Ethanol Alteration of the Neurogenic Niche

抽象的。 酒精使用障碍（AUDs）仍然是美国主要的公共卫生问题之一，近14%的 美国符合诊断标准的人群。酗酒者表现出认知障碍， 大脑质量的损失或海马体等区域的神经退行性变，这种影响可能会随着 禁欲这种恢复的机制尚不清楚，但我们实验室最近的发现表明， 酒精诱导的海马神经干细胞和成年神经发生的调节与海马神经干细胞的变化平行。 酒精中毒（减少/不足）与戒酒（增加/恢复）期间的脑质量和认知。 在上一个资助期间，我们的实验室已经表明，先前的酒精依赖会导致 成年人的神经发生在禁欲，效果由于招募神经干细胞和祖细胞进入活跃的 循环驱动这种反应性神经发生反应。虽然这种反应最初似乎是修复性的， 基于酒精大鼠在依赖于大脑的学习任务中表现出行为恢复，干细胞 激活具有长期后果。具体地说，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损伤， 海马的结构和功能。此外，神经干细胞激活的机制 在AUDs模型中的作用尚不清楚，但来自干细胞活化和酒精神经可塑性的证据 文献结合我们的初步数据支持哺乳动物雷帕霉素靶蛋白（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 通过诱导来自酒精依赖的mTOR信号传导，从静止状态中募集神经干细胞， 但神经干细胞的激活可能以神经干细胞耗竭为代价， 对海马结构和功能的影响。利用组织学，生物化学， 电生理和行为的方法，我们建议检查的作用，后果， 通过三个特定的目的，在AUD的四天狂欢模型中反应性神经发生的机制：1） 确定反应性神经发生在结构、功能和戒酒后恢复中的作用 2）验证酒精依赖后反应性神经发生激活神经干的假说 细胞从静止中出来，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活化和反应性神经发生的信号转导。我们的最终目标 目的是阐明成年神经发生在促进戒断后结构和功能恢复中的作用， 未来的研究可以将这一途径作为一种新的治疗策略， 酒精性脑损伤的治疗

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.