GL, Pistis M.

Institute of Neuroscience C.N.R., c/o University of Cagliari, Cittadella Universitaria, 09042 Monserrato (CA), Italy. almuntoni@c.cnr.it

The noradrenergic pathway arising from the locus coeruleus (LC) is involved in the regulation of attention, arousal, cognitive processes and sleep. These physiological activities are affected by Cannabis exposure – both in humans and laboratory animals. In addition, exogenous cannabinoids, as well as pharmacological and genetic manipulation of the endocannabinoid system, are known to influence emotional states (e.g. anxiety) for which a contributory role of the LC-noradrenergic system has long been postulated.

However, whether cannabinoid administration would affect the LC neuronal activity in vivo is still unknown. …. Altogether, these findings suggest the involvement of noradrenergic pathways in some consequences of Cannabis intake (e.g. cognitive and attention deficits, anxiety reactions), as well as a role for cannabinoid receptors in basic brain activities sustaining arousal and emotional states.

PMID: 16706846 [PubMed – indexed for MEDLINE

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Zarrindast et al 2008b

Life Sci. 2008 Jun 6;82(23-24):1175-81. Epub 2008 Apr 6.

Links

Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior.

Zarrindast MR, Babapoor-Farrokhran S, Babapoor-Farrokhran S, Rezayof A.

Department of Pharmacology, School of Medicine, Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran. zarinmr@ams.ac.ir

In the present study, the influence of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala on anxiety-related behavior was investigated in rats. …..

opioidergic system in the ventral hippocampus and the nucleus accumbens are involved in anxiety-related behaviors

and the ventral hippocampus may be the main site of action of the anxiolytic properties of morphine.

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Zarrindast et al 2008

Behav Pharmacol. 2008 Oct;19(7):716-23.

Links

Cannabinoid CB1 receptors of the rat central amygdala mediate anxiety-like behavior: interaction with the opioid system.

Zarrindast MR, Sarahroodi S, Arzi A, Khodayar MJ, Taheri-Shalmani S, Rezayof A.

Department of Pharmacology, School of Medicine and Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran. zarinmr@ams.ac.ir

Cannabinoids, which are the active compounds of marijuana, produce some pharmacological effects similar to the opioids.

In addition, there are functional interactions between the cannabinoid and opioid systems.

In this study, we investigated the effects of intraperitoneal (i.p.) injection of opioid drugs on responses induced by intracentral amygdala (intra-CeA) …. In conclusion, the results may indicate an

anxiolytic-like effect for cannabinoid CB1 receptors

of the CeA and the existence of an interaction

between the cannabinoid and the opioid systems

in the modulation of anxiety.

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See also:

Neuropsychopharmacology. 2005 Mar;30(3):516-24.

Links

Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear.

Chhatwal JP, Davis M, Maguschak KA, Ressler KJ.

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Center for Behavioral Neuroscience, Yerkes Research Center, Atlanta, GA 30329, USA.

Neuropsychopharmacology. 2005 Mar;30(3):516-24.

Links

Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear.

Chhatwal JP, Davis M, Maguschak KA, Ressler KJ.

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Center for Behavioral Neuroscience, Yerkes Research Center, Atlanta, GA 30329, USA.

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CONDUCT DISORDERS

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Jones et al 2008

Am J Psychiatry. 2009 Jan;166(1):95-102. Epub 2008 Oct 15.

Links

Amygdala hypoactivity to fearful faces in boys with conduct problems and callous-unemotional traits.

Jones AP, Laurens KR, Herba CM, Barker GJ, Viding E.

Medical Research Council’s Social, Genetic, and Developmental Psychiatry Centre, Department of Forensic Mental Health, Institute of Psychiatry, King’s College London, UK.

Although early-onset conduct problems predict both psychiatric and health problems in adult life, little research has been done to index neural correlates of conduct problems. Emerging research suggests that a subgroup of children with conduct problems and elevated levels of callous-unemotional traits may be genetically vulnerable to manifesting disturbances in neural reactivity to emotional stimuli indexing distress. Using functional MRI, the authors evaluated differences in neural response to emotional stimuli between boys with conduct problems and elevated levels of callous-unemotional traits [Linda note:  sounds linked to dismissive-avoidant insecure attachments to me] and comparison boys. Method Seventeen boys with conduct problems and elevated levels of callous-unemotional traits and 13 comparison boys of equivalent age (mean=11 years) and IQ (mean=100) viewed blocked presentations of fearful and neutral faces. For each face, participants distinguished the sex of the face via manual response. Results Relative to the comparison group,

boys with conduct problems and elevated levels of callous-unemotional traits manifested lesser right amygdala activity to fearful faces.

Conclusions This finding is in line with data from studies of adults with antisocial behavior and callous-unemotional traits (i.e., psychopaths), as well as from a recent study of adolescents with callous-unemotional traits, and suggests that the

neural substrates of emotional impairment associated with callous-unemotional antisocial behavior are already present in childhood. Duh, they are probably influenced in their development from childhood experiences – also linked to disorganized-disoriented insecure attachment and children who then “act out”

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Salvadore et al 2008

Biol Psychiatry. 2009 Feb 15;65(4):289-95. Epub 2008 Sep 25.

Links

Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine.

Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA Jr, Manji HK.

Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

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Moody et al 2007

Emotion. 2007 May;7(2):447-57.

Links

More than mere mimicry? The influence of emotion on rapid facial reactions to faces.

Moody EJ, McIntosh DN, Mann LJ, Weisser KR.

Department of Psychology, University of Denver, Denver, CO 80208, USA. eric.moody@du.edu

Within a second of seeing an emotional facial expression, people typically match that expression.

These rapid facial reactions (RFRs), often termed mimicry, are implicated in emotional contagion, social perception, and embodied affect, What about empathy?

yet ambiguity remains regarding the mechanism(s) involved. Two studies evaluated whether RFRs to faces are solely nonaffective motor responses or whether emotional processes are involved. Brow (corrugator, related to anger) and forehead (frontalis, related to fear) activity were recorded using facial electromyography (EMG) while undergraduates in two conditions (fear induction vs. neutral) viewed fear, anger, and neutral facial expressions. As predicted

fear induction

increased fear expressions to angry faces

within 1000 ms of exposure,

demonstrating an emotional component of RFRs.

This did not merely reflect increased fear from the induction, because responses to neutral faces were unaffected. Considering RFRs to be merely nonaffective automatic reactions is inaccurate.

