Project 1: The Reciprocal Relationship between Binge Drinking and Astrocytic Signaling

项目摘要：过度饮酒会导致严重的健康和社会经济问题 美国。不幸的是，这个国家的少数民族背负着不成比例的这些问题的负担。 尽管酗酒的发生率是一样的。因此，想方设法减少像消费这样的过度消费仍然是一个 这是消除健康差距和减少酒精依赖的重要研究领域。 该项目试图确定星形胶质细胞和神经免疫系统是否代表新的靶点 遏制过度消费。这项研究确定了过量酒精对星形胶质细胞激活的影响。 如果促炎细胞因子是导致神经胶质细胞适应不良的原因，海马区的功能也是如此 (目标1)。由于性别差异会改变神经免疫反应，这些研究将阐明 性行为对星形胶质细胞的激活及其功能的影响。其次，这些研究将确定海马体 星形胶质细胞信号可被转换以逆转乙醇对增加的促炎作用的影响 微环境和海马区谷氨酸能张力降低(目标2)。最后，因为两者 谷氨酸和前炎性细胞因子可影响海马区依赖记忆任务和损毁 行为，这些实验将确定星形胶质细胞信号对酒精消耗和 酒精引起的认知障碍(目标2)。星形胶质细胞特异性DREADD的发展使我们能够 利用定点定向立体定向病毒操纵海马区G蛋白偶联受体信号 送货。总之，这两个目标将检验我们的总体假设，即存在一个相互和强化的 酒精与星形胶质细胞对谷氨酸能影响所介导的星形胶质细胞激活 声调和促炎信号级联。这些创新的研究将为深入了解 星形胶质细胞在酒精依赖转化中的作用及酒精诱导的神经免疫的影响 星形胶质细胞反应的失调。

Project Abstract: Excessive binge alcohol consumption causes major health and socio-economic issues within the United States. Unfortunately, minorities in this country are disproportionately burdened by these problems despite equal incidences of binge drinking. Finding ways to reduce binge like consumption therefore remains an important field of research to combat health disparities and decrease the development of ethanol dependence. This project seeks to determine if astrocytes and the neuroimmune system represent novel targets by which to curb excessive consumption. This grant determines the influence of excessive ethanol on astrocytic activation and function in the hippocampus as well if the proinflammatory cytokines are responsible for glial maladaptations (Aim 1). Because sex-differences can alter neuroimmune responses, these studies will elucidate the impact of sex on both astrocyte activation and their function. Secondly, these studies will determine if hippocampal astrocytic signaling can be switched to reverse the influences of ethanol on the increased proinflammatory microenvironment and decreased glutamatergic tone of the hippocampus (Aim 2). Finally, because both glutamate and proinflammatory cytokines can impact hippocampal dependent memory tasks and consummatory behaviors, these experiments will determine the impact of astrocytic signaling on ethanol consumption and alcohol-induced cognitive deficits (Aim 2). The development of astrocyte specific DREADDs allows us to manipulate G-protein coupled receptor signaling in the hippocampus using site directed stereotactic viral delivery. Altogether, these two aims will test our overall hypothesis that there is a reciprocal and reinforcing relationship between alcohol and astrocyte activation mediated by the influence of astrocytes on glutamatergic tone and proinflammatory signaling cascades. These innovative studies will provide insight into the role of astrocytes in the transition to alcohol dependence as well as the influence of alcohol-induced neuroimmune dysregulation on the astrocytic response.