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.

项目概要 青春期过量饮酒与负面健康后果有关，包括皮质边缘 损害和认知缺陷。然而，这些负面后遗症背后的机制尚不清楚 明白了。小胶质细胞是存在于大脑内的巨噬细胞，在人类和动物体内均被激活 接触酒精。小胶质细胞激活促炎表型可导致组织损伤， 因此被认为是乙醇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与皮质边缘病理学相伴的证据 暴饮乙醇暴露的大鼠。鉴于小胶质细胞的功能比以前想象的更复杂，我们 相反，小胶质细胞可能在接触乙醇后发挥神经保护作用。为了测试这个 Aim 1 中的假设青春期大鼠将暴露于暴饮暴食 2 天的乙醇中，然后小胶质细胞 形态学和转录组分析来表征激活状态。小胶质细胞会先被耗尽 在乙醇暴露期间、整个过程中以及之后使用 CSF1R 拮抗剂来确定对标记物的影响 神经退行性变和认知功能。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反复恶化的基础 接触乙醇。在 Aim 2 中，青春期大鼠将经历 2 天的暴饮乙醇暴露，然后是小胶质细胞 在另外 2 天的暴饮乙醇暴露之前耗尽并重新填充。这种小胶质细胞的替代 群体可能有助于将这些细胞重置为基线表型。我们预计 (1) 暴露于两种物质的老鼠 酗酒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 相对于单次 2 天的暴饮暴食乙醇暴露，(2) 强制小胶质细胞更新将改善这些 影响。结合起来，这些目标将显着增强我们对小胶质细胞激活作用的理解 和记忆在接触乙醇后皮质边缘神经变性中的作用。