Molecular and Circuit Pathogenesis of Alcohol Use Disorder This NIAAA Alcohol Research Center (ARC) Grant is the catalytic element that integrates a large group of investigators across the University of North Carolina at Chapel Hill (UNC). The UNC School of Medicine Bowles Center for Alcohol Studies (BCAS), provides a foundation of administrative support and dedicated space for alcohol research. The UNC ARC fosters interdisciplinary collaborative research on alcohol use disorders, alcohol abuse and the impact of alcohol on health and disease - exactly the goal of an NIAAA ARC. The ARC has facilitated the growth and development of UNC into an outstanding alcohol research university, among the best in the world. Research and education have always centered on a theme of molecular pathogenesis of alcohol use disorders. This renewal focuses on alcohol-induced circuit pathology that underlies addiction. Ultimately, our guiding hypothesis is that alcohol-induced molecular signaling disruption and dysregulation of neural circuitry drives pathological behaviors and is thus the key cause of all alcohol-related pathology. This fifth renewal of the UNC ARC continues an emphasis on alcohol use disorder pathogenesis, integrating new leadership of existing faculty and new team members to investigate changes in neural circuits and molecular signaling in models of AUD as well as humans. The scope of these studies addresses the critical neurobiological changes leading to alcohol-related pathologies, i.e., the mechanisms leading to heavy chronic drinking. The ARC integrates studies of multiple signaling systems and neurocircuits that each focus on specific mechanisms within and across brain regions. A range of molecular mechanisms that drive these circuit alterations will be explored, particularly excitatory/inhibitory (E/I) balance - a theme that will be interrogated at multiple levels of analysis in all the brain circuits. Some Research Components also include the translational endpoint, functional magnetic resonance imaging (fMRI) connectivity of pathological circuits in the Scientific Resource Core. This approach is expected to increase discovery, improve models and gain strength from common assessments across preclinical models to the ARC human studies. This ARC renewal continues to be the catalytic element that integrates a broad group of investigators, pairing senior and junior faculty within ARC components that promote discovery across the BCAS and UNC. This proposal connects 11 independently funded faculty across multiple themes and projects. The ARC Information Dissemination Core informs practicing health professionals, professional and college students as well as youth through specific alcohol curricula for each group to have the greatest impact on health. In summary, the ARC will conduct, promote, support, and mentor research on the pathogenesis of alcohol use disorders and educate broad groups of the public, including health professionals, families, co...