RFRs are not purely motor mimicry;

emotion influences early facial responses to faces.

The relevance of these data to emotional contagion, autism, and the mirror system-based perspectives on imitation is discussed.

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Linda note:  They can identify circuits for fear, circuits for physical pain, but they cannot seem to identify circuitry for emotional pain, grief and sadness.  That seems mysterious to me.  Obviously sadness exits, yet can they track it in any way other than by calling it depression?  To call it depression seems to un-legitimize it, take away its right to exist, the fact that it exists.

I wonder if the only place I can look for “sadness circuits” is in the study of empathy.

If I search PubMed for cannabinoid and either sadness or grief, nothing comes up.  If I search for cannabinoid and depression, 440 entries appear – most concerned with drugs they can use to “fix” us.

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McIntosh et al 2006

Dev Sci. 2006 May;9(3):295-302.

Links

When the social mirror breaks: deficits in automatic, but not voluntary, mimicry of emotional facial expressions in autism.

McIntosh DN, Reichmann-Decker A, Winkielman P, Wilbarger JL.

Department of Psychology, University of Denver, CO 80208, USA. dmcintos@du.edu

Humans, infants and adults alike, automatically mimic a variety of behaviors.

Such mimicry facilitates social functioning, including establishment of interpersonal rapport and understanding of other minds.

This fundamental social process may thus be impaired in disorders such as autism characterized by socio-emotional and communicative deficits.

We examined automatic and voluntary mimicry of emotional facial expression among adolescents and adults with autistic spectrum disorders (ASD) and a typical sample matched on age, gender and verbal intelligence. Participants viewed pictures of happy and angry expressions while the activity over their cheek and brow muscle region was monitored with electromyography (EMG). ASD participants did not automatically mimic facial expressions whereas the typically developing participants did. However, both groups showed evidence of successful voluntary mimicry. The data suggest that autism is associated with an impairment of a basic automatic social-emotion process. Results have implications for understanding typical and atypical social cognition.

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McClure et al 2007

Arch Gen Psychiatry. 2007 Jan;64(1):97-106.

Links

Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder.

McClure EB, Monk CS, Nelson EE, Parrish JM, Adler A, Blair RJ, Fromm S, Charney DS, Leibenluft E, Ernst M, Pine DS.

Emotional Development and Affective Neuroscience Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH/DHHS, Bethesda, MD 20892, USA. emcclure@gsu.edu

CONTEXT: Considerable work implicates abnormal neural activation and disrupted attention to facial-threat cues in adult anxiety disorders. However, in pediatric anxiety, no research has examined attention modulation of neural response to threat cues. OBJECTIVE: To determine whether attention modulates amygdala and cortical responses to facial-threat cues differentially in adolescents with generalized anxiety disorder and in healthy adolescents. DESIGN: Case-control study. SETTING: Government clinical research institute. PARTICIPANTS: Fifteen adolescents with generalized anxiety disorder and 20 controls. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging. During imaging, participants completed a face-emotion rating task that systematically manipulated attention. RESULTS: While attending to their own subjective fear, patients, but not controls, showed greater activation to fearful faces than to happy faces in a distributed network including the amygdala, ventral prefrontal cortex, and anterior cingulate cortex (P<.05, small-volume corrected, for all). Right amygdala findings appeared particularly strong. Functional connectivity analyses demonstrated positive correlations among the amygdala, ventral prefrontal cortex, and anterior cingulate cortex. CONCLUSIONS: This is the first evidence in juveniles that generalized anxiety disorder-associated patterns of pathologic fear circuit activation are particularly evident during certain attention states. Specifically, fear circuit hyperactivation occurred in an attention state involving focus on subjectively experienced fear. These findings underscore the importance of attention and its interaction with emotion in shaping the function of the adolescent human fear circuit. That starts way before adolescence!

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[Anxiety is also connected to genetic and epigenetic levels of vasopressin]

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Telzer et al 2008

Biol Psychol. 2008 Oct;79(2):216-22. Epub 2008 May 29.

Links

Relationship between trait anxiety, prefrontal cortex, and attention bias to angry faces in children and adolescents.

Telzer EH, Mogg K, Bradley BP, Mai X, Ernst M, Pine DS, Monk CS.

Department of Psychology, University of California, Los Angeles, CA, USA. ehtelzer@ucla.edu

Using event-related functional magnetic resonance imaging (fMRI) with a visual-probe task that assesses attention to threat, we investigated the cognitive and neurophysiological correlates of trait anxiety in youth. During fMRI acquisition, 16 healthy children and adolescents viewed angry-neutral face pairs and responded to a probe that was on the same (angry-congruent) or opposite (angry-incongruent) side as the angry face. Attention bias scores were calculated by subtracting participants’ mean reaction time for angry-congruent trials from angry-incongruent trials.

Trait anxiety

was positively associated with attention bias

towards angry faces.

Neurophysiologically,

trait anxiety was positively associated with right dorsolateral prefrontal cortex (PFC) activation on a contrast of trials that reflect the attention bias for angry faces (i.e. angry-incongruent versus angry-congruent trials).

Trait anxiety was also positively associated with

right ventrolateral PFC activation on trials with face stimuli

(versus baseline),

irrespective of their emotional content.

Linda note:  That fits with the doves versus hawks – attention to detail – and my suspicion that we are more attuned for everything small, and certainly more sensitive and have heightened discriminatory abilities (even “psychic” ones) within and in reaction to the social sphere.

We run the risk, therefore, of being especially altered through terrible threat as our systems are forming, I believe

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A pubmed database search for “fear cannabinoid” brings up 68 articles.  Entering the words “anxiety cannabinoid” brings up 334 articles.

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Beall et al 2008

J Exp Child Psychol. 2008 Nov;101(3):206-23. Epub 2008 Jun 17.

Links

Rapid facial reactions to emotional facial expressions in typically developing children and children with autism spectrum disorder.

Beall PM, Moody EJ, McIntosh DN, Hepburn SL, Reed CL.

Department of Psychology, University of Denver, Denver, CO 80208, USA. pbeall@psy.du.edu

Typical adults mimic facial expressions within 1000 ms,

but adults with autism spectrum disorder (ASD) do not. These rapid facial reactions (RFRs) are associated with the development of social-emotional abilities.

Such interpersonal matching may be caused by motor mirroring or emotional responses.

