2/8 NADIA U01 Adolescent Alcohol Exposure Neural Contributors to Sex-and Exposure Timing-Specific Anxiety

Project Summary Our current work in the NIAAA consortium on the Neurobiology of Adolescent Drinking in Adulthood (NADIA) has revealed that long-lasting behavioral consequences of adolescent intermittent ethanol exposure (AIE) are sex- and exposure timing-dependent. When tested in adulthood, only male rats exposed to ethanol during early-mid adolescence (early AIE) demonstrate social alterations that include social anxiety and enhanced sensitivity to ethanol-induced social facilitation, with exposure to ethanol later in adolescence (late AIE) having no such consequences. Our most important translational finding is that a selective oxytocin receptor (OXTR) agonist reverses the male-specific social anxiety. At the cellular and molecular levels, sex-specific consequences of early AIE are evident as alterations in dendritic spine morphology and decreases in OXTR mRNA and protein expression in the hypothalamus. Our current proposal will address critical gaps arising from this work. Aim 1 will identify socially relevant regions differentially activated in adult males and females by social stimuli following early AIE and will test whether recruitment of neuronal ensembles in identified brain regions is required for male-specific social affective alterations. Aim 2 will further assess AIE-induced alterations of the OXT system contributing to male-specific social anxiety and will investigate neural mechanisms underlying the reversal effects of OXTR pharmacological activation. Aim 3 is designed to test whether AIE selectively disrupts epigenetic regulation of the OXT neuromodulatory peptide system in brain regions critical for normal social functioning.