From LeDoux Synaptic Self


“As a way of illustrating how glutamate, GABA, and modulators work, let us consider their role in the detection of danger by the amygdala.  (LeDoux/ss/61)”

“The amygdala detects danger by virtue of its position in a synaptically connected system.  In its simplest form, this system can be described in terms of a three-level excitatory chain of cells that releases glutamate – projection cells in sensory systems activate projection cells in the amygdala, which activate projection cells in motor areas….  This scheme leaves much out, but we’ll have the opportunity to embellish it later.  (LeDoux/ss/61)”

“Amygdala cells receive inputs from the sensory world constantly, but they ignore the majority of them.  In fact, they tend to be quiescent most of the time.  They do get worked up, though, when the right kind of stimulus is present – one that signifies danger or some other biologically significant event.  (LeDoux/ss/61)  This has been shown to be true in studies of both lower animals and humans.  So what keeps a projection cell in the amygdala from firing in response to meaningless stimuli?  The answer, as you’ve probably guessed, is GABA.  (LeDoux/ss/62)”

“As we’ve seen, the resting membrane potential of cells in many brain areas is about –60 mV.  In the amygdala, however, some cells can be as negative as –80 mV, due to sustained or tonic inhibition by GABA.  With GABA receptors on amygdala projection cells occupied and passing chloride, the inside of the cells becomes more negative, which means it takes extra excitation to turn the amygdala on.  As a result, not any old stimulus will do the trick.  The stimulus has to have special qualities that allow it to overcome the tonic inhibition produced by GABA.  (LeDoux/ss/62)”

“Stimuli that are inherently dangerous (the sight or smell of a predator) or unpleasant (intense stimuli, like noises or stimuli that cause pain) are able to overcome the tonic inhibition, as are stimuli that have emotional resonance acquired through past learning.  Thus, an otherwise meaningless sound of modest intensity that previously occurred in association with pain has the same effect as a natural (innate) form of danger.  Both innate (hardwired) and learned danger signals cause amygdala cells to fire rapidly for a sustained period, and are thus able to overcome the GABA guard.  (LeDoux/ss/63)”

“Even after fear-arousing stimuli get past tonic inhibition and cause amygdala cells to fire, however, they are still subject to GABA control.  The inputs to the amygdala activate GABA cells as well as projection neurons.  As a result, as the inputs become more active, the elicited inhibition in the amygdala builds up, which in turn begins to shut down the activity of amygdala cells.  (LeDoux/ss/63)”

“If the ability of GABA to keep meaningless stimuli from turning on the amygdala is compromised for some reason (either because the projection cells come to fire more easily or because the GABA cells fire less easily), stimuli that are not dangerous come to be responded to as though they were.  This may occur in certain fear and anxiety disorders.  By the same logic, things that make projection cells fire less readily or that make GABA cells fire more readily should reduce fear and anxiety.  Indeed, one of the most popular medications ever invented for the treatment of anxiety is Valium, which works by facilitating GABA transmission.  Although drugs taken orally reach many sites in the brain, it is likely that at least some of their effects on fear and anxiety are achieved by enhancing inhibition in the amygdala, and thereby making it harder for external or internal stimuli to elicit fear responses by activating amygdala circuits.  (LeDoux/ss/63)”

“The amygdala also receives modulatory inputs of various types.  For example, serotonin fibers terminate there, and when the amount of serotonin rises in the amygdala the activity of excitatory projection cells is inhibited.  The inhibition in this case is not due to the fact that serotonin directly affects projection cells, but rather that serotonin excites GABA cells, and thus increases the degree to which they inhibit projection neurons.  (LeDoux/ss/63)”

“Drugs like Prozac work by increasing the amount of serotonin available at synapses.  By enhancing serotonin transmission at GABA synapses in the amygdala, and thereby reducing the activity of projection neurons, Prozac may, like Valium, help control anxiety by reducing the ability of inputs to the amygdala to activate fear circuits.  (LeDoux/ss/63)”

“The amygdala is also the target of many hormones.  One of these is cortisol, which is released from the adrenal cortex during fear-arousing and other- (LeDoux/ss/63) wise stressful events.  The facilitation of GABA inhibition of amygdala projection cells by serotonin is modulated by cortisol.  Serotonin’s ability to facilitate inhibition by exciting GABA cells thus depends on the binding of cortisol to receptors located on amygdala neurons.  Cortisol is elevated in a variety of psychiatric disorders, and cortisol increases the intensity of fear reactions.  Drugs like Prozac may reduce exaggerated fear and anxiety in psychiatric disorders by enhancing the ability of serotonin to facilitate GABA inhibition in the presence of elevated cortisol.  (LeDoux/ss/64)”

“The fear system thus nicely illustrates the basic elements of neural transmission in the brain and its regulation by modulatory chemicals.  (LeDoux/ss/64)”

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