Using facial electromyography (EMG), this study evaluated mechanisms underlying RFRs during childhood and examined possible impairment in children with ASD. Experiment 1 found RFRs to happy and angry faces (not fear faces) in 15 typically developing children from 7 to 12 years of age. RFRs of fear (not anger) in response to angry faces indicated an emotional mechanism. So they responded to angry faces with fear of their own

in 11 children (8-13 years of age) with ASD, Experiment 2 found undifferentiated RFRs to fear expressions and no consistent RFRs to happy or angry faces. However, as children with ASD aged, matching RFRs to happy faces increased significantly, suggesting the development of processes underlying matching RFRs during this period in ASDThat sounds like social interaction learning over time.

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Williams et al 2008b

Eur J Neurosci. 2008 Jun;27(11):3074-82. Epub 2008 Jun 6.

Links

Stimulus-driven and strategic neural responses to fearful and happy facial expressions in humans.

Williams MA, McGlone F, Abbott DF, Mattingley JB.

Macquarie Centre for Cognitive Science, Macquarie University, Sydney, NSW 2109, Australia. mark.williams@maccs.mq.edu.au

The human amygdala

responds selectively to consciously and unconsciously perceived facial expressions,

particularly those that convey potential threat

such as fear and anger.

In many social situations, multiple faces with varying expressions confront observers yet little is known about the neural mechanisms involved in encoding several faces simultaneously. Here we used event-related fMRI to measure neural activity in pre-defined regions of interest as participants searched multi-face arrays for a designated target expression (fearful or happy). We conducted separate analyses to examine activations associated with each of the four multi-face arrays independent of target expression (stimulus-driven effects), and activations arising from the search for each of the target expressions, independent of the display type (strategic effects). Comparisons across display types, reflecting stimulus-driven influences on visual search, revealed activity in the

amygdala and

superior temporal sulcus (STS).

By contrast, strategic demands of the task did not modulate activity in either the amygdala or STS. These results imply an interactive threat-detection system involving several neural regions.

Crucially, activity in the amygdala increased significantly when participants correctly detected the target expression, compared with trials in which the identical target was missed, suggesting that the

amygdala has a limited capacity

for extracting affective facial expressions.

See also:

Neuroimage. 2005 Jan 15;24(2):417-25.

Links

Differential amygdala responses to happy and fearful facial expressions depend on selective attention.

Williams MA, McGlone F, Abbott DF, Mattingley JB.

Cognitive Neuroscience Laboratory, School of Behavioural Science, University of Melbourne, Victoria 3010, Australia.

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Wieser et al 2008

J Neural Transm. 2009 Jun;116(6):717-23. Epub 2008 Aug 9.

Links

Fear of negative evaluation and the hypervigilance-avoidance hypothesis: an eye-tracking study.

Wieser MJ, Pauli P, Weyers P, Alpers GW, Mühlberger A.

Department of Biological Psychology, Clinical Psychology and Psychotherapy, University of Würzburg, Marcusstr. 9-11, 97070 Würzburg, Germany.

The hypervigilance-avoidance hypothesis assumes that anxious individuals initially attend to and subsequently avoid threatening stimuli. This is happening very fast, within the first second of being presented with the stimulus.  My first thought is that this is related to how dissociation works – at this speed – that dissociation as a protective mechanism might be the response someone could have to the perceived threat

In this study pairs of emotional (angry or happy) and neutral facial expressions were presented to students of high or low fear of negative evaluation (FNE) while their eye movements were recorded. High fear of negative evaluation participants initially looked more often at emotional compared to neutral faces, indicating an attentional bias for emotional facial expressions. This effect was further modulated by the sex of the face, as

high fear of negative evaluation clearly showed a preference for happy female faces. Analysis of the time course of attention revealed that high FNE looked at the emotional faces longer during the first second of stimulus exposure, whereas they avoided these faces in the consecutive time interval from 1 to 1.5 s. These results partially support the hypervigilance-avoidance hypothesis and additionally indicate the relevance of happy faces for high FNE. Further research should clarify the meaning of happy facial expressions as well as the influence of the sex of the observed face in social anxiety.

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Mogg, Garner & Bradley 2007

Biol Psychol. 2007 Oct;76(3):163-9. Epub 2007 Jul 26.

Links

Anxiety and orienting of gaze to angry and fearful faces.

Mogg K, Garner M, Bradley BP.

School of Psychology, University of Southampton, Highfield, Southampton, UK. kmogg@soton.ac.uk

Neuroscience research indicates that individual differences in anxiety may be attributable to a neural system for threat-processing, involving the amygdala,

which modulates attentional vigilance,

and which is more sensitive to fearful than angry faces.

Complementary cognitive studies indicate that high-anxious individuals show enhanced visuospatial orienting towards angry faces, but it is unclear whether fearful faces elicit a similar attentional bias. This study compared biases in initial orienting of gaze to fearful and angry faces, which varied in emotional intensity, in high- and low-anxious individuals. Gaze was monitored whilst participants viewed a series of face-pairs. Results showed that fearful and angry faces elicited similar attentional biases.

High-anxious individuals were more likely to direct gaze

at intense negative facial expressions,

than low-anxious individuals,

whereas the groups did not differ in orienting to mild negative expressions. Implications of the findings for research into the neural and cognitive bases of emotion processing are discussed.

See also:

J Abnorm Psychol. 2006 Nov;115(4):760-70.

Links

Orienting and maintenance of gaze to facial expressions in social anxiety.

Garner M, Mogg K, Bradley BP.

Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom. m.j.garner@soton.ac.uk

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A pubmed database search for “faces cannabinoid” brings up 71 articles such as:

Eur J Neurosci. 2006 Apr;23(7):1944-8.

Links

Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces.

Chakrabarti B, Kent L, Suckling J, Bullmore E, Baron-Cohen S.

Autism Research Centre, Douglas House, 18 B, Trumpington Road, Cambridge CB2 2AH, UK. bc249@cam.ac.uk

Happy facial expressions are innate social rewards and evoke a response in the striatum, a region known for its role in reward processing in rats, primates and humans. The cannabinoid receptor 1 (CNR1) is the best-characterized molecule of the endocannabinoid system, involved in processing rewards. We hypothesized that genetic variation in human CNR1 gene would predict differences in the striatal response to happy faces. In a 3T functional magnetic resonance imaging (fMRI) scanning study on 19 Caucasian volunteers, we report that four single nucleotide polymorphisms (SNPs) in the CNR1 locus modulate differential striatal response to happy but not to disgust faces. This suggests a role for the variations of the CNR1 gene in underlying social reward responsivity. Future studies should aim to replicate this finding with a balanced design in a larger sample, but these preliminary results suggest neural responsivity to emotional and socially rewarding stimuli varies as a function of CNR1 genotype. This has implications for medical conditions involving hypo-responsivity to emotional and social stimuli, such as autism.

