Project Grant K99MH135212

MAPPING NEURAL DYNAMICS IN HORMONE-SENSITIVE NETWORKS - PROJECT SUMMARY/ABSTRACT DECIDING TO SELF-INITIATE SOCIAL INTERACTION (I.E., PROACTIVE SOCIAL BEHAVIOR) DEPENDS ON MANY VARIABLES: THE SOCIAL CONTEXT, OUR SOCIAL PARTNER, AND OUR HORMONAL STATE. GONADAL HORMONES IMPACT SOCIAL BEHAVIOR PRIMARILY BY REGULATING NEURAL GENE EXPRESSION ACROSS A NETWORK OF INTERCONNECTED, SUBCORTICAL BRAIN REGIONS. FURTHER, BEHAVIOR ITSELF CAN LEAD TO CHANGES IN HORMONE LEVELS, INDICATING BEHAVIOR AND HORMONAL STATE EXIST IN AN ONGOING FEEDBACK LOOP. MANY MOOD DISORDERS, SUCH AS DEPRESSION AND ANXIETY, EXHIBIT PROFOUND SEX DIFFERENCES, WHICH RELATE TO HORMONAL STATE AND INTERACT WITH SOCIAL BEHAVIOR DYSFUNCTION. CRITICALLY, PROACTIVE SOCIAL BEHAVIOR CAN INCREASE RESILIENCY TO THESE DISORDERS. UNRAVELING THE NEUROENDOCRINE MECHANISMS THAT PROMOTE PROACTIVE SOCIAL BEHAVIOR IS A CRITICAL STEP TOWARD IDENTIFYING THE ETIOLOGY OF MOOD DISORDER-ASSOCIATED SOCIAL DYSFUNCTION. RECENT WORK BY THE CANDIDATE DEMONSTRATES TWO NEURAL POPULATIONS OF THIS SUBCORTICAL NETWORK INTERACT TO REGULATE THE PROACTIVE SEEKING OF SOCIAL INTERACTION. HOWEVER, WE DO NOT KNOW HOW HORMONE-SENSITIVE POPULATIONS ACROSS THIS DISTRIBUTED NETWORK INTERACT TO ENCODE PROACTIVE SOCIAL BEHAVIOR AND RELATED SOCIAL VARIABLES (CONTEXT, PARTNER), NOR DO WE UNDERSTAND THE IMPACT OF HORMONAL CHANGE ON THIS ENCODING. THE GOAL OF THIS PROPOSAL IS TO COMPREHENSIVELY MAP THE INFLUENCE OF GONADAL HORMONES ON NETWORK-LEVEL CODING OF PROACTIVE SOCIAL BEHAVIOR AND RELATED VARIABLES (CONTEXT, PARTNER), AND IDENTIFY SITES OF IN VIVO HORMONAL ACTION. HERE, THE CANDIDATE DEVELOPS NEW METHODS FOR COMPUTATIONAL ANALYSIS OF SOCIAL BEHAVIOR AND NEW OPTICAL TOOLS FOR RECORDING NEURAL ACTIVITY ACROSS MULTIPLE BRAIN REGIONS IN SOCIALLY INTERACTING MICE. THE CANDIDATE LEVERAGES THESE TOOLS TO MAP MOUSE SOCIAL BEHAVIOR (AIM 1) AND NETWORK-WIDE NEURAL CODING ACROSS A CHANGE IN HORMONAL STATE (AIM 2). IN THE INDEPENDENT PHASE OF THE PROJECT, THE CANDIDATE COMBINES THE TOOLS DEVELOPED IN THIS PROPOSAL WITH A NOVEL FLUORESCENT REPORTER TO "CLOSE" THE FEEDBACK LOOP BY RECORDING THE DYNAMICS OF SOCIAL EXPERIENCE-DEPENDENT, HORMONE-MEDIATED NEURAL GENE TRANSCRIPTION ACROSS A HORMONE-SENSITIVE BRAIN NETWORK (AIM 3). THIS PROJECT WILL PROVIDE A NEW MECHANISTIC UNDERSTANDING OF HOW HORMONAL CHANGES, NEURAL FUNCTION, AND SOCIAL BEHAVIOR INTERACT AND PROVIDE KEY INSIGHTS INTO HOW THESE BEHAVIORS GO AWRY IN MOOD DISORDERS. THIS PROPOSAL BRINGS TOGETHER AN EXPERIENCED TEAM OF MENTORS AND COLLABORATORS WITH IDEAL EXPERTISE FOR THE WORK. THIS TEAM WILL PROVIDE CRITICAL TRAINING FOR THE CANDIDATES SHORT- AND LONG-TERM SUCCESS, INCLUDING IN SYSTEMS AND COMPUTATIONAL NEUROSCIENCE, BEHAVIOR QUANTIFICATION, AND NEUROENDOCRINOLOGY. THIS DIVERSE EXPERTISE WILL ALLOW THE CANDIDATE TO DEVELOP A COMPUTATIONAL NEUROENDOCRINOLOGY RESEARCH PROGRAM THAT APPLIES SYSTEMS NEUROSCIENCE TECHNIQUES TO PRESSING QUESTIONS IN NEUROENDOCRINOLOGY. THE PROPOSED TRAINING PROGRAM COMBINES TECHNICAL RESEARCH TRAINING WITH FORMAL MENTORSHIP AND PROFESSIONAL DEVELOPMENT. THE GOALS OUTLINED IN THE PROPOSAL BUILD ON THE CANDIDATE'S EXISTING SKILLSET AND INTERESTS TO ASSIST THE CANDIDATE IN A SUCCESSFUL TRANSITION TO INDEPENDENCE LEADING A LABORATORY WITH A NOVEL COMPUTATIONAL NEUROENDOCRINOLOGY FOCUS.