Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction

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PROJECT SUMMARY Acquisition and extinction of learned fear responses are critical for survival and require modification of conserved neural circuits that promote or suppress fear expression, respectively. Disruption of these important physiological processes are thought to underlie the development of stressor and trauma- related disorders including posttraumatic stress disorders. Understanding the neuronal circuits and synaptic mechanisms regulating fear memory formation and extinction could have important implications for elucidating pathophysiological mechanisms of stress-related disorders and provide insight into fundamental mechanisms subserving learning and memory processes. The central nucleus of the amygdala (CeA) is a striatal-like subcortical brain structure that sits functionally at the limbic-motor interface. Recent studies have identified distinct cell-types within this region that are sufficient to generate diverse survival-oriented behavioral responses including freezing, flight, hunting, and feeding. Relevant to the current proposal, very recent work has identified the CeA as a novel locus of fear-learning and identified distinct cell-types responsible for generating learned fear responses in the form of freezing and flight-like escape behavior. Despite these advances, how top-down cortical signals are able to select distinct behavioral outputs via targeted activation of different CeA cell-types is not well understood. Here we will utilize a combination of cutting-edge cell-type- specific electrophysiological, optogenetic, chemogenetic and viral reporter approaches combined with a Pavlovian fear-conditioning and extinction paradigm to gain insight into this critical open question. Aim 1 of this proposal will test the hypothesis that acquisition and extinction of conditioned fear responses is associated with dynamic shifts in the relative glutamatergic drive from the basolateral amygdala (BLA) to CeA corticotrophin releasing factor expressing (CRF+) and somatostatin-expressing (SOM+) neurons. We hypothesize that fear acquisition shifts BLA excitatory drive to favor SOM+ neurons, which have been shown to drive conditioned freezing behavior, while extinction learning reverses the relative input bias from the BLA to favor CRF+ neurons, which we show facilitate extinction of conditioned freezing behavior. Aim 2 will test the requirement for neuronal activity in the induction of this form of experience-dependent plasticity and its necessity for the expression of conditioned fear and extinction using circuit-specific chemogenetic and behavioral approaches. Aim 3 will test the hypothesis that retrograde endocannabinoid signaling is an important mediator of experience-dependent changes in synaptic strength between the BLA and CeA CRF+ and SOM+ neurons, and that modulation of eCB signaling within the BLA-CeA-SOM+ circuit promotes fear extinction. Completion of these studies will provide novel insight into the circuit and cell-type-specific mechanisms regulating fear acquisition and extinction and enhance our understanding of the pathophysiology of stressor and trauma- related psychiatric disorders.