Identification and manipulation of fear extinction engrams in prefrontal cortex

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PROJECT SUMMARY Broad Impact: Experiencing a fearful event creates a long-term memory that involves the plasticity of a distributed population of neurons throughout the brain. A variety of neuropsychiatric disorders—including post- traumatic stress disorder (PTSD), phobias, and generalized anxiety disorder—are characterized by the inability to regulate pathological fear; thus, it is crucial to understand the neural mechanisms through which learned fear can be attenuated in order to develop effective treatment strategies. Extinction is the primary clinical treatment for maladaptive fear,  but the neural mechanisms underlying extinction remain poorly understood. Specific Aims: A recent development for tagging and manipulating memory traces, or engrams, have shown that fear memories are encoded by `engram cells' across multiple brain regions whose activity is both necessary and sufficient for driving fearful behavior. The main goal of the proposal is to test the hypothesis that extinction learning would promote the generation of an `extinction engram': an ensemble of cells activated by extinction learning whose reactivation would lead to suppression of fear. The focus will be on the infralimbic (IL) portion of the medial prefrontal cortex, which has been identified as a critical region for the acquisition and consolidation of fear extinction. The proposed experiments will (1) determine if unique neuronal ensembles in IL code for extinction in stimulus-specific manner or act as a general inhibitor of fear behavior, and (2) assess the causal role of IL neuronal activity in the expression of fear and extinction learning. Methods: The activity-dependent neural tagging system of the ArcCreERT2 x R26R-STOP-floxed-Halo-eYFP mouse line will be used to permanently tag populations of neurons active during contextual fear conditioning (CFC) or extinction. These tagged cells can be visualized to quantify neural reactivation or silenced optogenetically to investigate their causal role in fear acquisition and extinction. Training Program: This two year training plan will (1) provide the applicant with technical expertise in optogenetics and activity-dependent neural tagging systems, (2) increase the applicant's knowledge of forebrain anatomy, function, and theoretical processing capabilities, (3) provide resources for disseminating the research findings to the larger scientific community, and (4) aide in developing a number of professional development skills that will be needed to make the next successful step in the applicant's scientific career.