PMID: 16623851 [PubMed – indexed for MEDLINE

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[The role of endocannabinoid system in physiological and pathological processes in the eye]

Nadolska K, Goś R.

Klin Oczna. 2008;110(10-12):392-6. Review. Polish.

PMID: 19195174 [PubMed – indexed for MEDLINE]

Related Articles

Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing.

Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, Seal M, Surguladze SA, O’Carrol C, Atakan Z, Zuardi AW, McGuire PK.

Arch Gen Psychiatry. 2009 Jan;66(1):95-105.

PMID: 19124693 [PubMed – indexed for MEDLINE]

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Potential roles of (endo)cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection.

Nucci C, Bari M, Spanò A, Corasaniti M, Bagetta G, Maccarrone M, Morrone LA.

Prog Brain Res. 2008;173:451-64. Review.

PMID: 18929127 [PubMed – indexed for MEDLINE]

Related Articles

Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression.

Domschke K, Dannlowski U, Ohrmann P, Lawford B, Bauer J, Kugel H, Heindel W, Young R, Morris P, Arolt V, Deckert J, Suslow T, Baune BT.

Eur Neuropsychopharmacol. 2008 Oct;18(10):751-9. Epub 2008 Jun 24.

Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users.

Nestor L, Roberts G, Garavan H, Hester R.

Neuroimage. 2008 Apr 15;40(3):1328-39. Epub 2008 Jan 12.

PMID: 18296071 [PubMed – indexed for MEDLINE]

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Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration.

Matias I, Wang JW, Moriello AS, Nieves A, Woodward DF, Di Marzo V.

Prostaglandins Leukot Essent Fatty Acids. 2006 Dec;75(6):413-8. Epub 2006 Oct 2.

PMID: 17011761 [PubMed – indexed for MEDLINE]

Related Articles

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Yoon & Zinbarg 2007

Behav Res Ther. 2007 Apr;45(4):839-47. Epub 2006 Jun 23.

Links

Threat is in the eye of the beholder: social anxiety and the interpretation of ambiguous facial expressions.

Yoon KL, Zinbarg RE.

Department of Psychology, Northwestern University, 2029 Sheridan Road, Evanston, IL 60208, USA. lirayoon@northwestern.edu

The current study investigated the tendency of individuals with high levels of social anxiety to interpret ambiguous facial expressions in a threatening manner. Results obtained from self-report measures were consistent with previous studies in which highly socially anxious individuals endorsed threatening interpretations for ambiguous social information.

More importantly, highly socially anxious participants showed relative facilitation of processing of threatening faces following neutral faces when a priming technique was used to eliminate artifact due to response selection bias. These findings support the hypothesized social anxiety-linked interpretive bias.

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J Neurosci. 2008 Mar 5;28(10):2313-9.

Links

Cannabinoid modulation of amygdala reactivity to social signals of threat in humans.

Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, de Wit H.

Department of Psychiatry, University of Michigan and Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan 48109, USA. luan@umich.edu

The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of delta(9)-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB(1) receptors localized within the basolateral amygdala, a critical brain region for threat perception. However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

PMID: 18322078 [PubMed – indexed for MEDLINE]

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Bar-Haim, Lamy & Glickman 2005

Brain Cogn. 2005 Oct;59(1):11-22.

Links

Attentional bias in anxiety: a behavioral and ERP study.

Bar-Haim Y, Lamy D, Glickman S.

Department of Psychology, Tel Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel. yair1@post.tau.ac.il

Accumulating evidence suggests the existence of a processing bias in favor of threat-related stimulation in anxious individuals. Using behavioral and ERP measures, the present study investigated the deployment of attention to face stimuli with different emotion expressions in high-anxious and low-anxious participants. An attention-shifting paradigm was used in which faces with neutral, angry, fearful, sad, or happy expressions were presented singly at fixation. Participants had to fixate on the face cue and then discriminate a target shape that appeared randomly above, below, to the left, or right of the fixated face. The behavioral data show that high-anxious participants were slower to respond to targets regardless of the emotion expressed by the face cue. In contrast, the ERP data indicate that threat-related faces elicited faster latencies and greater amplitudes of early ERP components in high-anxious than in low-anxious individuals. The between-group pattern in ERP waveforms suggests that the slower reaction times in high-anxious participants might reflect increased attentional dwelling on the face cues, rather than a general slowing of response enacting. Connects to the vasopressin and anxiety info

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Garner, Mogg & Bradley 2006

Behav Res Ther. 2006 Feb;44(2):201-17.

Links

Fear-relevant selective associations and social anxiety: absence of a positive bias.

Garner M, Mogg K, Bradley BP.

Centre for the Study of Emotion and Motivation, School of Psychology, University of Southampton, Southampton, UK. m.j.garner@soton.ac.uk

An illusory correlation paradigm was used to compare high and low socially anxious individuals’ initial, on-line and a posteriori covariation estimates between emotional faces and aversive, pleasant and neutral outcomes. Overall, participants demonstrated an initial expectancy bias for aversive outcomes following angry faces, and pleasant outcomes following happy faces. On-line expectancy biases indicated that

initial biases were extinguished during the task,

with the exception of low socially anxious individuals who continued to over-associate positive social cues with pleasant outcomes.

In addition to lacking this protective positive on-line bias, the high social anxiety group reported retrospectively more negative social cues than the low socially anxious group.

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Dannlowski et al 2008

Int J Neuropsychopharmacol. 2009 Feb;12(1):11-22. Epub 2008 Jun

Links

Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity.

Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, Hohoff C, Schöning S, Kersting A, Baune BT, Mortensen LS, Arolt V, Zwitserlood P, Deckert J, Heindel W, Suslow T.

Department of Psychiatry, University of Münster, Germany.

The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation.

In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls.

All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism

in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR)

which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects.

In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex.

Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H).

Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease.

We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.

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Kersting et al 2007

Neuropsychobiology. 2007;56(4):191-6. Epub 2008 Mar 13.

