Ethanol alteration of the neurogenic niche

乙醇改变神经源性生态位

• 批准号: 7873609
• 负责人: Kimberly Nixon
• 金额: $ 1.49万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873609
• 关键词: Abstinence; Address; Alcohol abuse; Alcoholic Intoxication; Alcoholism; Alcohols; American; Anti-Inflammatory Agents; Anti-inflammatory; Autopsy; Autoradiography; Behavior; Behavioral; Biological Assay; Brain; Brain Injuries; Brain Mass; Cell Death; Cell Proliferation; Cells; Cellular Morphology; Chronic; Cognition; Cognitive deficits; Data; Dependence; Diagnostic; Environment; Enzymes; Ethanol; Event; Future; Goals; Grant; 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

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.

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。慢性酗酒者表现出认知障碍，这与大脑质量的丧失或神经退化有关，这种影响可以通过戒酒来恢复。许多人认为这种恢复的机制是由于神经胶质再生，然而，我们实验室最近的发现表明，酒精诱导的神经干细胞（NSCs）的调节与海马在主动酒精中毒（减少）和戒酒（增加）期间脑质量和认知的变化相似。神经干细胞的调控依赖于局部环境或神经源性生态位。小胶质细胞是三种胶质细胞中的一种，为这个生态位做出了贡献。虽然小胶质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。一些激活的小胶质细胞分泌生长因子和抗炎细胞因子，这与最近的数据一致，即某些类型的小胶质细胞促进NSC增殖和成人神经发生。因此，当我们在慢性酒精中毒模型中观察到小胶质细胞反应先于神经源性反应时，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，这一提议将验证这样的假设，即酗酒会产生分级的小胶质细胞反应，促使静止的NSCs在戒酒时增殖和神经发生。三个特定的目标通过以下问题来解决这一假设：(1)暴饮暴食是否会募集额外的NSCs；(2)小胶质细胞是否表现出可预测前神经源性微环境的渐进式非吞噬表型；(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，即免疫组织化学来评估NSCs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的表达。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变性和再生中的作用。与公共卫生相关：本提案将通过研究激活的小胶质细胞对神经干细胞和神经源性环境的作用，揭示戒酒后大脑再生的机制。该结果将为我们治疗慢性酒精中毒相关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NSCs来修复损伤部位，以期逆转或预防与酒精性神经变性相关的认知缺陷。