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 青春期过量饮酒与包括边缘皮质炎在内的负面健康后果有关 损伤和认知缺陷。然而，这些负面后遗症背后的机制并不好。 明白了。小胶质细胞，即存在于大脑中的巨噬细胞，在人类和动物中都被激活。 暴露在酒精中。小胶质细胞活化为致炎表型可导致组织损伤和 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， 我们没有发现伴随皮质边缘病变的促炎小胶质细胞表型的证据。 暴饮式酒精暴露的大鼠。鉴于小胶质细胞的功能比之前估计的要复杂得多，我们 相反，考虑到小胶质细胞在接触乙醇后可能起到神经保护作用。为了测试这一点 目标1假设青春期大鼠将暴露于2天的狂欢酒精中，然后是小胶质细胞 形态和转录分析，以表征激活状态。然后小胶质细胞将被耗尽 使用CSF1R拮抗剂在酒精暴露之前、整个过程和之后确定对标志物的影响 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形式 先前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反复发作的皮质边缘病变恶化的基础 暴露在乙醇中。在Aim 2中，青春期大鼠将经历2天的酗酒暴露，然后是小胶质细胞 在接下来的两天暴饮暴饮式酒精暴露之前消耗和补充能量。这种小胶质细胞的替换 群体可能有助于将这些细胞重新设置为基线表型。我们预计(1)暴露于这两种环境的大鼠 酗酒将表现出更大的小胶质细胞激活，皮质边缘神经变性和认知障碍 相对于一次两天的酗酒暴露，以及(2)强迫小胶质细胞更替将改善这些 效果。这些目标结合在一起，将显著增强我们对小胶质细胞激活的作用的理解。 记忆在酒精暴露后的皮质边缘神经退行性变中起作用。