Chromatin remodeling in GABA neurons contributes to alcohol use disorder

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Alcohol misuse affects millions of people, resulting in numerous deaths each year. People who are resistant alcohol intoxication and sedation are more likely to consume high levels of alcohol (binge drinking) and are at higher risk of developing alcohol use disorder. One mechanism underlying the development of alcohol use disorder is neuronal plasticity, which involves the regulation of gene expression. How chromatin-mediated gene regulation in GABAergic neurons contributes to alcohol- induced sedation and tolerance is unknown. My preliminary data using Assay for Transposase- Accessible Chromatin by sequencing (ATAC-seq) shows that the chromatin landscape in GABA neurons is altered by alcohol exposure, particularly in genes associated with insulin receptor signaling. I propose to investigate relevant neuronal pathways identified by ATAC-seq to evaluate how chromatin remodeling affects alcohol sedation and tolerance. Further, my preliminary data indicate that alcohol alters gene regulation in GABA neurons, especially in genes that play a role in the insulin receptor pathway. Finally, I propose to identify GABA neuron subtypes and to develop genetic tools that allow subtype-specific manipulation, which will then be used to investigate how GABA neuron subtypes are involved in alcohol use disorders. These activities will identify potential therapeutic targets for alcohol use disorders. While I have experience in single-neuron physiology, I require additional training to become a successful independent investigator. Thus, my immediate career goals are to obtain extramural funding and produce manuscripts to establish expertise in alcohol-related research. My long-term career goals are to become an independent investigator and establish a successful research program investigating the role of GABAergic neurons in alcohol use disorder. This proposal leverages my previous training in single-neuron physiology and will provide extensive additional training in Drosophila model systems, the mechanisms of alcohol abuse, and bioinformatic analysis. I anticipate that each aim will produce at least two scientific manuscripts and will provide preliminary data for future R01 applications. Therefore, completing the activities proposed here will enable my transition to an independent principal investigator.