Project Grant R21MH133108

POSTERIOR HYPOTHALAMIC CONTRIBUTION TO STRESS ADAPTATION - PROJECT SUMMARY THE OVERALL AIM OF THIS PROJECT IS TO DETERMINE THE CONTRIBUTION OF THE ROSTRAL REGION OF THE POSTERIOR HYPOTHALAMIC NUCLEUS (RPH) IN STRESS ADAPTATION. MORE SPECIFICALLY, STRESS HABITUATION IS DEFINED AS A PROGRESSIVE REDUCTION IN RESPONSES UPON REPEATED EXPOSURES TO THE SAME (HOMOTYPIC) STRESSOR. PSYCHOLOGICAL OR "EMOTIONAL" STRESSORS ELICIT A RANGE OF BEHAVIORAL, AUTONOMIC, AND NEUROENDOCRINE RESPONSES THAT NORMALLY HELP ORGANISMS COPE WITH PERCEIVED OR ACTUAL THREATENING SITUATIONS. HOWEVER, PROLONGED, UNABATED AND CHRONIC STRESS EXPOSURE IS FREQUENTLY ASSOCIATED WITH THE DEVELOPMENT, PRECIPITATION, OR EXACERBATION OF SEVERAL PSYCHOPATHOLOGIES AND PHYSICAL DISORDERS. THE SUSTAINED ACTIVATION OF STRESS RESPONSIVE SYSTEMS CAN NEGATIVELY AFFECT PHYSIOLOGIC FUNCTIONS AND ULTIMATELY, SURVIVAL. THUS, THE REDUCTION OR INHIBITION OF STRESS-ELICITED RESPONSES AFFORDED BY HABITUATION IS LIKELY A VITAL MECHANISM SERVING TO REDUCE THE CUMULATIVE IMPACT OF THE SAME STRESSORS EXPERIENCED REPEATEDLY. IMPORTANTLY, IMPAIRED HABITUATION HAS BEEN REPORTED IN SEVERAL HUMAN CLINICAL POPULATIONS INCLUDING ANXIETY AND MOOD DISORDERS. UNFORTUNATELY, THE NEURAL MECHANISMS RESPONSIBLE FOR STRESS HABITUATION ARE STILL ILL- DEFINED, WHICH MAKES IT CURRENTLY IMPOSSIBLE TO EVALUATE THE CONTRIBUTION OF HABITUATION IN PSYCHOPATHOLOGIES. IN THIS APPLICATION, ROBUST HABITUATED NEUROENDOCRINE, AUTONOMIC AND BEHAVIORAL RESPONSES WILL BE OBTAINED TO REPEATED HOMOTYPIC STRESS PARADIGMS THAT WILL TEST THE RESPONSE SPECIFICITY AND GENERALITY OF THE PROPOSED BRAIN MANIPULATIONS. BASED ON DETAILED ANATOMICAL AND FUNCTIONAL RESULTS FROM OUR LABORATORY, EMPHASIS WILL BE PLACED ON THE ROLE OF THE RPH IN THE ACQUISITION OF STRESS HABITUATION. ANATOMICALLY, THE RPH IS LOCATED AT A FOCAL INTERSECTION BETWEEN SEVERAL SENSORY, LIMBIC FOREBRAIN, AND EFFECTOR RESPONSE SYSTEMS ACTIVATED BY VARIOUS STRESSORS, PLACING IT IN A UNIQUE POSITION TO UNDERGO HABITUATION-RELATED PLASTICITY THAT CAN REGULATE COORDINATED RESPONSES TO STRESS. THE FIRST AIM IS THEREFORE DIRECTED AT EVALUATING THE NOVEL HYPOTHESIS THAT THE RPH REGION, AND SOME OF ITS SPECIFIC CELL POPULATIONS, CONTRIBUTE TO THE ACQUISITION OF STRESS HABITUATION. AIM 2 SEEKS TO EVALUATE THE POSSIBILITY THAT INTRINSIC RPH NEURAL ACTIVITY IS MODIFIED BY REPEATED HOMOTYPIC STRESS. THROUGHOUT THESE AIMS, BOTH FEMALE AND MALE RATS WILL BE EVALUATED FOR PUTATIVE RPH-RELATED DIFFERENCES IN STRESS ADAPTATION DUE TO THE DIFFERENTIAL PREVALENCE OF GENDER TO ANXIETY AND MOOD DISORDERS AND THE WIDELY REPORTED SEX DIFFERENCES IN HABITUATION TO STRESS. THE PROPOSED ANATOMICAL, FUNCTIONAL AND BEHAVIORAL ANALYSES OF THE RPH IN STRESS ADAPTATION THROUGH HABITUATION IS NOVEL AND WILL PROVIDE CONVERGING EVIDENCE IMPLICATING THIS BRAIN REGION IN STRESS ADAPTATION AND ITS SEQUELAE.