Adolescent alcohol exposure: impact on neuronal activation, steroids, and metabolomic profiles

Scientific Abstract Alcohol use disorders are a major public health concern afflicting approximately 17 million Americans, often beginning with binge drinking during adolescence. In recent years drinking in adolescent females has surpassed that of adolescent males. However, the sex-specific neurobiological mechanisms underlying the impact of adolescent binge drinking are not well understood. We have previously shown sex-specific changes in behavioral and brain protein changes following adolescent intermittent ethanol (AIE) exposure. In the proposed work, we focus on sex steroid regulation of neuronal activation with a particular emphasis on the medial prefrontal cortex. Sex steroids are critically important for pubertal hormonal function and is altered by early alcohol exposure. Specifically, we examine the long-lasting sex-specific changes induced by AIE exposure with withdrawal in male and female mice. If binge alcohol exposure changes normal adolescent brain development, alterations in neuronal activation in sex steroid containing neurons likely plays an important role in the lasting effects of adolescent binge alcohol exposure and increased susceptibility to development of an alcohol use disorder. Aim 1 will determine (1) sex-specific and time-dependent changes in neuronal activation and steroid receptors in mesocorticolimbic brain structures after withdrawal from AIE and ethanol re-exposure. Aim 2 will determine sex- specific and time-dependent changes in metabolomic and sex steroid profiles after withdrawal from AIE and ethanol re-exposure. Aim 3 will determine if activation/inhibition of medial prefrontal cortex (mPFC) after AIE exposure impacts subsequent ethanol drinking. Completion of this work will elucidate short- and long-term impacts of adolescent ethanol exposure on neuronal activity in steroid receptor containing neurons in mesocorticolimbic regions, metabolic and sex steroid profiles, and prefrontal regulation of subsequent ethanol drinking behavior.