The Role of Microglia in Adolescent Ethanol-Induced Corticolimbic Damage

小胶质细胞在青少年乙醇引起的皮质边缘损伤中的作用

• 批准号: 10388585
• 负责人: Jennifer Kate Melbourne
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388585
• 关键词: Acute; Adolescence; Adolescent; Adult; Alcohol consumption; Alcohol-Induced Disorders; Alcohols; Animal Model; Animals; Anti-Inflammatory Agents; Behavior; Behavioral; Bioinformatics; Biology; Blood; Brain; CSF1R gene; Cell Death; Cells; Classification; Clinical Research; Clinical Trials; Cognitive deficits; Complex; Data; Development; Disease; Epigenetic Process; Ethanol; Exhibits; Exposure to; Future; Goals; Health; Heavy Drinking; Histologic; Histology; Human; Image Analysis; Immune; Immunohistochemistry; Immunologic Memory; Inflammation; Inflammatory; Lead; Mediating; Memory; Microglia; Modeling; Modification; Morphology; Nerve Degeneration; Nervous System Trauma; Neuraxis; Pathology; Pattern; Performance; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Population; Process; Rattus; Recovery; Reporting; Research; Role; Saline; Structure; Surveys; Techniques; Teenagers; Testing; Therapeutic; Time; Tissues; Training; United States; alcohol effect; alcohol exposure; alcohol measurement; alcohol use disorder; behavior test; cognitive function; drinking; in vivo; inhibitor/antagonist; macrophage; morris water maze; neuron loss; pre-clinical research; recreational drug use; response; time use; tissue injury; transcriptome; transcriptomics; underage drinking; young adult

Project Summary Excess alcohol use in adolescence is associated with negative health consequences including corticolimbic damage and cognitive deficits. However, the mechanisms underlying these negative sequelae are not well understood. Microglia, macrophages that reside within the brain, are activated in both humans and animals exposed to alcohol. Activation of microglia to a proinflammatory phenotype can lead to tissue damage and is thus considered a possible cause of adolescent corticolimbic damage following ethanol exposure. Interestingly, we do not see evidence of a proinflammatory microglial phenotype concomitant with corticolimbic pathology in binge ethanol exposed rats. Given that microglial function is more complex than previously appreciated, we consider instead that microglia may serve a neuroprotective role following exposure to ethanol. To test this hypothesis in Aim 1 adolescent rats will be exposed to 2 days of binge ethanol following by microglial morphological and transcriptomic analysis to characterize activation state. Microglia will then be depleted prior to, throughout, and following ethanol exposure using a CSF1R antagonist to determine the effects on markers of neurodegeneration and cognitive function. Interestingly, microglia are known to exhibit a form of immune memory by which prior exposure results in altered responsivity to future activation. We hypothesize that persistent changes to the microglial set-point underlie exacerbation of corticolimbic pathology with repeat exposure to ethanol. In Aim 2 adolescent rats will undergo 2 days of binge ethanol exposure followed by microglia depletion and repopulation before another 2 days of binge ethanol exposure. This replacement of the microglia population may serve to reset these cells to a baseline phenotype. We expect (1) that rats exposed to both ethanol binges will show greater microglial activation, corticolimbic neurodegeneration and cognitive deficits relative to a single 2-day binge ethanol exposure, and (2) that forced microglia turnover will ameliorate these effects. In combination, these aims will significantly enhance our understanding of role that microglial activation and memory play in corticolimbic neurodegeneration following exposure to ethanol.

项目摘要 青春期过量的饮酒与包括皮质脂蛋白的负面健康后果有关 损害和认知缺陷。但是，这些负后遗症的基础机制不好 理解。小胶质细胞，驻留在大脑内的巨噬细胞，在人类和动物中都被激活 暴露于酒精。小胶质细胞激活促炎表型会导致组织损伤，并且 因此，被认为是乙醇暴露后青春期皮质降损伤的可能原因。有趣的是， 我们看不到促炎的小胶质细胞表型与皮质脂蛋白症病理学相关的证据 暴饮暴食的乙醇暴露大鼠。鉴于小胶质函数比以前所欣赏的更为复杂，我们 相反，考虑到暴露于乙醇后，小胶质细胞可以发挥神经保护作用。测试这个 AIM 1中的假设1青少年大鼠将暴露于2天的狂饮乙醇之后。 形态学和转录组分析以表征激活状态。然后，小胶质细胞将耗尽 使用CSF1R拮抗剂来确定对标记的影响 神经退行性和认知功能。有趣的是，已知小胶质细胞表现出一种免疫形式 以前暴露会导致对未来激活的响应性改变的记忆。我们假设这一点 小胶质固定点的持续变化是皮质胶体病理的加重基础 暴露于乙醇。在AIM 2中，青少年大鼠将经历2天的暴饮暴食，然后进行小胶质细胞 在狂饮乙醇暴露的另外2天之前，耗竭和重新流产。小胶质细胞的替代品 种群可以将这些细胞重置为基线表型。我们期望（1）大鼠暴露于两者 乙醇缠绕将显示出更大的小胶质细胞激活，皮层神经变性和认知缺陷 相对于一个为期2天的暴饮暴食乙醇暴露，（2）强迫小胶质细胞更新会改善这些 效果。结合起来，这些目标将显着增强我们对小胶质激活的作用的理解 在暴露于乙醇后，在皮质脂质神经变性中发挥了记忆作用。