Ethanol alteration of the neurogenic niche

描述（由申请人提供）：酒精使用障碍仍然是美国主要的公共卫生问题之一，超过1700万美国人符合酒精滥用或依赖的诊断标准。慢性酗酒者表现出与大脑质量损失或神经退行性变有关的认知障碍，这些影响可能通过戒酒而恢复。许多人认为这种恢复的机制是由于神经胶质细胞再生，然而，我们实验室最近的发现表明，酒精诱导的神经干细胞（NSC）调节与海马中主动酒精中毒（减少）与戒酒（增加）期间脑质量和认知的变化平行。神经干细胞的调节依赖于局部环境的微环境或神经原性生态位。小胶质细胞，三种类型的神经胶质细胞之一，有助于这个利基。虽然小胶质细胞事件在历史上是细胞毒性的同义词，但在神经发生中的新作用正在出现。一些活化的小胶质细胞分泌生长因子和抗炎细胞因子，这种作用与最近的数据一致，即某些类型的小胶质细胞促进NSC增殖和成体神经发生。因此，当我们在慢性酒精中毒模型中观察到神经源性反应之前的小胶质细胞反应时，我们怀疑小胶质细胞事件与促进神经发生之间存在因果关系。因此，这项建议将测试的假设，即酗酒暴露产生分级的小胶质细胞反应，推动招聘静止的神经干细胞增殖和神经发生的禁欲。三个具体的目标解决这个假设，通过问：（1）是否酗酒暴露招募额外的神经干细胞，（2）小胶质细胞是否显示一个分级的，非吞噬细胞的表型预测前神经微环境和（3）我们是否可以调节这种表型，以改变神经发生在慢性酒精中毒模型。将使用多种方法，即免疫组织化学来评估NSC的募集和增殖动力学、小胶质细胞的形态，以及原位杂交、受体放射自显影和酶联免疫吸附测定来确定小胶质细胞表型和细胞因子表达。最后，神经解剖学和行为学研究将证实小胶质细胞表型在酗酒后神经退化和再生中的作用。与公共卫生的相关性：这项提案将通过研究激活的小胶质细胞对神经干细胞和神经原性环境的作用，揭示戒酒后大脑再生的机制。研究结果将为我们治疗与慢性酒精中毒相关的脑损伤的长期目标提供一种新的方法：确定促进小胶质细胞保护作用的药物或行为，以招募NSC修复损伤部位，希望逆转或预防与酒精性神经变性相关的认知缺陷。

DESCRIPTION (provided by applicant): 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 Assays to 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 alcohol exposure. 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 behaviors that 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.