The Reciprocal Relationship between Binge Drinking and Astrocytic Signaling

暴饮暴食与星形胶质细胞信号传导之间的相互关系

• 批准号: 10541714
• 负责人: Simon Alexander Marshall
• 金额: $ 5.41万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/10541714
• 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：过度暴饮暴食会导致重大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对这些问题负担不足 尽管暴饮暴食也相同。因此寻找减少狂风像消费的方法仍然是 对抗健康差异并减少乙醇依赖性发展的重要研究领域。 该项目旨在确定星形胶质细胞和神经免疫系统是否代表了新的目标 遏制过度消费。该赠款决定了过度乙醇对星形细胞激活的影响 如果促炎细胞因子负责神经胶质疾病，以及海马的功能 （目标1）。由于性别差异可以改变神经免疫反应，因此这些研究将阐明 星形胶质细胞激活及其功能上的性别。其次，这些研究将确定海马是否 可以切换星形胶质细胞信号传导以逆转乙醇对增加促炎的影响 微环境和降低海马的谷氨酸能张力（AIM 2）。最后，因为两者兼而有之 谷氨酸和促炎细胞因子会影响海马依赖的记忆任务和完整性 行为，这些实验将决定星形胶质细胞信号对乙醇消耗和 酒精引起的认知缺陷（AIM 2）。星形胶质细胞特定恐惧的发展使我们能够 使用定向的立体定向病毒在海马中操纵G蛋白耦合受体信号传导 送货。总之，这两个目标将检验我们的总体假设，即存在互惠和加强 酒精与星形胶质细胞激活之间的关系是由星形胶质细胞对谷氨酸能的影响所介导的 音调和促炎信号传导级联。这些创新的研究将洞悉 在过渡到酒精依赖性的星形胶质细胞以及酒精诱导的神经免疫的影响 星形细胞反应的失调。