Ethanol-Induced Reactive Astrocytes and Recovery

项目摘要 患有酒精使用障碍（AUD）的人经常会出现认知缺陷，这被认为是 与酒精引起的皮质边缘损伤有关戒酒后，个人可以恢复 有一些功能，但这个过程背后的机制却知之甚少。星形胶质细胞，神经胶质细胞， 大脑中许多重要的稳态功能在暴露于乙醇后表现出表型变化 在动物模型中。星形胶质细胞的反应性具有高度的病理特异性， 尚未使用酒精依赖和神经变性的动物模型进行详细研究。证据 迄今为止收集到的数据表明，这种反应性导致星形胶质细胞结构的变化，并在星形胶质细胞结构的爆发之前， 在禁欲中观察到的神经发生。鉴于星形胶质细胞在释放神经递质和生长因子中的作用， 这些酒精诱导的反应性星形胶质细胞可能在AUD的恢复中起重要作用。该项目将 利用两个目的，首先描述这些星形胶质细胞的表型，然后探索可能的机制， 在复苏中的作用。在这两个目标中，大鼠将暴露于乙醇，在一个模拟中毒的模型中， 依赖和患有AUD的人经历的神经变性。在目标1中，一个多方面的方法将 可用于描述星形胶质细胞形态、可能参与恢复的感兴趣的蛋白质和基因 表情在目标2中，将采取药理学方法来调节星形胶质细胞中的谷氨酸信号传导， 了解这方面的表型变化如何影响神经发生和从AUD中恢复。培训内容： 该项目将通过提供先进的教学大大推进申请人的培训目标 科学技术和专业发展，以帮助申请人实现他的职业目标， 独立研究员。数据科学课程的培训，伴随着教师的指导，将有助于 分析完成该项目所需的大型数据集。专业发展培训将包括 本科生指导，在内部和会议上介绍科学，研究行为培训， 和职业发展机会。

Project Summary Individuals with Alcohol Use Disorder (AUD) frequently experience cognitive deficits, which are believed to be related to alcohol-induced corticolimbic damage. Following abstinence from alcohol, individuals can recover some function, but the mechanism behind this process is poorly understood. Astrocytes, glial cells which perform numerous important homeostatic functions in the brain, exhibit phenotypic changes following exposure to ethanol in animal models. Astrocyte reactivity is highly pathology specific, and many of the characteristics of this reactivity have not been studied in detail using an animal model of alcohol dependence and neurodegeneration. Evidence collected thus far indicates that this reactivity results in changes to astrocyte structure and precedes a burst in neurogenesis seen in abstinence. Given the role of astrocytes in releasing neurotransmitters and growth factors, these alcohol-induced reactive astrocytes might play an important role in recovery from AUD. This project will utilize two aims to first describe the phenotype of these astrocytes, and then probe a possible mechanism for their role in recovery. In both aims, rats will be exposed to ethanol, in a model which mimics the intoxication, dependence, and neurodegeneration experienced by humans with AUD. In Aim 1, a multi-faceted approach will be utilized to describe astrocyte morphology, proteins of interest that may be involved in recovery, and gene expression. In Aim 2, a pharmacologic approach will be taken to modulate glutamate signaling in astrocytes, to understand how this facet of phenotypic change may affect neurogenesis and recovery from AUD. Training: This project will significantly advance the training goals of the applicant by providing instruction in advanced scientific techniques and professional development to help the applicant achieve his career goal of becoming an independent researcher. Training in data science classes, accompanied by faculty mentorship, will assist with analyzing large data sets needed to complete this project. Professional development training will include undergraduate mentoring, presentation of science both internally and at conferences, research conduct training, and career development opportunities.