Links

Association of MAO-A variant with complicated grief in major depression.

Kersting A, Kroker K, Horstmann J, Baune BT, Hohoff C, Mortensen LS, Neumann LC, Arolt V, Domschke K.

Department of Psychiatry, University of Munster, Münster, Germany.

BACKGROUND/AIMS: It has been suggested that monoamine oxidase A (MAO-A) activity is involved in the pathogenesis of major depression.

Bereavement-related complicated grief

significantly increases the risk of major depression

and has been shown to be influenced by serotonergic tonus,

possibly conferred by MAO-A activity.

Complicated grief–whose inclusion in DSM-V as a separate mental disorder is under discussion–has been shown to be a distinct syndrome with symptoms not seen in depression.

Therefore, in the present study, genetic variation in the MAO-A gene was investigated for its influence on complicated grief in major depression. METHODS: Sixty-six unrelated Caucasian patients (41 female, 25 male) with major depression and a history of bereavement were evaluated for complicated grief using the Inventory of Complicated Grief (ICG), the posttraumatic stress reaction after the loss by means of the Impact of Event Scale (IES-R) and further psychopathological measures. Patients were additionally genotyped for the functional variable number tandem repeat (VNTR) in the promoter region of the MAO-A gene.

RESULTS: The more active longer allele of the MAO-A VNTR was significantly associated with complicated grief in the female subgroup of patients … whereas there was no such effect in male patients.

Higher posttraumatic stress reaction was only nominally associated with the more active longer allele of the MAO-A VNTR in the female subgroup of patients (genotypes: chi(2) = 5.939, p = 0.015, OR = 5.333, 95% CI 1.366-20.557, Bonferroni-corrected p = 0.087). No significant associations of MAO-A VNTR with the severity of depressive symptoms (Beck Depression Inventory), anxiety symptoms (Spielberger State-Trait Anxiety Inventory), general mental health (Brief Symptom Inventory), or perceived social support (F-SozU) were found (all p > 0.10). CONCLUSION: The present pilot study for the first time suggests a gender-specific contribution of the more active

MAO-A VNTR

variant to an increased vulnerability for complicated grief as a potential intermediate phenotype of major depression.

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Szanto et al 2006

J Clin Psychiatry. 2006 Feb;67(2):233-9.

Links

Indirect self-destructive behavior and overt suicidality in patients with complicated grief.

Szanto K, Shear MK, Houck PR, Reynolds CF 3rd, Frank E, Caroff K, Silowash R.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. szantok@upmc.edu

BACKGROUND: Complicated grief is associated with increased suicidal ideation in samples of bereaved individuals; however, suicidal behavior has not been assessed in these patients. Additionally, there are no reports of suicidality among help-seeking individuals with complicated grief. Therefore, we examined suicidal behavior and its correlates in 149 patients who signed informed consent statements to participate in a National Institute of Mental Health-funded treatment study of complicated grief. METHOD: All patients met criteria for complicated grief (Inventory of Complicated Grief score>or=25). Suicidality was assessed using a structured clinical interview administered prior to beginning treatment. Participants also completed self-report questionnaires and interview assessment measures rating the presence or absence of DSM-IV Axis I diagnosis and symptom severity. Data were gathered between April 2001 and April 2004.

RESULTS: Thoughts of wanting to die following the death of a loved one were reported by 65% of participants.

More than half of this group (38% of the study sample) engaged in self-destructive behavior,

….including 9% who made a suicide attempt

…..and 29% who engaged in indirect suicidal behavior.

DISCUSSION: Consistent with reports of non-help-seeking bereaved people, a high rate of individuals seeking treatment for complicated grief endorsed a wish to die. Notably, 13% of this group made at least 1 suicide attempt, and 44% engaged in indirect self-destructive behavior. Given its frequency, this behavior should be included in assessment of bereaved people.

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See also on grief:

J Affect Disord. 2009 Mar 4. [Epub ahead of print]

Links

Complicated grief in patients with unipolar depression.

Kersting A, Kroker K, Horstmann J, Ohrmann P, Baune BT, Arolt V, Suslow T.

Department of Psychiatry, University of Muenster, Germany.

BACKGROUND: The loss of a close family member (e.g. child or spouse) has been shown to be one of the most stressful life-events increasing the risk of affective disorders. In the present study, we investigated for the first time the frequency of complicated grief in psychiatric inpatients with unipolar depression. Further, the study was aimed to identify characteristics predicting a complicated grief reaction in depressed patients. METHODS: In a sample of 73 DSM-IV diagnosed unipolar affective disordered inpatients grief, depression, anxiety and psychological stress reaction were assessed. RESULTS: A high prevalence of loss and impairing complicated grief was found in this sample of unipolar depressed patients. Depressed patients with complicated grief were more severely depressed than depressed patients without complicated grief reactions. Higher traumatic stress and close family membership of the lost person were associated with higher severity of grief. CONCLUSIONS: Comorbid complicated grief appears to contribute to greater severity and poorer functioning in unipolar depressed patients and should be specifically addressed in psychotherapeutic treatment.

See also:

J Neurochem. 2008 Apr;105(2):565-72. Epub 2007 Nov 28.

Links

BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice.

Aso E, Ozaita A, Valdizán EM, Ledent C, Pazos A, Maldonado R, Valverde O.

Grup de Recerca de Neurobiologia del Comportament (GRNC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
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Vaynman, Ying & Gomez-Pinilla 2003

Neuroscience. 2003;122(3):647-57.

Links

Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity.

Vaynman S, Ying Z, Gomez-Pinilla F.

Department of Physiological Science, UCLA, 621 Charles E. Young Drive, Los Angeles, CA 90095, USA.

.

This study was designed to

identify molecular mechanisms

by which exercise affects synaptic-plasticity

in the hippocampus,

a brain area whose function, learning and memory,

depends on this capability.

We have focused on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the effects of exercise on synaptic-plasticity. In fact, this impact of exercise is exemplified by our finding

that BDNF regulates the mRNA levels of

two end products important for neural function, i.e.

cAMP-response-element binding (CREB) protein and

synapsin I.

CREB and synapsin I

have the ability to modify neuronal function

by regulating gene-transcription

and affecting synaptic transmission, respectively.

