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: 10705859
• 负责人: Simon Alexander Marshall
• 金额: $ 18.75万
• 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/10705859
• 关键词: Addictive Behavior; Address; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anti-Inflammatory Agents; Area; Astrocytes; Behavior; Behavioral; Biological Assay; Brain Injuries; Brain-Derived Neurotrophic Factor; Cells; Cognitive deficits; Consummatory Behavior; Consumption; Country; Darkness; 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; Human; Immune; Immunocompetent; Immunohistochemistry; Incidence; Inflammatory; Inflammatory Response; 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; Production; 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; inflammatory marker; 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。不幸的是，这个国家的少数族裔承受着这些问题的沉重负担 尽管酗酒的发生率相同。因此，寻找减少暴饮暴食的方法仍然是一个问题 消除健康差异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标 抑制过度消费。该资助确定了过量乙醇对星形胶质细胞激活的影响 如果促炎细胞因子是神经胶质适应不良的原因，那么海马体也会发挥作用 （目标 1）。由于性别差异会改变神经免疫反应，这些研究将阐明性别差异的影响 性别对星形胶质细胞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逆转乙醇对促炎细胞增加的影响 微环境和海马谷氨酸能降低（目标 2）。最后，因为双方 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 行为，这些实验将确定星形细胞信号传导对乙醇消耗和 酒精引起的认知缺陷（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 送货。总而言之，这两个目标将检验我们的总体假设，即存在互惠且相互促进的关系。 星形胶质细胞对谷氨酸能的影响介导的酒精与星形胶质细胞活化之间的关系 音调和促炎信号级联。这些创新研究将深入了解 星形胶质细胞向酒精依赖的转变以及酒精诱导的神经免疫的影响 星形胶质细胞反应失调。