Ethanol alteration of the neurogenic niche

酒精使用障碍仍然是这个国家的主要公共卫生问题之一，有1700多万人 符合酒精滥用或依赖诊断标准的美国人。慢性酗酒者表现出 与大脑质量丧失或神经变性有关的认知障碍，这些影响可能会恢复 带着节制。然而，许多人认为这种恢复的机制是由于神经胶质细胞的再生。 我们实验室的最新发现表明，酒精诱导神经干细胞(NSCs)的调节 活性酒精中毒(减少)与戒酒期间大脑质量和认知的变化相似 (增加)在海马区。对NSCs的监管取决于当地环境的环境，或 神经性的利基。小胶质细胞是三种神经胶质细胞之一，为这一利基做出了贡献。尽管小胶质细胞事件 在历史上，它们是细胞毒性的代名词，在神经发生中的新角色正在出现。有些被激活了 小胶质细胞分泌生长因子和抗炎细胞因子，这一作用与最近的数据一致 某些类型的小胶质细胞促进神经干细胞增殖和成年神经发生。因此，当我们观察到一个 在我们的慢性酒精中毒模型中，小胶质细胞反应先于神经源性反应，我们 怀疑小胶质细胞事件和促进神经发生之间存在因果联系。因此，这 该提案将检验这样一个假设，即酗酒会产生分级的小胶质细胞反应， 促使静止的神经干细胞在戒断状态下进行增殖和神经再生。三个具体的 我的目标是通过以下问题来解决这一假设：(1)酗酒是否会招募更多的NSC，(2) 小胶质细胞是否表现为分级的非吞噬表型预示着神经源性微环境 以及(3)我们是否可以调节这种表型来改变慢性酒精中毒模型中的神经发生。 将使用多种方法，即免疫组织化学方法来评估募集和增殖 神经干细胞的动态、小胶质细胞的形态以及原位杂交、受体放射自显影 酶联免疫吸附试验测定小胶质细胞表型和细胞因子表达。和 最后，神经解剖学和行为学研究将证实小胶质细胞表型在神经分化中的作用。 以及酗酒后的再生。 与公共健康相关：这项提议将揭示戒除酒精后大脑再生的机制 通过研究激活的小胶质细胞对神经干细胞和神经发生环境的作用。 这一结果将为我们治疗脑损伤的长期目标带来一种新的方法。 慢性酒精中毒：在招募过程中识别促进小胶质细胞保护作用的因素或行为 神经干细胞修复受损部位，希望逆转或预防与 酒精性神经变性。

Alcohol use disorders remain as one of the nation's major public health problems with over 17 million Americans meeting the diagnostic criteria for alcohol abuse or dependence. Chronic alcoholics demonstrate cognitive impairments that are related to a loss of brain mass or neurodegeneration, effects that may recover with abstinence. Many assumed that the mechanism of this recovery was due to glial regeneration, however recent discoveries from our laboratory show that alcohol-induced regulation of neural stem cells (NSCs) parallels the changes in brain mass and cognition during active alcoholism (decrease) versus abstinence (increase) in the hippocampus. The regulation of NSCs relies on the milieu of the local environment, or neurogenic niche. Microglial, one of three types of glia, contribute to this niche. Though microglial events historically were synonymous with cytotoxicity, a new role in neurogenesis is emerging. Some activated microglia secrete growth factors and anti-inflammatory cytokines, an effect that is consistent with recent data that certain types of microglia promote NSC proliferation and adult neurogenesis. Thus, when we observed a microglial response that precedes the neurogenic response in our model of chronic alcoholism, we suspected a causal link between microglial events and the promotion of neurogenesis. Therefore, this proposal will test the hypothesis that binge alcohol exposure produces a graded microglial response that drives the recruitment of quiescent NSCs into proliferation and neurogenesis in abstinence. Three specific aims address this hypothesis by asking: (1) whether binge alcohol exposure recruits additional NSCs, (2) whether microglia show a graded, nonphagocytic phenotype predictive of a proneurogenic microenvironment and (3) whether can we modulate this phenotype to alter neurogenesis in a model of chronic alcoholism. Multiple approaches will be used, namely immunohistochemistry to assess the recruitment and proliferative dynamics of NSCs, the morphology of microglia, as well as in situ hybridization, receptor autoradiography and Enzyme-Linked ImmunoSorbant Assaysto determine microglia phenotype and cytokine expression. And finally, neuroanatomical and behavioral work will confirm the role of microglia phenotype in neurodegneration and regeneration following binge alcoholexposure. Relevance to public health: This proposal will uncover a mechanism of brain regrowth in abstinence from alcohol by investigating the role of activated microglia on neural stem cells and the neurogenic environment. The results will lead to a novel approach in our long term goal of treating brain damage associated with chronic alcoholism: Identifying agents or behaviorsthat promote protective actions of microglia in recruiting NSCs to repair sites of damage with the hope of reversing or preventing cognitive deficits associated with alcoholic neurodegeneration.