Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral mechanisms of adult AUD

Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, molecular, and behavioral mechanisms of adult AUD Brian McCool, Kimberly Raab-Graham The neurobiological mechanisms controlling the transition from alcohol use to abuse are poorly understood. Our overall approach is to examine vulnerable populations to highlight specific cellular/molecular pathways involved in this transition. For example, human adolescents exposed to heavy alcohol use are at much greater risk for the development of alcoholism as adults. Recent studies suggest similar liabilities for adolescent animals including rodents. Our published work indicates chronic ethanol exposure differentially modulates both glutamatergic and GABAergic neurotransmission in the lateral/basolateral amygdala (BLA), a ‘node’ within circuits critical for the integration cognitive and sensory information during emotional responses, in an input- specific fashion. We provide preliminary evidence within this application that chronic ethanol differentially facilitates glutamatergic and GABAergic neurotransmission onto young adult BLA neurons projecting to the nucleus accumbens core (BLANAc cells) and those projecting to the bed nucleus of the stria terminalis (BLABNST cells). These effects are both input- and sex-specific. Together our findings strongly suggest that chronic ethanol differentially influences BLA neurons that control both reward- and aversion-like responses. The overall goal of the current project is to therefore to understand the neurobiological, molecular, and behavioral vulnerabilities of adolescent rats compared to mature adults. We will specifically test the central hypothesis that periadolescent vulnerability to chronic ethanol is conferred by unique neurobiological and molecular responses within distinct reward/aversion circuits. The proposed work includes three specific aims: Aim 1 will characterize age-dependent vulnerability of BLA neurophysiology within BLANAc and BLABNST neurons; Aim 2 will help us understand the molecular basis for adolescent circuit- and sex-specific vulnerability to chronic ethanol; and, Aim 3 will define the behavioral consequences of circuit- and sex-specific functional/molecular adaptations within the BLA. Together these aims are significant because they leverage a vulnerable population (adolescents), innovative technical and conceptual approaches, and the substantial expertise of our research team to help identify specific cellular signaling processes governing the impact of ethanol exposure across multiple levels of analysis. We will also directly test if these processes represent potential therapeutic targets for treatments designed to interrupt the transition from ethanol use to abuse.