Furthermore, we show that

BDNF is capable of concurrently increasing the mRNA levels of both itself and its tyrosine kinaseB (TrkB) receptor,

suggesting that exercise may employ a feedback loop

to augment the effects of BDNF on synaptic-plasticity.

This is the way our bodies evolved – by being active!

The use of a novel microbead injection method in our blocking experiments and Taqman reverse transcription polymerase reaction (RT-PCR) for RNA quantification, have enabled us to evaluate the contribution of different pathways to the exercise-induced increases in the mRNA levels of BDNF, TrkB, CREB, and synapsin I. We found that

although BDNF mediates exercise-induced hippocampal plasticity,

additional molecules, i.e. the

N-methyl-D-aspartate receptor,

calcium/calmodulin protein kinase II and the

mitogen-activated protein kinase cascade,

modulate its effects.

Since these molecules have a well-described association to BDNF action,

our results illustrate a basic mechanism through which exercise

may promote synaptic-plasticity in the adult brain.

See also:

Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity.

Vaynman S, Ying Z, Wu A, Gomez-Pinilla F.

Neuroscience. 2006;139(4):1221-34. Epub 2006 Mar 31.

PMID: 16580138 [PubMed – indexed for MEDLINE]

Related Articles

Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition.

Gomez-Pinilla F, Vaynman S, Ying Z.

Eur J Neurosci. 2008 Dec;28(11):2278-87.

PMID: 19046371 [PubMed – indexed for MEDLINE]

Related Articles

Vaynman, Ying & Gomez-Pinilla 2004

J Neurosci Res. 2004 May 1;76(3):356-62.

Links

Exercise induces BDNF and synapsin I to specific hippocampal subfields.

Vaynman S, Ying Z, Gómez-Pinilla F.

Department of Physiological Science, UCLA, Los Angeles, California 90095, USA.

To assess the relationship between brain-derived neurotrophic factor (BDNF) and synapsin I in the hippocampus during exercise, we employed a novel microsphere injection method to block the action of BDNF through its tyrosine kinase (Trk) receptor and subsequently measure the mRNA levels of synapsin I, using real-time TaqMan RT-PCR for RNA quantification. After establishing a causal link between BDNF and exercise-induced synapsin I mRNA levels, we studied the exercise-induced distribution of BDNF and synapsin I in the rodent hippocampus. Quantitative immunohistochemical analysis revealed increases of BDNF and synapsin I in CA3 stratum lucidum and dentate gyrus, and synapsin I alone in CA1 stratum radiatum and stratum laconosum moleculare. These results indicate that

exercise induces plasticity of select hippocampal transsynaptic circuitry, possibly comprising a spatial restriction on synapsin I regulation by BDNF.

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Vaynman, Ying & Gomez-Pinilla 2004b

Eur J Neurosci. 2004 Nov;20(10):2580-90.

Links

Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition.

Vaynman S, Ying Z, Gomez-Pinilla F.

Department of Physiological Science, UCLA, 621 Charles E. Young Drive, Los Angeles, CA 90095, US

We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the

highest expression of BDNF and associated CREB mRNA levels.

These findings suggest a functional role for CREB

under the control of BDNF

in mediating the exercise-induced enhancement in learning and memory.

Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.

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Vaynman et al 2006

Neuroscience. 2006;139(4):1221-34. Epub 2006 Mar 31.

Links

Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity.

Vaynman S, Ying Z, Wu A, Gomez-Pinilla F.

Department of Physiological Science, UCLA, Los Angeles, CA 90095, USA.

Synaptic plasticity and behaviors

are likely dependent on the capacity of neurons

to meet the energy demands imposed by neuronal activity.

We used

physical activity,

a paradigm intrinsically associated with energy consumption/expenditure and cognitive enhancement, to study

how energy metabolism interacts

with the substrates for neuroplasticity.

We found that in an area

critical for learning and memory, the hippocampus,

exercise modified aspects of energy metabolism

by decreasing oxidative stress and

increasing the levels of

cytochrome c oxidase-II,

a specific component of mitochondrial machinery.

We infused 1,25-dihydroxyvitamin D3, a modulator of energy metabolism, directly into the hippocampus during 3 days of voluntary wheel running and measured its effects on brain-derived neurotrophic factor-mediated synaptic plasticity. Brain-derived neurotrophic factor is a central player for the effects of exercise on synaptic and cognitive plasticity. We found that 25-dihydroxyvitamin D3 decreased exercise-induced brain-derived neurotrophic factor but had no significant effect on neurotrophin-3 levels, thereby suggesting a level of specificity for brain-derived neurotrophic factor in the hippocampus.

25-Dihydroxyvitamin D3 injection also abolished the effects of exercise on the consummate end-products of brain-derived neurotrophic factor action, i.e. cyclic AMP response element-binding protein and synapsin I, and modulated phosphorylated calmodulin protein kinase II, a signal transduction cascade downstream to brain-derived neurotrophic factor action that is important for learning and memory. We also found that exercise significantly increased the expression of the mitochondrial uncoupling protein 2, an energy-balancing factor concerned with ATP production and free radical management. Our results reveal a fundamental mechanism by which key elements of energy metabolism may modulate the substrates of hippocampal synaptic plasticity.

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Ding et al 2006

Neuroscience. 2006 Jul 7;140(3):823-33. Epub 2006 May 2.

Links

Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function.

Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F.

Department of Physiological Science, UCLA, 621 Charles E. Young Drive, Los Angeles, CA 90095, USA.

The ability of exercise to benefit neuronal and cognitive plasticity is well recognized. This study reveals that the effects of exercise on brain neuronal and cognitive plasticity are in part modulated by a central source of insulin-like growth factor-I.

Exercise selectively increased insulin-like growth factor-I expression without affecting insulin-like growth factor-II expression

in the rat hippocampus.

To determine the role that insulin-like growth factor-I holds in mediating exercise-induced neuronal and cognitive enhancement, a specific antibody against the insulin-like growth factor-I receptor was used to block the action of insulin-like growth factor-I in the hippocampus during a 5-day voluntary exercise period. A two-trial-per-day Morris water maze was performed for five consecutive days, succeeded by a probe trial 2 days later. Blocking hippocampal insulin-like growth factor-I receptors did not significantly attenuate the ability of exercise to enhance learning acquisition, but abolished the effect of exercise on augmenting recall.

