Ethanol alteration of the neurogenic niche

乙醇改变神经源性生态位

• 批准号: 8515883
• 负责人: Kimberly Nixon
• 金额: $ 31.37万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515883
• 关键词: Abstinence; Address; Alcohol abuse; Alcohol dependence; Alcoholic Intoxication; Alcoholism; Alcohols; American; Anti-Inflammatory Agents; Anti-inflammatory; Autopsy; Autoradiography; Behavioral; Brain; Brain Injuries; Brain Mass; Cell Death; Cell Proliferation; Cells; Cellular Morphology; Chronic; Cognition; Cognitive deficits; Data; Diagnostic; Environment; Enzymes; Ethanol; Event; Future; Goals; Growth Factor; Hippocampus (Brain); Image; Immunohistochemistry; Impaired cognition; In Situ Hybridization; Intention; Laboratories; Lead; Link; Microglia; Modeling; Morphology; Natural regeneration; Nerve Degeneration; Neuroglia; Neuroprotective Agents; Outcome; Pathway interactions; Pharmacotherapy; Phenotype; Population; Proliferating; Public Health; Recovery; Recruitment Activity; Regulation; Research Personnel; Role; Site; Stem cells; Structure; Testing; Work; adult neurogenesis; alcohol abstinence; alcohol abuse therapy; alcohol exposure; alcohol use disorder; binge drinking; cognitive function; cytokine; cytotoxicity; macrophage; meetings; nerve stem cell; neural recruitment; neurogenesis; neuroprotection; new therapeutic target; novel; novel strategies; preconditioning; prevent; problem drinker; receptor; relating to nervous system; repaired; response; stem

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.

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。慢性酗酒者证明了这一点 与脑质量或神经退行性丧失有关的认知障碍，可能恢复的影响 禁欲。许多人认为这种恢复的机制是由于神经胶质再生而引起的，但是 我们实验室的最新发现表明，酒精诱导的神经干细胞调节（NSC） 与活跃酒精中毒期间的脑质量和认知的变化相似（减少）与禁欲的变化 （增加）海马。 NSC的监管依赖于当地环境的环境，或 神经源性小众。小胶质细胞是三种类型的神经胶质之一，促成了这种利基市场。虽然小胶质事件 从历史上看，是细胞毒性的代名词，在神经发生中的新作用正在出现。一些激活 小胶质细胞分泌生长因子和抗炎细胞因子，这种作用与最新数据一致 某些类型的小胶质细胞促进了NSC增殖和成人神经发生。因此，当我们观察到一个 在我们的慢性酒精中毒模型中的神经源反应之前的小胶质响应，我们 怀疑小胶质事件与促进神经发生之间存在因果关系。因此，这个 提案将检验以下假设：暴饮暴食会产生分级的小胶质细胞反应 将静态NSC募集到戒酒中的增殖和神经发生。三个具体 目的是通过询问：（1）暴饮酒精暴露是否招募其他NSC，（2） 小胶质细胞是否表现出逐步的，非近形细胞表型的预测性微环境 （3）我们是否可以调节这种表型以改变慢性酒精中毒模型中的神经发生。 将使用多种方法，即免疫组织化学来评估募集和增殖 NSC的动力学，小胶质细胞的形态以及原位杂交，受体自显影术 酶联免疫吸附测定确定小胶质细胞表型和细胞因子表达。和 最后，神经解剖学和行为工作将确认小胶质细胞表型在神经变性中的作用 和饮酒后的再生。 与公共卫生的相关性：该提案将揭示戒酒中大脑再生的机制 通过研究活化的小胶质细胞对神经干细胞和神经源环境的作用。 结果将导致一种新的方法，即我们的长期目标是治疗与 慢性酒精中毒：识别药物或行为，从而促进小胶质细胞的保护作用 NSC修复损坏部位，希望逆转或预防与之相关的认知缺陷 酒精神经变性。