PROJECT ABSTRACT This Ruth L. Kirschstein PreDoctoral Individual National Research Award describes a research and training program that will prepare the applicant, Dylan Kirsch, for a career as an independent research scientist focused on the role of psychiatric illness in alcohol use disorders. The proposed research plan will test neurobiological mechanisms that contribute to altered sensitivity to alcohol in bipolar disorder and typically developing young adults. Differences in subjective response to alcohol predict alcohol use problems and risk for alcohol use disorders in typically developing youth, however the mechanisms that contribute to this risk—or if similar mechanisms are observed—in psychiatric illness are unclear. We will test the hypothesis that structural connectivity within ventral prefrontal cortical networks is related to alcohol-induced changes in network functional connectivity, and therefore, subjective sensitivity to alcohol. Results from the project have the potential to inform our understanding of neurobiological mechanisms that contribute to risk for alcohol use disorders in bipolar disorder and typically developing young adults. The applicant and mentors, Drs. Elizabeth Lippard and Kim Fromme have designed a comprehensive research and training plan to test this hypothesis. The training plan emphasizes 1) conceptual training in the neurobiological mechanisms and clinical issues in bipolar and alcohol use disorders; 2) methodological training in advanced neuroimaging (functional connectivity and diffusion tensor imaging [DTI] methodology) and placebo-controlled alcohol administration; and 3) career development skills, including mentorship, statistics, teaching, writing, and responsible conduct of research. Research aims are to 1) determine if changes in ventral prefrontal network functional connectivity in response to alcohol—during emotional processing—are different in bipolar disorder, compared to typically developing young adults, and if alcohol-induced changes in functional connectivity within these networks relate to subjective response to alcohol; and 2) if structural connectivity within ventral prefrontal networks relates to subjective response to alcohol and alcohol-induced changes in functional connectivity. Young adults (ages 21-26) with bipolar disorder and typically developing controls (n=30 per group) will complete DTI at baseline and functional MRI during placebo-controlled laboratory alcohol administration sessions (within subject, counter-balanced). We predict alcohol will weaken functional connectivity in the ventral prefrontal network and that magnitude of change will be smaller in bipolar disorder, compared to controls, with smaller magnitude of change associated with lower subjective response to alcohol. We predict weaker structural connectivity will relate to lower subjective response to alcohol and smaller alcohol-induced changes in functional connectivity in both groups. Findings will aid in our unde...