ABSTRACT The goal of this proposal is to investigate the role of the gut microbiota in alcohol seeking and reward-related decision-making. Alcohol is the leading risk factor for premature death and disability for individuals between 15 and 49 years old, accounting for 3 million deaths worldwide yearly. Chronic alcohol consumption results in escalated alcohol seeking and impaired reward-related decision-making, which are core factors in perpetuating alcohol consumption. Mounting evidence supports a role for the gut microbiota in alcohol consumption. However, the role of the gut microbiota in alcohol seeking and in reward-related decision-making have not been systematically evaluated. Prebiotics, indigestible fibers that feed beneficial gut microbes, ameliorate alcohol- induced damage to the intestinal lining, enhance cognition, and may reduce alcohol withdrawal symptoms, suggesting that prebiotics may comprise a treatment target for the behavioral impact of alcohol. Here, we will use operant conditioning approaches in mouse models to dissect the role of the gut microbiota in alcohol seeking and alcohol-induced changes in reward-related decision-making. Aim 1 is to determine the role of the gut microbiota in alcohol seeking using prebiotics to alter the microbiota (Aim 1a) and fecal microbial transplant from prebiotic-receiving donor mice to determine a causal role for the microbiota (Aim 1b). Aim 2 is to determine the role of the gut microbiota in alcohol-induced changes in reward-related decision-making. To test this, mice will perform a novel, multi-stage decision-making task that we adapted directly from a human task to assess reward- related decision-making using computational modeling. Mice will receive prebiotics (Aim 2a) or fecal transplant from prebiotic receiving donors (Aim 2b) to determine whether prebiotics ameliorate alcohol-induced changes in decision-making, and whether these effects are mediated by the gut microbiota. The profile of the gut microbiome will be assessed using metagenomic sequencing and bioinformatics to determine what aspects of behavior, intestinal permeability, and inflammation correlate with the gut microbiota. Completion of these aims will test the feasibility of mitigating alcohol seeking and decision-making impairments by manipulating the gut microbiota using a putative alternative treatment target and determine whether the gut microbiota play a causal role. Dr. Thompson’s main career goal is to investigate the potential of the gut microbiota to provide alternative treatment options for psychiatric disorders. The proposed aims will provide Dr. Thompson with crucial training, research experience, and data that will advance this career goal. Dr. Thompson’s integrated mentorship team is comprised of experts in addiction models, clinical and translational alcohol research, host-microbe interactions, and computational modeling of decision-making, ensuring successful completion of the research and training aims. Dr. ...