The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse

星形胶质细胞 GPCR 信号传导对酒精滥用的功能影响

• 批准号: 10089613
• 负责人: Simon Alexander Marshall
• 金额: $ 36.65万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089613
• 关键词: Address; Adult; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; American; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Area; Astrocytes; Behavior; Behavioral; Blood; Blood alcohol level measurement; Brain; Brain Injuries; Cells; Consummatory Behavior; Consumption; Data; Development; Economic Burden; Ethanol; Ethanol dependence; Event; G Protein-Coupled Receptor Signaling; G alpha q Protein; G-Protein-Coupled Receptors; GLAST Protein; Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; Grant; Healthcare; Heavy Drinking; Immunohistochemistry; Individual; Inflammatory; Influentials; Interleukin-1 beta; Interpersonal Relations; Measures; Mediating; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Nerve Degeneration; Neurobiology; Neuroimmune; Neuroimmune system; Neuronal Plasticity; Operative Surgical Procedures; Pathologic; Pattern; Population; Procedures; Production; Property; Quantitative Reverse Transcriptase PCR; Recording of previous events; Regulation; Research; Role; Safety; Sex Differences; Signal Pathway; Signal Transduction; Societies; Testing; Time; United States; Virus; Work; alcohol behavior; alcohol consequences; alcohol effect; alcohol exposure; alcohol misuse; alcohol pharmacology; alcohol use disorder; binge drinking; cost; cytokine; density; designer receptors exclusively activated by designer drugs; drinking; glial activation; glutamatergic signaling; health economics; immunoreactivity; innovation; insight; interest; neurobiological mechanism; neuroinflammation; neurotransmission; new therapeutic target; novel; novel therapeutics; promoter; receptor expression; response; sex; social; socioeconomics

Project Description Problematic alcohol consumption is a major health and socio-economic issue within the United States, but much of the economic burden and pathological consequences from alcohol misuse is associated with binge drinking. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has defined binge drinking as a pattern of drinking that results in a blood ethanol concentration (BEC) of greater than 80mg/dL. Repetitive binge drinking episodes greatly increases the likelihood of developing ethanol dependence. As such, it is critical to consider the neurobiological mechanisms that modulate binge drinking in order to develop novel therapeutic areas to curb alcohol misuse. The neuroimmune system has become of increasing interest as alcohol abuse can elicit neuroinflammatory cascades that can contribute to alcohol-induced neurodegeneration, but of more relevance to this study, alcohol can alter the neuroimmune systems role in neurotransmission and therein contribute to alcohol-related behaviors. This grant furthers our previous studies of binge-like alcohol’s effects on cytokines in the amygdala by specifically determining the impacts of alcohol misuse on astrocyte activation and expression patterns (Aim 1). Moreover, the impact of repeated binge-like drinking episodes on the permanence or plasticity of an altered astrocyte population will be ascertained (Aim 1). Secondly, these studies will determine the role of astrocytic signaling on ethanol consumption and alcohol- induced anxiolytic behavior (Aim 2), but Aim 3 will also determine whether alcohol’s impact on astrocytic glutamate and cytokine regulation is related to changes in alcohol consumption and pharmacologic properties. This will be accomplished by manipulating G-protein coupled receptors specifically in astrocytes using DREADDs under a GFAP promoter. Because sex-differences can alter neuroimmune responses, these studies will elucidate the impact of sex on both astrocytes effects on behavior and binge drinking on astrocytes. Together these three aims will test the overall hypothesis that there is a reciprocal and reinforcing relationship between alcohol and astrocyte activation associated with the impact of astrocytes on glutamatergic tone and cytokine production. These innovative studies will provide insight into the role of astrocytes in the transition to alcohol dependence, novel information regarding the impact of sex on alcohol-induced neuroimmune changes, and a shift in our understanding of the relationship between alcohol misuse and neuroimmune dysregulation.

项目说明 在美国，有问题的饮酒是一个主要的健康和社会经济问题，但 酗酒造成的大部分经济负担和病理后果都与酗酒有关。 喝酒。国家酒精滥用和酒精中毒研究所(NIAAA)将酗酒定义为 导致血液酒精浓度(BEC)大于80 mg/dL的饮酒模式。重复性 大量饮酒极大地增加了发展成酒精依赖的可能性。因此，它是 关键是要考虑调节酗酒的神经生物学机制，以开发新的 控制酒精滥用的治疗领域。神经免疫系统越来越受到人们的关注，因为 酒精滥用可引发神经炎性级联反应，从而导致酒精诱导 神经变性，但与这项研究更相关的是，酒精可以改变神经免疫系统在 神经传递和其中促成了与酒精相关的行为。这笔拨款进一步加深了我们以前的研究。 通过具体确定酒精对杏仁核细胞因子的影响来研究酗酒对杏仁核细胞因子的影响 误用星形胶质细胞的激活和表达模式(目标1)。此外，反复暴饮暴食的影响 饮酒对改变的星形胶质细胞种群的持久性或可塑性的影响将被确定(目的 1)。其次，这些研究将确定星形胶质细胞信号在酒精消费和酒精- 诱导焦虑行为(目标2)，但目标3也将决定酒精对星形胶质细胞的影响 谷氨酸和细胞因子的调节与酒精消费和药理特性的变化有关。 这将通过操纵星形胶质细胞中的G蛋白偶联受体来实现 GFAP启动子下的DREADDS。因为性别差异会改变神经免疫反应，这些研究 将阐明性别对星形胶质细胞的影响、对行为的影响以及酗酒对星形胶质细胞的影响。 这三个目标加在一起将检验总体假设，即存在互惠和强化的关系 酒精和星形胶质细胞激活之间的关系星形胶质细胞对谷氨酸能张力和 细胞因子的产生。这些创新的研究将深入了解星形胶质细胞在向 酒精依赖，关于性行为对酒精诱导的神经免疫变化的影响的新信息， 以及我们对酒精滥用和神经免疫失调之间关系的理解发生了转变。