Neuromolecular consequences of adolescent binge drinking

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According to the CDC, “binge drinking is the most common, costly and deadliest pattern of alcohol use”. The adolescent period is marked by formative changes in neuronal structure and function; therefore, alcohol abuse during this vulnerable time period can result in permanent neurological damage and adult behavioral deficits. Our research and others from the past decade have described numerous long-lasting and transgenerational neurobiological consequences that can result from adolescent binge drinking. However, the molecular mechanism of how EtOH exerts immediate effects on the cellular microenvironment to perpetuate these long- term effects have not been fully ascertained. EtOH can readily enter cells and immediately activate the cellular stress response, which can then impact transcriptional and translational processes as well as post-translational modifications of existing proteins. We predict these immediate EtOH-induced effects on the cellular environment prime the cell to drive the long-term changes we and others have observed. This proposal is a competitive renewal and this next phase of the project will mechanistically define how EtOH induced modifications to the glucocorticoid receptor (GR), which then impacts long-term GR function. GRs sit at a pivotal interface to direct long-lasting changes in the cellular transcriptome and proteome, as they are the core molecular mediators of the systemic and cellular stress response. Our published and preliminary data suggest that these key mediators of cellular homeostasis are vulnerable to perturbations by EtOH, especially during adolescence. Aim 1 will determine by absolute quantification the amount of phosphorylated GR (pGR) in the brain using our in vivo model of adolescent repeated binge EtOH exposure and mechanistically link GR phosphorylation with long-term HPA axis dysfunction. In addition, we will investigate novel post-translational modifications to GR that are induced by adolescent binge EtOH exposure. Aim 2 will determine the suite of proteins interacting with pGR at specific target genes and identify how EtOH disrupts these GR-protein association. Aim 3 will investigate how EtOH induces alternative GR mRNA splicing and the mechanisms regulating splicing. Understanding these fundamental molecular changes could uncover novel therapeutic targets that may prevent dysregulated cellular signaling leading to behavioral abnormalities later in life.