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1/1 U24 NADIA Administrative Core

Principal Investigator: Fulton T. Crews, Ph.D., University of North Carolina at Chapel hill
Co-Investigator: Donita L. Robinson, Ph.D., University of North Carolina at Chapel Hill


This is the second renewal of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) Administrative Core (NADIA Administrative Core-U24, RFA-AA-20-004). The Administrative Core provides organizational and scientific leadership to achieve the goal of our Consortium: to elucidate persistent changes in complex brain function-behavior relationships following adolescent alcohol exposure. Adolescent binge and extreme drinking are common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure on the brain and behavior during this crucial developmental period. In the previous funding periods, the NADIA discovered that adolescent intermittent ethanol (AIE) led to multiple behavioral, neurochemical and physiological pathologies in adulthood. Mechanistic studies revealed that these AIE-induced changes could be prevented or re-versed by targeting specific neurotransmission, neuroinflammation, or epigenetic regulation of genes. The Consortium has been very productive, as evidenced by our recent literature reviews and over 200 publications. To promote and facilitate continued progress, the NADIA Administrative Core is the main organizational unit of the Consortium and serves as the liaison between the Scientific Core, the eight Research Components, the NADIA Steering Committee, the External Advisory Board, and the NIAAA. The Administrative Core organizes all Consortium activities including retreats, progress reports and External Advisory Board evaluations of cores and components. The Administrative Core ensures consistent and forward progress by facilitating communication and promoting integration of data among the components and cores. The Core develops scientific and conceptual themes as well as recommended operating procedures that cross components. The Core provides a repository for all publications generated by the Consortium. Finally, the Core facilitates dissemination and translation of NADIA-generated data, in part by targeted interactions with the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) and other alcohol research groups. This NADIA renewal exactly fulfills the molecular mechanism and translation goals of this RFA leading to development of therapeutic interventions of adult psychopathologies of adolescent alcohol consumption. Understanding the impact of underage drinking on adult neurobiology is important to guide public health initiatives, and the NADIA Administrative Core creates synergies for such discoveries across the Consortium.


Specific Aims:

The NADIA Administrative Core provides leadership by communication, discussion, and hypothesis development. It encourages collaboration and inspires integration and discovery across eight research Components and through the development of Cores. This NADIA renewal builds upon discoveries that have demonstrated that adolescent intermittent ethanol (AIE) exposure causes long-lasting changes in adult brain molecular, cellular, physiological and psychological measures that persist into adulthood, long after AIE exposure. Many of these changes are hypothesized to occur through neuroimmune and epigenetic gene regulatory mechanisms which is why, in this renewal, our Scientific Core will have a strong focus on epigenetic measures. A major crosscutting theme, supported by the Epigenetic/Molecular Scientific Core, is that many AIE-induced neural pathologies occur through persistent epigenetic gene enhancing/silencing mechanisms, particularly in neuroimmune and neurotransmitter pathways. Additionally, it is posited that these changes may in fact be preventable or reversible by understanding and addressing the causes of AIE pathology. In the first 10 years of NADIA funding, the goal was to determine if AIE exposure altered adult neurobiology. NADIA Investigators discovered that AIE caused: persistent anxiety-like behavior, reduced cognitive flexibility, sleep disruption, increased impulsivity, and risky decision-making strategies in adulthood. We also found that AIE promoted increased alcohol drinking, blunted extinction of operant drinking, and decreased alcohol sensitivity in adulthood. These behavioral outcomes were found to be associated with a number of molecular changes in neurons, microglia, and astrocytes that included markers of neurotransmitter changes (particularly choline acetyltransferase). These findings firmly established that AIE is linked to lasting adult brain pathology.

This renewal integrates 5 existing, productive Components that have honed their aims to include mechanism-driven hypotheses as well as robust behavioral and physiological endpoints. It also includes 2 new Components that will address exciting and novel additional measures and hypotheses. Across the Consortium, we continue to investigate the mechanisms underlying AIE effects by using new technologies and experimental designs with precise pharmacological and Core-provided CRISPR/dCAS9 epigenetic gene-editing tools. All projects also consider the role of sex in AIE-induced pathology. Specific hypotheses of individual Components are complemented by collaborations across the NADIA that integrate and extend Component findings to converge upon common, robust discoveries, with an eye toward translatable measures that can inform clinical research. Further, the Administrative Core promotes these translational studies and experimental designs by holding joint retreats with the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), an NIAAA-funded human adolescent alcohol research consortium.

The Administrative Core continues to coordinate and support research through the following specific aims:

Aim 1. To provide administrative leadership to the NADIA Consortium. The Administrative Core is the liaison between the Research Components, the NADIA Executive Committee, and the External Advisory Board (EAB), and the NIAAA. This Core organizes Consortium activities including retreats, progress reports, EAB evaluations of Cores and Components, as well as coordinating the Epigenetic/Molecular Scientific Core. The Administrative Core provides public access to NADIA publications via a central repository and supports data-sharing with the scientific community. The Core, along with NIAAA, responds to requests for information from NIH, other governmental units, media, and community, and supports the dissemination of research to stakeholders in adolescent health.

Aim 2. To provide scientific leadership, guiding integration of NADIA discoveries into new emerging themes, Components, and Cores. The Administrative Core develops scientific and conceptual themes and provides scientific leadership by communication, symposium organization, hypothesis development, encouraging collaboration and replication, and writing reviews, as well as by inspiring integration and discovery across eight research Components and the Scientific Core. Frequent presentation of cutting-edge discoveries, accomplished through monthly online “lab meetings,” annual retreats, and ad hoc meetings at scientific conferences, informs faculty and promotes discoveries. Joint retreats with NCANDA assure discussions of human relevance and create translation opportunities.

The NADIA Administrative Core creates synergies for discoveries across the Consortium and disseminates these discoveries to the broader scientific community and the general public.