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Overview and Goals

UNC Alcohol Research Center

MOLECULAR AND CIRCUIT PATHOGENESIS OF ALCOHOL USE DISORDER

The 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 Thurston-Bowles Building space for alcohol research. The UNC-ARC fosters interdisciplinary collaborative research on alcohol addiction, 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 the BCAS into an outstanding alcohol research organization, among the best in the world. Research and training in the BCAS have always centered on a theme of molecular and cellular pathology in alcohol use disorders. Since 2016, we shifted our focus to the molecular mechanisms of alcohol-induced circuit pathology across the stages of addiction. Ultimately, our guiding hypothesis is that alcohol-induced dysregulation of neural circuitry and its molecular underpinnings drive pathological behaviors and are the key to finding effective treatments for alcohol-related disease.

This fifth renewal of the UNC-ARC continues an emphasis on alcohol use disorder pathology, integrating existing and new faculty with existing and new leadership. Drs. Thomas Kash and Leslie Morrow now lead the ARC as Co-PDs, while Drs. Clyde Hodge and Fulton Crews serve as Co-Scientific Directors. Dr. Leon Coleman joins the faculty Pls as Co-Pl with Dr. Joyce Besheer in Component 2. Dr. Melissa Herman leads Component 4 with Dr. Leslie Morrow as Co-Pl. New proposed studies in this ARC renewal will investigate changes in neural circuits and molecular signaling in male and female models of drinking across the stages of addiction. We will broadly test the conceptual model that altered signaling in discrete neural circuits drives specific pathological behaviors associated with discrete models of alcohol exposure. The scope of these studies addresses the critical neurobiological changes leading to all alcoholic pathologies, i.e., the mechanisms leading to heavy chronic drinking in males and females. The ARC studies the integration of multiple signaling systems and neurocircuits that address pathological mechanisms within and across brain regions. The Research Components will also include the translational endpoint, resting-state functional magnetic resonance imaging (rsfc-MRI) assessments within and across multiple pathological circuits. This is critical, as it provides the means to translate and reverse-translate circuit pathology across species – from humans to rodents and vice versa. This approach is expected to increase discovery, improve animal models and gain relevance from common assessments across preclinical models to the ARC human studies. The UNC-ARC continues to be the catalytic element that integrates a broad group of UNC investigators, pairing faculty within ARC components and across leadership roles to promote discovery and collaboration across the BCAS and UNC.

The following Specific Aims guide and integrate the overall efforts of this ARC:

  1. To investigate neural circuit and molecular mechanisms of the pathogenesis of alcohol use disorder. This proposal connects 11 principal investigators with independent funding in a collaborative effort to solve the problem of alcohol addiction. By design, each Research Component of this ARC will focus on specific models that capture distinct endophenotypes associated with alcohol abuse. A range of molecular mechanisms that drive circuit alterations will be explored, focusing on shifts in balance of excitation and inhibition in discrete cell types. By conducting focused investigations that integrate neurocircuitry and molecular signaling mechanisms across brain regions, the ARC creates synergies that promote and catalyze discoveries.
  2. To disseminate scientific information on alcohol to the public, youth, adolescents and health professionals. The ARC leads the state in alcohol education efforts. To have the greatest impact on health, the ARC informs practicing health professionals, health professional students and youth through specific curricula for each group.

This UNC-ARC proposal continues a research focus on pathogenesis of alcohol addiction with an emphasis on molecular and circuit mechanisms that lead to dysfunctional brain networks, a theme at the cutting edge of neuroscience. The UNC-ARC will conduct, promote, support, and mentor research on the pathology of alcohol use disorders and educate broad groups of the public, including health professionals, families, college students and youth in North Carolina on the causes and prevention of these disorders.