Cell Type Specific Genomic and Functional Dissection of Fear-Off Amygdala Pathways

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Fear-related disorders such as Post-Traumatic Stress Disorder (PTSD) are often characterized by an inability to inhibit and extinguish fear memories leading to pathological expression of fear-related behaviors. For progress to occur with targeted rationally-designed therapeutic approaches, a greater understanding of the neural circuitry mediating fear inhibition and extinction is needed. This proposal utilizes cutting-edge, cell- type specific approaches targeting circuits that control amygdala fear inhibition and extinction, via medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) cell-type specific neural pathways, to align with NIMH research priorities by cutting across RDoC domains in the NIH strategic plan for identifying the pathophysiology of fear-related disorders. It is critical that we understand the role of specific cell types projecting to the amygdala supporting fear inhibition and fear extinction learning. This Competitive Renewal expands our prior work dissecting function of cell-type-specific mechanisms in the amygdala that differentially mediate fear and extinction. In addition to other neuronal subtypes, our prior work dissected roles of the CRF and Thy1-specific neuronal populations within the mouse Basolateral Amygdala (BLA) nuclei, demonstrating distinct molecular and physiological functions underlying fear and extinction pathways. Here we aim to extend this work using a variety of currently available intersectional circuit dissection tools, to understand the role of medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) projections in regulating amygdala CRF and Thy1 populations. We predict that this approach will identify novel pharmacological targets for fear inhibition and extinction, pursuing new pathways for fear-related anxiety disorders. Our central hypothesis is that the specific pathways within the mPFC and vHPC to BLA circuits, involving projections to fear-controlling amygdala CRF- and Thy1-positive cells, contribute to the mechanisms of fear retention. Targeting these specific pathways will provide greater understanding of fear inhibitory control. This hypothesis will be tested through the following Specific Aims: 1) Explore the role of mPFC and vHPC projections to CRF and Thy1 cells in amygdala in control of fear and extinction. 2) Identify activity patterns in mPFC and vHPC neurons projecting to fear-controlling cells in amygdala using GCaMP miniscope and fiber photometry. 3) Explore synaptic and network-level mechanisms of repeated stress-triggered fear renewal, focusing on mPFC and vHPC projections to amygdala CRF and Thy1 positive neurons, respectively. 4) Perform cell type specific RNA profiling of amygdala-projecting mPFC and vHPC neurons (both CRH/Thy1 targeted cells and engram activity dependent cells) with and without chronic stress. The identification of novel targets will advance our understanding of circuitry underlying fear behaviors and will provide unique avenues for therapeutics.