Project Grant F31AA033558

EARLY LIFE STRESS EFFECTS ON INSULA FUNCTION AND ALCOHOL USE DISORDER VULNERABILITY - PROJECT SUMMARY EARLY LIFE STRESS (ELS) AND ALCOHOL USE DISORDER (AUD) ARE PREVALENT IN THE U.S. COLLECTIVELY ATTRIBUTING SUBSTANTIAL FINANCIAL BURDEN. WITH NEARLY 60% OF AMERICANS REPORTING THE EXPERIENCE OF ADVERSE CHILDHOOD EVENTS (E.G., RESOURCE SCARCITY, ABUSE) IT IS IMPERATIVE TO INVESTIGATE THE BASIC MECHANISMS DRIVING ELS- INDUCED AUD VULNERABILITY. A POSITIVE RELATIONSHIP BETWEEN THE NUMBER OF STRESSORS AND RISK FOR AUD HIGHLIGHTS THE ROLE OF STRESS SYSTEMS TO MODULATE AUD SUSCEPTIBILITY IN THE ELS POPULATION. TO BRIDGE THE KNOWLEDGE GAP OF HOW THESE DYSREGULATED SYSTEMS RELATE TO FUTURE AUD VULNERABILITY, WE NEED LONGITUDINAL STUDIES THAT CAN TRACK THE DYSFUNCTIONAL NEURAL MECHANISMS ASSOCIATED WITH ELS. RESOURCE SCARCITY IS A PROMINENT EARLY LIFE STRESSOR IN THE HUMAN POPULATION THAT CAN BE TRANSLATED TO RODENT MODELS. THE LIMITED BEDDING AND NESTING (LBN) RESOURCE SCARCITY RODENT MODEL IMPLEMENTS STRESS DURING THE HYPORESPONSIVE STRESS CRITICAL DEVELOPMENTAL PERIOD THAT ALLOWS FOR THE INVESTIGATION OF ELS EFFECTS ON NEURODEVELOPMENT. ELS INCREASES THE RISK OF STRESS SUSCEPTIBILITY MODULATED BY HYPOTHALAMIC AND AMYGDALA DYSREGULATION. AT A SYSTEMATIC LEVEL, ELS INDUCES GABA SYSTEM DYSREGULATION, PROMOTING HYPEREXCITABILITY. THOUGH STUDIES HAVE CHARACTERIZED BASIC MECHANISMS DRIVING ELS-INDUCED STRESS SUSCEPTIBILITY, THE MECHANISM DRIVING ELS-INDUCED DRINKING BEHAVIOR IS UNCLEAR. THIS PROPOSAL INVESTIGATES THE GABA SYSTEM TO UNCOVER THE LINK BETWEEN ELS-INDUCED NEURODEVELOPMENTAL CHANGES AND DRINKING BEHAVIOR IN ADULTHOOD. WE FOCUS ON INVESTIGATING GABAERGIC SIGNALING IN THE INSULAR CORTEX (INSULA), AN INTEGRATIVE REGION INTEGRAL IN SALIENCE PROCESSING AND INFLUENCING STRESS AND EMOTIONAL RESPONSES. THIS REGION OFFERS NOVEL INSIGHT INTO HOW ELS INFLUENCES AUD-RELATED BEHAVIOR, REVEALING A POTENTIAL TARGET FOR TRACKING THE PROGRESSION OF ELS-INDUCED AUD VULNERABILITY. BY 1) UNCOVERING THE EFFECTS OF ELS ON INSULAR DEVELOPMENT AND MATURATION, 2) ASSESSING ELS EFFECTS ON ETHANOL-INDUCED INHIBITION, AND 3) MEASURING GABA RELEASE DURING BINGE DRINKING, WE WILL UNCOVER GABA'S ROLE IN ELS-INDUCED AUD VULNERABILITY. WE POSIT ELS TO DEVELOPMENTALLY DYSREGULATE GABA SIGNALING RESULTING IN HYPEREXCITABILITY IN THE INSULA THAT DRIVES HYPOSENSITIVITY TO ETHANOL AND INCREASE BINGE-DRINKING IN ADULTHOOD. OVERALL, THIS PROPOSAL WILL DEEPEN OUR UNDERSTANDING OF THE ACUTE AND CHRONIC EFFECTS OF ELS, ENLIGHTENING THE FIELD WITH NEW TARGETS FOR AUD PREVENTION.