7/8 NADIA U01 Recovery of Adolescent Alcohol Disruption of Basal Forebrain-Cortical Projection Circuits

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Project Summary The requested Research Supplement to Promote Diversity in Health-Related Research will support the training of an outstanding Early Investigator developing an independent research career in the field of developmental alcohol and later brain pathology. Heavy alcohol consumption during adolescence is associated with persistent changes in brain structure, connectivity, and adult hippocampal and cortical-mediated cognitive functions. Enduring pathological changes consistently observed in rodent models of adolescent ethanol exposure (Adolescent Intermittent Ethanol; AIE) include reductions of nerve growth factor, suppression of the cholinergic phenotypes, changes in activity-dependent acetylcholine release, and blunted hippocampal neurogenesis. The current Supplement to Promote Diversity extends the research scope of the Parent Project by examining whether AIE increases amyloid-β (Aβ) hippocampal levels, serving as a synergistic mediator of cellular pathology. At high levels, Aβ also binds to the p75 neurotrophin receptor, contributes to cell death, and may predispose the brain toward an accelerated pathological response. Given that pathological Aβ release is activity-dependent, a novel γ-aminobutyric-acid type-A receptor modulator (GABAAα5) will be used to correct AIE- induced Aβ dysfunction. These research activities will expand the research experiences and scientific scope of the candidate. Specifically, the research plan will expose the candidate to developmental ethanol perspectives and several innovative technical approaches (in vivo brain activity; programming, data science essentials). The mentoring plan will entail training in equitable and inclusive mentoring and teaching, effective publication and grant writing, and networking with leading researchers with expertise in developmental alcohol exposure and adult neuropathology. Critically, the candidate will be exposed to an academic model that blends teaching, mentoring, and research. Career development and mentoring plans are cohesively devised to facilitate a successful transition to a tenure-track faculty position by the candidate.