Project Summary Alcohol Use Disorder (AUD) is a major public health problem within the United States. Alcohol is the third leading cause of preventable death in the country and nearly 6% of the adult population meets criteria for an AUD. Unfortunately, due to the complex relationship between genetics and environment which contribute to the development of AUD, the mechanisms behind its etiology remain unclear. This project aims to elucidate the role of glycogen synthase kinase 3 beta (GSK3B) in modulating ethanol behaviors. Previous research has revealed Gsk3b to be a hub gene in a network highly regulated by ethanol in the mouse medial prefrontal cortex (mPFC). In response to acute ethanol, GSK3B undergoes inhibitory phosphorylation in both the mPFC and nucleus accumbens (NAc). Additionally, studies on rodent drinking behavior have demonstrated pharmacological inhibition of GSK3B decreases ethanol consumption. Gene targeting studies have further implicated GSK3B in an ethanol-response pathway, showing knock-out decreases ethanol consumption while overexpression produces an increase. The exact cell type specificity behind this response is yet unknown, however evidence suggests deletion of GSK3B within CamKIIa+ cells of the entire forebrain is capable of decreasing drinking behavior. This proposal seeks to increase our knowledge on the critical cell type behind this response by more specifically targeting CamKIIa+ cells exclusively within the mPFC. Additionally, it is our hypothesis that GSK3B’s response to ethanol occurs within a circuit between the NAc and PFC to regulate ethanol behaviors. Finally, we seek to investigate how adaptations of the GSK3B response within this circuit during the shift from acute ethanol exposure to chronic drinking may be contributing to the development of progressive ethanol consumption.

Project Narrative Nearly 6% of the US adult population meets criteria for Alcohol Use Disorder (AUD), yet few effective, long- term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3B) has been implicated in ethanol behaviors through microarray, gene targeting, and pharmacological inhibition experiments, and as such poses as a potential therapeutic target in the treatment of AUD. We propose to further investigate the role of GSK3B in ethanol consumption by identifying precise cell types of interest and its regulation throughout the shift from initial ethanol exposure through progressive, chronic consumption.