Synaptic mechanisms of amygdala-dependent behaviors

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Neural activity in the amygdala forms the basis for expression of emotional behavior, and the role of the amygdala in anxiety and conditioned fear is under investigation. Our main goal is to understand how amygdala circuitry triggers fear behaviors and how neuronal activity changes during transition from normal to pathological states. This knowledge will provide information that will help in developing treatments for mental disorders associated with pathological fear.
 The amygdala operates by analyzing incoming information with emotional content and triggering defensive responses. We study how the amygdala integrates, at the synaptic level, incoming signals that process sensory and affective information and signals that provide executive control. To address this question, we interrogate a specific input by selectively stimulating nerve fibers coming from a specific brain area. To address this question, we established opsin-based techniques for selective activation or silencing of amygdala inputs from perirhinal cortical area TeA, which transmits sensory information, and from the anterior cingulate cortex (ACC), which is implicated in affect, pain and cognition. Both inputs target individual intermingled neurons within the amygdala. We found a significant difference in synaptic plasticity between the two input pathways. While long-term potentiation (LTP) of synaptic transmission in the input from perirhinal cortex required suppression of GABA-A receptor-mediated inhibition, LTP in the ACC-amygdala pathway did not. Moreover, severing connections between external capsule and amygdala enabled LTP in the input from perirhinal cortex even in the presence of GABA-A receptor-mediated inhibition. In addition, we found that these two inputs exhibit differential connectivity to the amygdala inhibitory neurons. The ACC input was more effective in activating interneurons that express serotonin receptor 3, whereas the TeA input was more effective in recruiting the pericapsular cells. Our studies revealed that small GTPase Rap1 suppresses release of glutamate in the cortical inputs to the basolateral amygdala. We investigated molecular mechanisms of this suppression by imaging presynaptic release in primary cortical neurons, while manipulating the Rap1-Erk1/2 signaling pathway. The study revealed that the Rap1-Erk1/2 signaling suppressed presynaptic release by preventing participation of the L-type calcium channel in presynaptic release, possibly by preventing insertion of the channel into the plasma membrane. We continued to investigate the mechanisms responsible for amygdala disinhibition and focused on dopaminergic modulation of local microcircuits. Using interneuron-specific lines of transgenic Cre-mice, we selectively activated parvalbumin positive neurons in the basolateral amygdala and found that dopamine selectively suppressed GABA release towards principal cells, but not towards interneurons.
 The selectivity was explained by our finding that in parvalbumin-positive neurons, cAMP signaling regulated GABA release at synapses that targeted principal cells but not interneurons.