PROJECT SUMMARY Alcohol use disorder (AUD) affects about 16 million people in the United States. Unfortunately, despite the few currently-available treatments, the rate of relapse is extraordinarily high. Stress is a common trigger of relapse; therefore it is a prime target for AUD treatment. This proposal will investigate the combined effects of stress and alcohol use on neurocircuitry in the limbic system, the primary group of structures involved in emotional processing. The first specific aim of this proposal is to test the hypothesis that stress and ethanol interact to promote beta2-adrenergic receptor (b2-AR) signaling in the bed nucleus of the stria terminalis (BNST) and increase voluntary ethanol intake. This will be tested using whole-cell patch-clamp electrophysiology, chemogenetic manipulations of BNST neurons, and fluorescent in situ hybridization. The second aim is to test the hypothesis that targeting glucocorticoid receptor (GR)-mediated signaling in the BNST will mitigate b2-AR dependent behavioral and neurocircuit changes following stress and ethanol intake. This will be achieved through chromatin immunoprecipitation (ChIP), electrophysiology, and pharmacological manipulations of the GR. Keeping consistent with the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), this research proposal will investigate alcohol’s effect on health and well-being by identifying neurocircuitry differences between stress and alcohol-exposed mice and naïve mice. Ultimately the findings from these studies will help when developing prevention and treatments for stress-related alcohol use disorder.