Modeling alcohol exposure in gestation and adolescence

Abstract The CDC reports that ~10% of pregnant women drink alcohol (exposing the fetus to prenatal alcohol exposure) as do ~26% of 12th grade students (adolescent alcohol exposure). Either exposure alone induces a variety of persistent outcomes in cognition and proinflammatory signaling in humans and animal models. Prenatal alcohol exposure is a risk factor for adolescent and adult drinking, adolescent drinking is a risk factor for adult drinking, and adult drinking is a risk factor for prenatal alcohol exposure, thereby creating a cycle of exposure and use that can perpetuate alcohol use disorder and harmful drinking across the lifespan. Emerging studies show that two developmental insults (“double-hit”) in an individual exacerbate outcomes. We propose to test the hypothesis that the “double-hit” of prenatal + adolescent alcohol exposure worsens cognitive outcomes in rodent models and to investigate two potential mechanisms that underlie these effects: loss of the cholinergic neurons in the basal forebrain that are critical for cognition and gliosis indicative of neuroinflammatory priming. Dr. Mooney’s lab has experience with the prenatal alcohol exposure model and studying gliosis and Dr. Robinson’s lab has experience with the adolescent alcohol exposure model and the role of acetylcholine-positive neurons. This project will generate the “double-hit” model of prenatal + adolescent alcohol exposure in mice and rats. After phenotyping the effect of exposure on cognitive behavior, brain sections will be assessed for differences in cholinergic and glial phenotype. The models developed in this proposal will be of use to us and other researchers to investigate mechanisms that underlie or contribute to the cycle of alcohol use and exposure across the lifespan, and understanding the mechanisms will allow identification of therapeutic targets and optimal windows for interventions to break the cycle.