Project Summary/Abstract Alcohol use disorder (AUD) is associated with high morbidity and mortality, but only limited treatment options currently exist. Craving (i.e., desire, urge, want) for alcohol predicts alcohol relapse, and is a diagnostic criterion for AUD. This proposal uses a well-established procedure, i.e., cue-elicited alcohol craving in a bar- like setting to evaluate the effects of environmental enrichment on alcohol craving. Environmental enrichment refers to a novel and complex environment that produces multisensory stimulation to an organism. The effects of an enriched environment have been almost exclusively studied in animal models. Rodent models of environmental enrichment show that it attenuates measures of depressive- and anxiety-like behaviors, as well as alcohol consumption and self-administration. As such, environmental enrichment has therapeutic potential, possibly in combination with pharmacotherapies, for AUD. Studying the effects of environmental enrichment in a controlled and rigorous manner in humans to draw causality has been challenging. As such, this proposal seeks to develop and validate a virtual reality-based protocol for testing the effects of environmental enrichment in people with AUD and heathy controls in a controlled, inpatient setting (Aim 1). Next, we propose to use this protocol to test the effects of environmental enrichment on alcohol craving, using the alcohol cue reactivity procedure (Aim 2). Finally, we will take an unbiased approach to initiate the investigation of potential biological mechanisms underlying the effects of environmental enrichment, using RNA-sequencing (Aim 3). Gene ontology analysis will be used to focus analyses on the brain-derived neurotrophic factor (BDNF) signaling pathways. We predict that virtual reality can be used to generate a reliable protocol for environmental enrichment in humans. Furthermore, we predict that people with AUD will show greater cue-elicited craving for alcohol, and that environmental enrichment will attenuate craving for alcohol. Furthermore, we predict that AUD will be associated with altered gene expression related to BDNF signaling pathways, which will be in part remediated following exposure to environmental enrichment. This proposal will set the stage for well-controlled investigation of environmental enrichment in humans (Aim 1) and will be the first to rigorously test the effects of environmental enrichment on alcohol craving in people with AUD (Aim 2). Finally, this proposal also generates preliminary data to begin investigating the molecular effects of environmental enrichment in humans (Aim 3).