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

项目摘要 所要求的促进卫生相关研究多样性的研究补编将 支持培训优秀的早期研究者开展独立研究 在酒精发育和后来的大脑病理学领域的职业生涯。重度饮酒 在青春期与大脑结构的持续变化，连接， 成年海马和皮质介导的认知功能。持久病变 在青少年乙醇暴露的啮齿动物模型中一致观察到（青少年间歇性 乙醇（AIE）包括神经生长因子的减少，胆碱能神经递质的抑制， 表型，活动依赖性乙酰胆碱释放的变化，以及钝性海马 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）海马水平， 作为细胞病理学的协同介质。在高水平下，Aβ还与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 加速病理反应。鉴于病理性Aβ释放是活性依赖性的， 新的γ-氨基丁酸A型受体调节剂（GABAAα5）将用于纠正AIE， 诱发Aβ功能障碍。这些研究活动将扩大研究经验， 候选人的科学范围。具体来说，研究计划将使候选人接触到 乙醇的发展前景和一些创新的技术方法（在体内脑 活动;编程，数据科学基础）。辅导计划将包括以下方面的培训： 公平和包容的指导和教学，有效的出版和赠款写作，以及 与具有发育性酒精暴露和成人酒精暴露方面专业知识的领先研究人员建立联系 神经病理学至关重要的是，候选人将接触到一种融合的学术模型 教学指导和研究职业发展和指导计划是连贯的 旨在促进候选人成功过渡到终身教职职位。

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.