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: 10569508
• 负责人: Jennifer Kate Melbourne
• 金额: $ 2.34万
• 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 2023-06-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569508
• 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; Central Nervous System; 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; Macrophage; Mediating; Memory; Microglia; Modeling; Modification; Morphology; Nerve Degeneration; Nervous System Trauma; Pathology; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Play; Population; Predisposition; 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; antagonist; behavior test; cognitive function; drinking; glial activation; in vivo; inhibitor; morris water maze; neuron loss; neuroprotection; pharmacologic; pre-clinical research; recreational drug use; response; 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 青春期过量饮酒与负面健康后果有关，包括皮质边缘神经系统 损伤和认知缺陷。然而，这些负面后遗症背后的机制并不好 明白小胶质细胞，巨噬细胞，居住在大脑中，被激活，在人类和动物 暴露在酒精中小胶质细胞活化为促炎表型可导致组织损伤， 因此被认为是酒精暴露后青少年皮质边缘损伤的可能原因。有趣的是， 我们没有看到促炎性小胶质细胞表型伴随皮质边缘病理的证据， 酒精中毒的老鼠鉴于小胶质细胞的功能比以前认识到的更复杂，我们 相反，认为小胶质细胞在暴露于乙醇后可能起到神经保护作用。为了验证这一 假设在目标1中，青春期大鼠将暴露于2天的酒精狂欢，然后小胶质细胞 形态学和转录组学分析以表征活化状态。小胶质细胞会在 使用CSF1R拮抗剂在乙醇暴露前、暴露期间和暴露后测定对标志物的影响 神经退化和认知功能。有趣的是，已知小胶质细胞表现出一种免疫调节形式， 先前的暴露导致对未来激活的反应性改变的记忆。我们假设 小胶质细胞设定点的持续变化是皮质边缘病理学恶化的基础， 接触乙醇。在Aim 2中，青春期大鼠将经历2天的酒精暴露，然后小胶质细胞 在另外2天的酒精暴露之前消耗和重新繁殖。这种小胶质细胞的替代 群体可以用于将这些细胞重置为基线表型。我们预计（1）暴露于这两种物质的大鼠 酒精狂欢会表现出更大的小胶质细胞激活，皮质边缘神经变性和认知缺陷 相对于一个单一的2天狂欢乙醇暴露，（2）强迫小胶质细胞周转将改善这些 方面的影响.结合起来，这些目标将大大提高我们对小胶质细胞激活的作用的理解， 和记忆发挥在皮质边缘神经变性后暴露于乙醇。