Ethanol Alteration of the Neurogenic Niche

乙醇对神经源性生态位的改变

• 批准号: 10025627
• 负责人: Kimberly Nixon
• 金额: $ 2.14万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025627
• 关键词: Abstinence; Alcohol dependence; Alcoholic Intoxication; Alcoholism; Alcohols; Animal Model; Behavioral; Biochemical; Birth; Brain; Brain Injuries; Brain Mass; Cells; Cognition; Coupled; Data; Diagnostic; Electrophysiology (science); Ethanol; FRAP1 gene; Funding; Future; Goals; Hippocampus (Brain); Histologic; Human; Impaired cognition; Impairment; Laboratories; Learning; Life; Literature; Mental disorders; Modeling; Nerve Degeneration; Neuronal Plasticity; Neurons; Pathology; Pathway interactions; Pharmacology; Population; Public Health; Rattus; Recovery; Recovery of Function; Regulation; Retroviridae; Role; Signal Transduction; Sirolimus; Structure; Testing; Time; adult neurogenesis; alcohol consequences; alcohol use disorder; base; exhaust; in vivo; knock-down; meetings; nerve stem cell; neural recruitment; neurogenesis; neuromechanism; newborn neuron; novel; novel therapeutics; problem drinker; progressive neurodegeneration; recruit; relating to nervous system; response; stem; stem cell population; stem cells

Abstract. Alcohol use disorders (AUDs) remain one of the nation's major public health problems with nearly 14% of U.S. population meeting diagnostic criteria. Alcoholics demonstrate cognitive impairments that are related to a loss of brain mass or neurodegeneration in regions such as the hippocampus, an effect that may recover with abstinence. The mechanism of this recovery is not clear, however recent discoveries from our laboratory show that alcohol-induced regulation of hippocampal neural stem cells and adult neurogenesis parallel the changes in brain mass and cognition during alcohol intoxication (decrease/deficit) versus abstinence (increase/recovery). Across the last funding period, our lab has shown that prior alcohol dependence results in a striking increase in adult neurogenesis in abstinence, an effect due to the recruitment of neural stem and progenitor cells into active cycling that drives this reactive neurogenesis response. Although this response appears reparative initially, based on ethanol rats showing behavioral recovery on a hippocampal-dependent learning task, stem cell activation has long term consequences. Specifically, reactive neurogenesis via neural stem cell activation can deplete or exhaust the neural stem cell pool, ultimately resulting in decreased neurogenesis and impairments in hippocampal structure and function in the long-term. Furthermore, the mechanism of neural stem cell activation in models of AUDs is not known, but converging evidence from stem cell activation and alcohol neuroplasticity literatures coupled with our preliminary data support a role for mammalian target of rapamycin (mTOR) signaling. Thus, our overarching hypothesis is that reactive neurogenesis is initially beneficial, resulting from the recruitment of neural stem cells out of quiescence via an induction of mTOR signaling from alcohol dependence, but neural stem cell activation may come at the expense of neural stem cell depletion and an eventual detrimental impact on hippocampal structure and function. Using an interdisciplinary array of histological, biochemical, electrophysiological and behavioral approaches, we propose to examine the role of, consequences of, and mechanisms of reactive neurogenesis in a four-day binge model of an AUD through three specific aims: 1) Determine the role of reactive neurogenesis in structure, function, and recovery in abstinence after alcohol dependence, 2) Test the hypothesis that reactive neurogenesis after alcohol dependence activates neural stem cells out of quiescence to ultimately deplete / exhaust the neural stem cell pool, and 3) Define the role of mTOR signaling in neural stem cell activation and reactive neurogenesis after alcohol dependence. Our ultimate goal is to elucidate the role of adult neurogenesis in promoting structural and functional recovery in abstinence so that future studies can target this pathway pharmacologically or behaviorally as a novel therapeutic strategy in the treatment of alcoholic brain damage.

抽象的。 酒精使用障碍 (AUD) 仍然是美国主要的公共卫生问题之一，近 14% 符合诊断标准的美国人口。酗酒者表现出的认知障碍与以下因素有关 脑质量损失或海马体等区域的神经退行性变，这种影响可能会通过以下方法恢复： 节制。这种恢复的机制尚不清楚，但我们实验室的最新发现表明 酒精诱导的海马神经干细胞和成人神经发生的调节与 酒精中毒期间（减少/缺乏）与戒酒期间（增加/恢复）的脑质量和认知能力。 在上一个资助期间，我们的实验室表明，先前的酒精依赖会导致酒精依赖性显着增加 禁欲中的成体神经发生，是由于神经干细胞和祖细胞招募到活跃状态而产生的效应 驱动这种反应性神经发生反应的循环。尽管这种反应最初看起来是修复性的， 基于乙醇大鼠在海马依赖性学习任务中表现出的行为恢复，干细胞 激活会产生长期后果。具体来说，通过神经干细胞激活的反应性神经发生可以 耗尽或耗尽神经干细胞库，最终导致神经发生减少和神经损伤 海马的长期结构和功能。此外，神经干细胞激活的机制 AUD 模型中的作用尚不清楚，但来自干细胞激活和酒精神经可塑性的综合证据 文献与我们的初步数据支持哺乳动物雷帕霉素靶点 (mTOR) 信号传导的作用。 因此，我们的总体假设是，反应性神经发生最初是有益的，这是由于 通过诱导酒精依赖的 mTOR 信号传导，将神经干细胞从静止状态中招募出来， 但神经干细胞的激活可能会以神经干细胞耗竭为代价，并最终产生有害的结果。 对海马结构和功能的影响。利用组织学、生物化学、 电生理学和行为学方法，我们建议检查其作用、后果和 通过三个具体目标，在四天的 AUD 暴饮暴食模型中反应性神经发生机制：1) 确定反应性神经发生在戒酒后的结构、功能和恢复中的作用 依赖，2）检验酒精依赖后反应性神经发生激活神经干的假设 细胞脱离静止状态，最终耗尽/耗尽神经干细胞库，以及 3) 定义 mTOR 的作用 酒精依赖后神经干细胞激活和反应性神经发生中的信号传导。我们的最终目标 是为了阐明成人神经发生在促进禁欲中结构和功能恢复中的作用，以便 未来的研究可以从药理学或行为上针对这一途径作为一种新的治疗策略 治疗酒精性脑损伤。