VENTRAL HIPPOCAMPAL CIRCUIT REGULATION OF STRESS-INDUCED FEAR AND ANXIETY - PROJECT SUMMARY / ABSTRACT CHRONIC STRESS IS A WELL-ESTABLISHED CONTRIBUTOR TO NEUROBIOLOGICAL CHANGES THAT INFLUENCE BEHAVIORAL RESPONSES TO THREAT AND UNCERTAINTY. THE HIPPOCAMPUS PLAYS A CENTRAL ROLE IN STRESS-RELATED PLASTICITY, YET THE SPECIFIC CIRCUITS AND MOLECULAR MECHANISMS THROUGH WHICH STRESS ALTERS HIPPOCAMPAL OUTPUT REMAIN INCOMPLETELY DEFINED. ONE PATHWAY OF INTEREST IS THE PROJECTION FROM THE VENTRAL HIPPOCAMPUS TO THE MEDIAL PREFRONTAL CORTEX (VHIPP-MPFC), WHICH HAS BEEN IMPLICATED IN MODULATING BEHAVIORAL REACTIVITY TO AVERSIVE STIMULI. MY PRELIMINARY DATA INDICATE THAT CHRONIC UNPREDICTABLE STRESS (CUS) ENHANCES ACTIVITY IN THIS CIRCUIT, COINCIDING WITH INCREASED DEFENSIVE BEHAVIORAL RESPONSES. THE CURRENT PROJECT AIMS TO UNCOVER THE TRANSCRIPTIONAL MECHANISMS DRIVING STRESS-INDUCED HYPERACTIVITY IN THE VHIPP-MPFC CIRCUIT AND ASSESS ITS CAUSAL ROLE IN STRESS-RELATED BEHAVIORAL ADAPTATIONS. IN SPECIFIC AIM 1, I WILL USE CIRCUIT-SPECIFIC LABELING COMBINED WITH SINGLE-NUCLEUS RNA SEQUENCING (SNRNASEQ) TO IDENTIFY STRESS-INDUCED TRANSCRIPTIONAL CHANGES IN THE VHIPP-MPFC PATHWAY FOLLOWING CUS. THEN, I WILL ASSESS THE RELEVANCE OF THESE CHANGES TO HUMAN PATHOLOGY BY COMPARING DIFFERENTIALLY EXPRESSED GENES TO SINGLE-NUCLEUS DATA COLLECTED FROM INDIVIDUALS WITH POST-TRAUMATIC STRESS DISORDER (PTSD) USING THE PSYCHENCODE HUMAN HIPPOCAMPAL PTSD DATASET. IN SPECIFIC AIM 2, I WILL USE CHEMOGENETIC TOOLS TO BIDIRECTIONALLY MANIPULATE VHIPP-MPFC PATHWAY ACTIVITY IN MICE EXPOSED TO CUS TO DETERMINE WHETHER HYPERACTIVITY IN THIS PATHWAY IS NECESSARY AND/OR SUFFICIENT TO DRIVE CHANGES IN DEFENSIVE BEHAVIOR. THE PROPOSED RESEARCH WILL ADVANCE OUR UNDERSTANDING OF HOW CHRONIC STRESS ALTERS HIPPOCAMPAL-PREFRONTAL CIRCUITS TO INFLUENCE BEHAVIOR, POTENTIALLY IDENTIFYING NEW BIOMARKERS OR MOLECULAR TARGETS FOR THERAPEUTIC DEVELOPMENT. THE PROJECT INTEGRATES TRANSCRIPTOMIC PROFILING, CIRCUIT-LEVEL MANIPULATION, AND BEHAVIORAL ANALYSIS, PROVIDING ME WITH COMPREHENSIVE AND RIGOROUS TRAINING IN BOTH BIOINFORMATICS AND SYSTEMS NEUROSCIENCE AND PREPARING ME FOR A CAREER THAT INTEGRATES THESE FIELDS TO ELUCIDATE THE NEUROBIOLOGY OF STRESS-RELATED DISORDERS.