Blocking the insulin-like growth factor-I receptor significantly reversed the exercise-induced increase in the levels of brain-derived neurotrophic factor mRNA and protein and pro-brain-derived neurotrophic factor protein, suggesting that the effects of insulin-like growth factor-I may be partially accomplished by modulating the precursor to the mature brain-derived neurotrophic factor.

A molecular analysis revealed that

exercise significantly elevated proteins downstream

to brain-derived neurotrophic factor activation

important for synaptic function, i.e. synapsin I, and signal transduction cascades associated with memory processes, i.e. phosphorylated calcium/calmodulin protein kinase II and phosphorylated mitogen-activated protein kinase II.

Blocking the insulin-like growth factor-I receptor abolished these exercise-induced increases. Our results illustrate a possible mechanism by which insulin-like growth factor-I interfaces with the brain-derived neurotrophic factor system to mediate exercise-induced synaptic and cognitive plasticity.

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Ying et al 2005

Exp Neurol. 2005 Jun;193(2):411-9.

Links

Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury.

Ying Z, Roy RR, Edgerton VR, Gómez-Pinilla F.

Department of Physiological Science, UCLA, Los Angeles, CA 90095-1527, USA; Division of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA 90095-1527, USA.

We have conducted studies to determine the potential of exercise to benefit the injured spinal cord using neurotrophins. Adult rats were randomly assigned to one of three groups…. These results are consistent with the concept that synaptic pathways under the regulatory role of BDNF induced by exercise can play a role in facilitating recovery of locomotion following spinal cord injury.

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Viding, Frick & Plomin 2007

Br J Psychiatry Suppl. 2007 May;49:s33-8.

Links

Aetiology of the relationship between callous-unemotional traits and conduct problems in childhood.

Viding E, Frick PJ, Plomin R.

Social Genetic and Developmental Psychiatry Centre, P080, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. e.viding@iop.kcl.ac.uk.

A callous and unemotional disposition is an indicator of early-onset antisocial behavior. AIMS: To investigate the extent to which genetic influences contribute to the overlap between callous-unemotional traits and conduct problems in a large population sample of 7-year-old twins. METHOD: Teachers provided ratings of callous-unemotional traits and conduct problems for 3434 twin pairs from the Twins Early Development Study. Model-fitting analyses were performed across the continuum of scores and at the extremes. RESULTS: The phenotypic relationship was primarily genetically mediated, both across the continuum and at the extremes and was substantial. What genes did they identify?  Vasopressin?  Overly sensitive trait might be connected on the other end of this same continuum, am calling for article CONCLUSIONS: At 7 years of age, genetic influences on callous-unemotional traits overlap substantially with genetic influences on conduct problems. This combination should guide selection criteria in future molecular genetic studies.

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See also:

Dev Sci. 2008 Jan;11(1):17-22.

Links

Heritability of antisocial behaviour at 9: do callous-unemotional traits matter?

Viding E, Jones AP, Frick PJ, Moffitt TE, Plomin R.

Department of Psychology, University College London, and SGDP Centre, Institute of Psychiatry, King’s College London, London, UK. e.viding@ucl.ac.uk

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Viding et al 2008

Dev Sci. 2008 Jan;11(1):17-22.

Links

Heritability of antisocial behaviour at 9: do callous-unemotional traits matter?

Viding E, Jones AP, Frick PJ, Moffitt TE, Plomin R.

Department of Psychology, University College London, and SGDP Centre, Institute of Psychiatry, King’s College London, London, UK. e.viding@ucl.ac.uk

A previous finding from our group indicated that teacher-rated antisocial behavior (AB) among 7-year-olds is particularly heritable in the presence of callous-unemotional (CU) traits. Using a sample of 1865 same-sex twin pairs, we employed DeFries-Fulker extremes analysis to investigate whether teacher-rated AB with/without CU traits also shows aetiological differences among 9-year-olds. Furthermore, we assessed whether the differences in the magnitude of heritability would be evident even when hyperactive symptoms were controlled for in the statistical analysis. AB among 9-year-olds was more heritable with than without concomitant CU. The heritability difference was even more pronounced in magnitude when hyperactive symptoms were controlled. CU traits thus appear to index one valid way of sub-typing children with early-onset AB.

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Viding & Jones 2008b

Q J Exp Psychol (Colchester). 2008 Jan;61(1):171-81.

Links

Cognition to genes via the brain in the study of conduct disorder.

Viding E, Jones AP.

Department of Psychology and Institute of Cognitive Neuroscience, University College London, London, UK. e.viding@ucl.ac.uk

Although a single diagnostic label, conduct disorder, is currently applied to children exhibiting antisocial behavior, multiple routes to the same behavioural phenomena exist. Morton and Frith’s (1995) causal modeling has been fundamentally important in influencing models of cognitive/affective and associated neural

differences between callous-unemotional (CU) and r

eactive/threat-based antisocial behavior.

Current behavioural genetic research is still catching up with the developmental cognitive neuroscience, and very few genetically informative studies differentiate between these two subtypes of antisocial behavior. Our own work with preadolescent twins suggests that while the CU subtype is genetically vulnerable to antisocial behavior, the non-CU subtype manifests a primarily environmental aetiology to their antisocial behavior.

Molecular genetic work to date has not differentiated between these two subtypes, and we highlight why it might be of interest to do so. Finally, we discuss how the novel approach of imaging genetics could be harnessed to study genes to cognition pathways for different subtypes of conduct disorder. Uta Frith’s contributions to articulating research strategies for developmental disorders are important in conducting and interpreting this work.

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Woodworth & Waschbusch 2008

Child Care Health Dev. 2008 Mar;34(2):234-44. Epub 2007 Nov 20.

Links

Emotional processing in children with conduct problems and callous/unemotional traits.

Woodworth M, Waschbusch D.

UBC Okanagan, Unit of Psychology and Computer Science, 3333 University Way, Kelowna, BC, Canada. Michael.Woodworth@ubc.ca

BACKGROUND: A considerable body of evidence now suggests that conduct problem (CP) children with callous/unemotional (CU) traits differ in many ways from CP children without these characteristics. Previous research has suggested that there are important differences for youth with CP and CU characteristics in their ability to process emotional information. The current study investigated the ability of children with disruptive behavior disorders to label emotional faces and stories. METHODS: Participants (aged 7-12) were involved in a summer day treatment and research program for children with disruptive behavior problems. Two tasks were administered that were designed to measure participant’s ability to recognize and label facial expressions of emotion, as well as their ability to label emotions in hypothetical situations. RESULTS: Results indicated that children with higher levels of CU traits, regardless of whether they had elevated CP scores, were less accurate in identifying sad facial expressions.

