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

项目摘要 所要求的促进与健康相关研究的多样性的研究副刊将 支持培训一名优秀的早期研究人员开展独立研究 在发育酒精和后来的脑病理学领域的职业生涯。大量饮酒 在青春期与大脑结构、连通性和 成人海马区和大脑皮层的认知功能。持久的病理变化 在青春期酒精暴露(青少年间歇性)啮齿动物模型中持续观察到 乙醇；AIE)包括减少神经生长因子，抑制胆碱能 表型、活性依赖性乙酰胆碱释放的变化和钝化的海马区 神经发生。目前的促进多样性补编扩大了 父母项目通过检查AIE是否增加淀粉样蛋白β(Aβ)的海马区水平， 作为细胞病理学的协同介体。在高水平时，Aβ也与p75结合 神经营养素受体，有助于细胞死亡，并可能使大脑倾向于 病理反应加速。鉴于病理性Aβ的释放是活性依赖的，A 新型γ-氨基丁酸-A型受体调节剂(GABA-α5)将用于纠正AIE- 诱发A-β功能障碍。这些研究活动将扩大研究经验和 候选人的科学范围。具体地说，研究计划将使候选人暴露于 酒精的发展前景和几种创新的技术方法(活体大脑 活动、编程、数据科学要领)。指导计划将包括以下方面的培训 公平和包容的指导和教学，有效的出版和赠款撰写，以及 与具有发育期酒精暴露和成人方面专业知识的领先研究人员建立联系 神经病理学。关键是，候选人将接触到一种混合了 教学、指导和研究。职业发展和指导计划是紧密结合的 旨在促进候选人成功过渡到终身教职。

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.