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

项目 1：酗酒与星形胶质细胞信号传导之间的相互关系

• 批准号: 10540965
• 负责人: Simon Alexander Marshall
• 金额: $ 18.65万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540965
• 关键词: Address; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Anti-Inflammatory Agents; Area; Astrocytes; Attenuated; Behavior; Behavioral; Biological Assay; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Cells; Cognitive deficits; Consummatory Behavior; Consumption; Country; Dependence; Development; Enzyme-Linked Immunosorbent Assay; Ethanol; Ethanol dependence; Event; Functional disorder; Future; G Protein-Coupled Receptor Signaling; GLAST Protein; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; Grant; Heavy Drinking; Hippocampus (Brain); Human; Immune; Immunocompetent; Immunohistochemistry; Incidence; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-10; Intoxication; Lead; Link; Measures; Mediating; Memory; Memory impairment; Microdialysis; Minority; Modeling; Molecular; Morphology; Mus; Neuroimmune; Neuroimmune system; Neuroimmunomodulation; Neuronal Plasticity; Phenotype; Play; Procedures; Quantitative Reverse Transcriptase PCR; Receptor Signaling; Regulation; Reporting; Research; Risk; Role; Sex Differences; Signal Transduction; Site; Testing; United States; Viral; Work; alcohol abuse therapy; alcohol effect; alcohol research; alcohol use disorder; anakinra; binge drinking; combat; cytokine; designer receptors exclusively activated by designer drugs; drinking; experimental study; extracellular; glutamatergic signaling; health disparity; health economics; improved; innovation; insight; neuroinflammation; neurotransmission; novel; novel therapeutics; object recognition; prevent; response; sex; socioeconomics; synaptic function; uptake

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.

项目摘要：过度饮酒会导致严重的健康和社会经济问题， 美国的不幸的是，这个国家的少数民族不成比例地承受着这些问题的负担 尽管酗酒的发生率相同因此，找到减少暴饮暴食的方法仍然是一个问题。 这是消除健康差距和减少乙醇依赖的重要研究领域。 该项目旨在确定星形胶质细胞和神经免疫系统是否代表新的靶点， 抑制过度消费。这项研究确定了过量乙醇对星形胶质细胞活化的影响 如果促炎细胞因子是神经胶质适应不良的原因， (Aim 1）。由于性别差异可以改变神经免疫反应，这些研究将阐明 性别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是否 星形胶质细胞信号传导可以被转换以逆转乙醇对增加的促炎性细胞因子的影响。 微环境和降低海马的神经元紧张性（Aim 2）。最后，因为两者 谷氨酸和促炎细胞因子可以影响海马依赖性记忆任务和完成性记忆任务。 行为，这些实验将确定星形胶质细胞信号对乙醇消耗的影响， 酒精诱导的认知缺陷（目标2）。星形胶质细胞特异性DREADD的发展使我们能够 使用定点立体定向病毒操纵海马中的G蛋白偶联受体信号传导 交付.总而言之，这两个目标将检验我们的总体假设，即存在一种相互强化的 酒精与星形胶质细胞活化的关系--星形胶质细胞对酒精代谢的影响 紧张和促炎信号级联。这些创新的研究将提供深入了解的作用， 星形胶质细胞向酒精依赖转化过程中的作用及酒精对神经免疫的影响 星形胶质细胞反应失调。