Interestingly, children with higher callous/unemotional CU scores were more accurate in labeling fear than were children with lower callous/unemotional CU scores, while

children with high conduct problem CP but low callous/unemotional CU traits were less accurate than other children in interpreting fearful facial emotions.

Further, children’s recognition of various emotional vignettes was not associated with CP, CU traits or their interaction.

CONCLUSIONS: The current study demonstrated that it was the combination of CP and a high number of CU traits that differentiated emotional attributions. Consistent with previous research, youth with callous/unemotional CU traits had more difficulty in identifying sad facial expressions. However, contrasting with some previous studies,

higher callous/unemotional CU traits were associated with more accurate perceptions of fearful expressions. It is possible that there is something specific to fear recognition for individuals with more psychopathic, callous/unemotional CU traits that actually make them more successful for observing or recognizing fearful expressions. Additional research is needed to clarify both the recognition and processing of fear expression in CP children with and without CU.

I need to find that study that linked fear expression and recognition of same with dominance recognition – probably modulated in part by oxytocin and vasopressin

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Steiner et al 2008c

Pharmacogenomics J. 2008 Jun;8(3):196-208. Epub 2007 Aug 7.

Links

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice.

Steiner MA, Wanisch K, Monory K, Marsicano G, Borroni E, Bächli H, Holsboer F, Lutz B, Wotjak CT.

Max Planck Institute of Psychiatry, Munich, Germany. steiner@mpipsykl.mpg.de

Dysregulation of the endocannabinoid system is known to interfere with emotional processing of stressful events.

Here, we studied the role of cannabinoid receptor type 1 (CB1) signaling in stress-coping behaviors using the forced swim test (FST) with repeated exposures. We compared effects of genetic inactivation with pharmacological blockade of CB1 receptors both in male and female mice. In addition, we investigated potential interactions of the endocannabinoid system with monoaminergic and neurotrophin systems of the brain. Naive CB1 receptor-deficient mice (CB1-/-) showed increased passive stress-coping behaviors as compared to wild-type littermates (CB1+/+) in the FST, independent of sex. These findings were partially reproduced in C57BL/6N animals and fully reproduced in female CB1+/+ mice by pharmacological blockade of CB1 receptors with the CB1 receptor antagonist SR141716. The specificity of SR141716 was confirmed in female CB1-/- mice, where it failed to affect behavioral performance. Sensitivity to the antidepressants desipramine and paroxetine was preserved, but slightly altered in female CB1-/- mice. There were no genotype differences between CB1+/+ and CB1-/- mice in monoamine oxidase A and B activities under basal conditions, nor in monoamine content of hippocampal tissue after FST exposure. mRNA expression of vesicular glutamate transporter type 1 was unaffected in CB1-/- mice, but mRNA expression of brain-derived neurotrophic factor (BDNF) was reduced in the hippocampus. Our results suggest that

impaired CB1 receptor function promotes passive stress-coping behavior, which, at least in part,

might relate to alterations in BDNF function

See also in pain section:

Steiner et al 2008b

Psychoneuroendocrinology. 2008 Jan;33(1):54-67. Epub 2007 Oct 31.

Links

Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice.

Steiner MA, Marsicano G, Nestler EJ, Holsboer F, Lutz B, Wotjak CT.

Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. steinmi@uni-mainz.de

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Marsh et al 2008b

Am J Psychiatry. 2008 Jun;165(6):712-20. Epub 2008 Feb 15.

Links

Reduced amygdala response to fearful expressions in children and adolescents with callous-unemotional traits and disruptive behavior disorders.

Marsh AA, Finger EC, Mitchell DG, Reid ME, Sims C, Kosson DS, Towbin KE, Leibenluft E, Pine DS, Blair RJ.

Mood and Anxiety Program, NIMH, 15K North Dr., MSC 2670, Bethesda, MD 20892, USA. amarsh@post.harvard.edu

OBJECTIVE: Extensive work implicates abnormal amygdala activation in emotional facial expression processing in adults with callous-unemotional traits. However, no research has examined amygdala response to emotional facial expressions in adolescents with disruptive behavior and callous-unemotional traits. …

RESULTS: In youths with callous-unemotional traits, amygdala activation was reduced relative to healthy comparison subjects and youths with ADHD while processing fearful expressions, but not neutral or angry expressions. Functional connectivity analyses demonstrated greater correlations between the amygdala and the ventromedial prefrontal cortex in comparison subjects and youths with ADHD relative to those with callous-unemotional traits so CU had less functional connectivity. Symptom severity in the callous-unemotional traits groups was negatively correlated with connectivity between amygdala and ventromedial prefrontal cortex. CONCLUSIONS: This is the first study to demonstrate reduced amygdala responsiveness in youths with callous-unemotional traits. These findings support the contention that

callous and unemotional personality traits

are associated with reduced amygdala response

to distress-based social cues.

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See also:

Arch Gen Psychiatry. 2008 May;65(5):586-94.

Links

Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning.

Finger EC, Marsh AA, Mitchell DG, Reid ME, Sims C, Budhani S, Kosson DS, Chen G, Towbin KE, Leibenluft E, Pine DS, Blair JR.

National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. elizabeth.finger@lhsc.on.ca

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Marsh & Blair 2008

Neurosci Biobehav Rev. 2008;32(3):454-65. Epub 2007 Sep 1.

Links

Deficits in facial affect recognition among antisocial populations: a meta-analysis.

Marsh AA, Blair RJ.

National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. marsha@mail.nih.gov

Individuals with disorders marked by antisocial behavior frequently show deficits in recognizing displays of facial affect. Antisociality may be associated with specific deficits in identifying fearful expressions, which would implicate dysfunction in neural structures that subserve fearful expression processing. A meta-analysis of 20 studies was conducted to assess:

(a) if antisocial populations show any consistent deficits in recognizing six emotional expressions;

(b) beyond any generalized impairment, whether specific fear recognition deficits are apparent; and

(c) if deficits in fear recognition are a function of task difficulty.

Results show a robust link between antisocial behavior and specific deficits in recognizing fearful expressions. This impairment cannot be attributed solely to task difficulty. These results suggest dysfunction among antisocial individuals in specified neural substrates, namely the amygdala, involved in processing fearful facial affect.

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