Project Summary/Abstract This proposal is for a four-year research career development program, focused on the study of the neurophysiology of fear and safety discrimination, which has relevance to anxiety disorders and post-traumatic stress disorder. By the start of the project, the candidate will have been appointed an Instructor in the Department of Psychiatry at Weill Cornell Medical Center. The proposal is a natural extension of the candidate's previous research and clinical training on safety signals in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). It outlines a plan for the candidate to achieve his goal of becoming an expert in the circuit mechanisms of fear and anxiety disorders, extending the training of the candidate in two dimensions, which are reflected in the mentorship of Drs. Conor Liston and Joshua Levitz: 1. Encoding of fear and safety- related information in large, distributed mPFC and BLA ensembles and 2. Cell-surface receptors that modulate prefrontal output to the BLA for successful fear discrimination and represent promising pharmacological targets for treating generalized fear. The proposed experiments and multi-faceted training plan will impart the candidate with a unique combination of skills that will position him to transition into a successful independent career as a physician-scientist studying the neurophysiology of fear and anxiety in psychiatric disorders. Anxiety disorders are the most prevalent mental disorders, affecting one-fifth to one-third of the adult US population, and the disorders are typically chronic, associated with high disease burden and significant healthcare cost. While effective treatments exist, a substantial proportion of patients are minimally responsive, underpinning the need to develop therapeutics that work through different cellular mechanisms. Anxiety disorders are highly co-morbid with each other and with other psychiatric disorders, highlighting the value of research into common neurocircuit mechanisms with trans-diagnostic relevance. Patients with PTSD or anxiety disorders have both been found to exhibit the overgeneralization of conditioned fear, which is associated with abnormal reactivity of the mPFC and BLA. The goal of my proposal is to investigate the encoding of fear and safety discrimination in interconnected mPFC and BLA neurons. Specifically, this proposal investigates the role of metabotropic glutamate receptor 2 (mGluR2) in controlling mPFC-to-BLA output by: 1. Defining high- dimensional fear and safety encoding mechanisms in mGluR2+ and mGluR2- mPFC-BLA projectors; 2. Elucidating fear discrimination learning-related changes in connectivity between mGluR2+ and mGluR2- mPFC cells and functionally-distinct downstream BLA ensembles; 3. Dissecting the role of mGluR2 signaling specifically at mPFC-BLA presynaptic terminals in fear discrimination learning. Collectively, these experiments provide novel insight into the neurophysiology of fear and safety discri...