Ethanol-Induced Reactive Astrocytes and Recovery

项目摘要 患有酒精使用障碍(AUD)的人经常经历认知缺陷，据信 与酒精引起的皮质边缘损伤有关。戒酒后，个人可以康复 一些功能，但这一过程背后的机制尚不清楚。星形胶质细胞，执行 大脑中许多重要的动态平衡功能，在接触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学特异性，这种反应性的许多特征 尚未使用酒精依赖和神经退行性变的动物模型进行详细研究。证据 到目前为止收集的数据表明，这种反应性导致星形胶质细胞结构的变化，并在星形胶质细胞爆裂之前 在禁欲中看到的神经再生。鉴于星形胶质细胞在释放神经递质和生长因子方面的作用， 这些酒精诱导的反应性星形胶质细胞可能在AUD的康复过程中发挥重要作用。这个项目将 利用两个目标首先描述这些星形胶质细胞的表型，然后探索可能的机制 他们在复苏中的作用。在这两个目标中，大鼠都将暴露在乙醇中，在一个模拟醉酒的模型中， 依赖，以及患有澳门氏症的人类经历的神经退行性变。在目标1中，一个多方面的方法将 用来描述星形胶质细胞的形态、可能参与恢复的感兴趣的蛋白质和基因 表情。在目标2中，将采取一种药理学方法来调节星形胶质细胞中的谷氨酸信号，以 了解表型改变的这一方面可能如何影响神经发生和AUD的恢复。培训： 该项目将通过提供高级课程的指导，显著推进申请者的培训目标 科学的技术和专业的发展，帮助申请者实现成为一名 独立研究人员。在教师指导下，数据科学课程的培训将有助于 分析完成此项目所需的大型数据集。职业发展培训将包括 本科生指导，内部和会议上的科学陈述，研究指导培训， 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.