Project Grant R03MH134181

ROLE OF GONADAL STEROIDS IN STRESS-SENSITIVE NEURAL CIRCUITS - PROJECT SUMMARY SOCIAL STRESS IS A RISK FACTOR FOR SEVERAL STRESS-RELATED PSYCHOPATHOLOGIES, INCLUDING POST-TRAUMATIC STRESS DISORDER (PTSD). HOWEVER, MOST INDIVIDUALS EXPOSED TO TRAUMA DO NOT DEVELOP STRESS-RELATED PSYCHOPATHOLOGIES AND PREVIOUS SOCIAL EXPERIENCE HAS THE POTENTIAL TO IMPROVE COPING STRATEGIES AND ENABLE STRESS RESILIENCE. ONE SOCIAL EXPERIENCE THAT CONTRIBUTES TO THE DEVELOPMENT OF STRESS RESILIENCE IS A DOMINANT POSITION IN A SOCIAL HIERARCHY. IN THIS PROPOSAL, WE USE A SYRIAN HAMSTER MODEL IN WHICH DOMINANT ANIMALS SHOW LESS STRESS-RELATED BEHAVIOR THAN THEIR SUBORDINATE COUNTERPARTS. OUR PRELIMINARY DATA INDICATE THAT MALE DOMINANTS SHOW INCREASED C-FOS IMMUNOREACTIVITY IN ANDROGEN RECEPTOR (AR)-POSITIVE CELLS IN DORSAL ASPECTS OF THE POSTERIOR MEDIAL AMYGDALA (MEPD) COMPARED TO THEIR SUBORDINATE COUNTERPARTS. IN ADDITION, THEY SHOW INCREASED C-FOS IMMUNOREACTIVITY IN MEPD CELLS PROJECTING TO POSTERIOR REGIONS OF THE BED NUCLEUS OF THE STRIA TERMINALIS (BNSTP) COMPARED TO SUBORDINATES. UNLIKE MALES, DOMINANT FEMALE HAMSTERS HAVE A GREATER NUMBER OF ESTROGEN RECEPTOR ALPHA (ERA)-POSITIVE CELLS IN THE MEPD COMPARED TO SUBORDINATES. HOWEVER, DOMINANT FEMALES DO NOT SHOW ELEVATED C-FOS IMMUNOREACTIVITY IN BNSTP-PROJECTING MEPD CELLS COMPARED TO SUBORDINATES. ALTOGETHER, THESE FINDINGS SUGGEST THAT WHILE AR EXPRESSION IN A MEPD-BNSTP PATHWAY MAY BE CRITICAL FOR STATUS-DEPENDENT DIFFERENCES IN STRESS VULNERABILITY IN MALE HAMSTERS, ERA EXPRESSION IN MEPD- BNSTP PATHWAY MAY NOT CONTRIBUTE TO STATUS-DEPENDENT DIFFERENCES IN STRESS VULNERABILITY IN FEMALE HAMSTERS. BECAUSE OF THESE SEX DIFFERENCES, WE HAVE TWO SEPARATE HYPOTHESES IN THIS PROPOSAL. WE HYPOTHESIZE THAT AR+ NEURONS IN A MEPD-BNSTP PATHWAY ARE ESSENTIAL FOR STATUS-DEPENDENT DIFFERENCES IN STRESS-RELATED BEHAVIOR IN MALE HAMSTERS. ALSO, WE HYPOTHESIZE THAT ERA+ CELLS IN THE MEPD ARE NECESSARY FOR STATUS- DEPENDENT DIFFERENCES IN STRESS-RELATED BEHAVIOR IN FEMALE HAMSTERS. WE WILL USE A CRE-DEPENDENT AAV VECTOR THAT EXPRESSES A SHORT HAIRPIN RNA (SHRNA) FOR AR TO SELECTIVELY KNOCKDOWN AR RECEPTORS IN A MEPD-BNSTP PATHWAY. IN ADDITION, WE WILL USE AN AAV-SHRNA TO KNOCKDOWN ERA RECEPTORS IN THE MEPD IN A NON-CRE- DEPENDENT MANNER IN BOTH FEMALES AND MALES. OVERALL, THIS PROJECT WILL INVESTIGATE THE CELLULAR MECHANISMS AND NEURAL CIRCUITS BY WHICH GONADAL STEROID HORMONE RECEPTORS CONTRIBUTE TO STATUS-DEPENDENT CHANGES IN STRESS VULNERABILITY. THIS LINE OF RESEARCH WILL DETERMINE HOW SOCIAL EXPERIENCE GENERATES NEURAL PLASTICITY IN SELECT NEURAL ENSEMBLES AND THEREBY CHANGES STRESS VULNERABILITY IN A SEX-DEPENDENT MANNER.