Project Summary: Adolescents’ overwhelming drug of choice is alcohol, and when they drink, it is in binges, consuming more than four drinks in a few hours. Ongoing frontal cortex development makes adolescent drinkers particularly vulnerable to long-term consequences of binge ethanol. Early alcohol use is associated with cognitive impairments, reduced white matter content, and synaptic pruning in the frontal cortex. The risk for developing an alcohol use disorder increases the younger one begins to drink. However, the molecular mechanisms underlying alcohol-induced persistent changes in prefrontal cortex development are not fully understood. We recently reported that adolescent binge ethanol altered ethanol sensitivity and increased cognitive deficits that persist into adulthood. These behavioral changes were accompanied by reduced expression of genes responsible for regulating histone methylation and myelination, suggesting that binge ethanol alters the transcriptional landscape and the development of myelin in the frontal cortex. This proposal will test the hypothesis that regulation of histone methylation by binge ethanol may be a mechanism underlying the reduction of myelin in the frontal cortex and consequent behavioral changes that persist into adulthood. This proposal will test these hypotheses using chromatin immunoprecipitation coupled with massively parallel RNA- sequencing to identify the epigenetic loci and concurrent gene expression profiles altered by adolescent binge ethanol and transcript profiles that persist into adulthood. We will first characterize the trajectory of ethanol’s insults on oligodendrocyte development using a time course and dose response in adolescents. We will investigate the role of histone methylation on oligodendrocyte maturation by directly interrogating the responsible genes in oligodendrocyte-enriched cell populations in the frontal cortex. Finally, we will mechanistically test the effects of modulating histone methylation levels using viral vector delivery to rescue the adult cognitive and ethanol sensitive behaviors. These studies will use developmental and sex dependent models to perform a combined epigenetic, genomic, and behavioral analysis of the response to adolescent ethanol exposure. Our goals in this proposal are to identify the mechanisms underlying the immediate and long lasting transcriptional changes in the PFC and determine their contributions to the persistent cognitive deficits and increased ethanol sensitivity resulting from binge ethanol during adolescence. These studies will begin to identify and mechanistically test possible novel therapeutic targets for intervention in early alcoholism or alcohol-related neurological disease.