Long-term effects of binge drinking on astrocyte-synaptic interactions

酗酒对星形胶质细胞-突触相互作用的长期影响

• 批准号: 10256125
• 负责人: Mary-Louise Risher
• 金额: --
• 依托单位: HUNTINGTON VETERANS AFFAIRS MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10256125
• 关键词: Acute; Affect; Afghanistan; Age; Alcohol abuse; Alcohols; Anxiety; Astrocytes; Automobile Driving; Behavior; Behavioral; Cells; Chronic; Cognitive deficits; Communication; Consumption; Coupling; Data; Dendritic Spines; Development; Drug Exposure; Electron Microscopy; Electrophysiology (science); Ethanol; Female; Freedom; Fright; Functional disorder; Goals; Health; Hippocampus (Brain); Homeostasis; Hyperactivity; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Ions; Knowledge; Label; Lead; Learning; Link; Long-Term Effects; Mediating; Mediator of activation protein; Memory impairment; Military Personnel; Mission; Modeling; Molecular; Morphology; Neuraxis; Neurons; Output; Pharmacotherapy; Population; Populations at Risk; Positioning Attribute; Prevalence; Prevention; Process; Rattus; Regulation; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Short-Term Memory; Signal Transduction; Site; Slice; Structure; Substance abuse problem; Surveys; Synapses; Synaptic Transmission; Time; Vertebral column; Veterans; Viral; Vulnerable Populations; active duty; aged; alcohol abuse therapy; alcohol exposure; alcohol misuse; alcohol use disorder; binge drinking; combat veteran; depressive symptoms; design; drinking; drinking behavior; hazardous drinking; in vivo; innovation; insight; male; member; military veteran; neuronal circuitry; novel; operation; peer; prevent; resilience; spatiotemporal; symptom treatment; synaptic function; targeted treatment

Operation Enduring Freedom in Afghanistan and Operation Iraqi Freedom (OEF/OIF) studies report that combat veterans are at increased risk for binge drinking and the development of alcohol use disorder (AUD). 38% of Army active duty members surveyed returning from OEF/OIF deployments between 2008 and 2011 reported binge drinking. Furthermore, veterans between the ages of 20 and 25 are 2.21 times more likely to binge drink and 2.24 times more likely to have an AUD than their peers aged 46 years or older, outlining the prevalence of alcohol abuse in the young veteran population. Importantly, more than 50% of males surveyed reported hazardous binge drinking even prior to deployment. Despite repeated binge drinking being associated with acute and long-term cognitive impairment and increased likelihood of developing AUD, the underlying mechanisms are not well understood. Studies using a rat model of binge drinking called chronic intermittent ethanol exposure (CIE) demonstrate long-term deficits in hippocampal neuronal structure, function, and behavior. We have shown that, coincident with changes in CA1 hippocampal neuronal circuit function, binge ethanol (EtOH) exposure results in chronic dysregulation of astrocyte-secreted signaling factors known to be involved in synaptic remodeling. Astrocytes tightly regulate synaptic activity and ion homeostasis through their perisynaptic astrocyte processes (PAPs), allowing for bi-directional communication through various contact-mediated and secreted signaling factors that modulate synaptic transmission. In addition, the behavioral relevance of astrocyte/synaptic communication is beginning to emerge through exciting new advances showing astrocytes to be involved in behavioral resiliency, fear learning, and contributing to working memory deficits following drug exposure. Our current data demonstrate that EtOH-induced persistence of immature dendritic spines (i.e. sites of excitatory synaptic input) is spatiotemporally linked with PAP-synaptic decoupling. We predict that disruption of PAP proximity to synapses compromises the ability of astrocytes to regulate synaptic homeostasis. Therefore, the overall objective of this application is to elucidate how EtOH-induced disruption of astrocyte function and PAP-synaptic coupling contributes to long-term changes in synaptic networks. Achieving this objective will allow us to reach our long-term goal, which is to identify the cellular and molecular mechanisms that may inform novel treatments for the prevention and reversal of synaptic dysfunction and the emergence of AUD after repeated binge EtOH exposure. Our central hypothesis is that repeated binge EtOH exposure triggers aberrant astrocyte signaling and disruption of PAP-synaptic proximity that drive lasting deficits in synaptic structure and homeostasis. The rationale behind this project is that understanding how disruption of astrocyte function and PAP-synaptic communication occur will contribute key insight into the mechanisms underlying synaptic dysfunction following binge EtOH exposure. The proposed research is significant since successful completion will result in the identification of non-neuronal processes critical for the prevention and reversal of neuronal circuit remodeling following binge ethanol exposure. An interdisciplinary team of investigators with expertise in the field of alcohol, astrocytes, serial section electron microscopy, and electrophysiology will conduct this innovative project.

阿富汗的持久自由行动和伊拉克自由行动（OEF/OIF）研究报告 战斗退伍军人的暴饮暴食风险增加和饮酒障碍的发展（AUD）。 在2008年至2011年期间，有38％的陆军现役成员从OEF/OIF部署返回 据报道暴饮暴食。此外，20至25岁之间的退伍军人的可能性高2.21倍 暴饮暴食，拥有AUD的可能性是46岁或46岁以上的同龄人的2.24倍 年轻退伍军人人口中酗酒的患病率。重要的是，被调查的男性中有50％以上 据报道，甚至在部署之前，危险的暴饮暴食。尽管一再狂欢饮酒有联系 随着急性和长期认知障碍和发展AUD的可能性增加 机制尚不清楚。 使用称为慢性间歇性乙醇暴露（CIE）的暴饮暴食大鼠模型的研究表明 海马神经元结构，功能和行为的长期缺陷。我们已经表明，巧合 随着CA1海马神经元电路功能的变化，暴饮暴食（ETOH）暴露导致慢性 已知参与突触重塑的星形胶质细胞分泌信号传导因子的失调。星形胶质细胞 通过其突触的星形胶质细胞过程（PAPS），严格调节突触活动和离子稳态， 允许通过各种接触介导的和分泌的信号因素进行双向通信 调节突触传输。此外，星形胶质细胞/突触通信的行为相关性是 通过令人兴奋的新进步开始出现，表明星形胶质细胞参与行为弹性， 害怕学习，并导致药物暴露后的工作记忆不足。 我们当前的数据表明，EtOH诱导的未成熟树突状棘突的持久性（即 兴奋性突触输入）时空与子宫颈突触的脱钩相关。我们预测破坏 PAP接近突触会损害星形胶质细胞调节突触稳态的能力。所以， 该应用的总体目的是阐明EtoH诱导的星形胶质细胞功能的破坏和 PAP突触耦合有助于突触网络的长期变化。实现这一目标将 允许我们达到长期目标，即确定可能的细胞和分子机制 为预防和逆转突触功能障碍和AUD的出现提供新的治疗方法 反复暴饮暴食后。我们的中心假设是重复的暴饮暴食触发触发器 异常的星形胶质细胞信号传导和PAP突触接近的破坏，使突触中持续不足 结构和稳态。该项目背后的理由是了解星形胶质细胞的干扰 功能和子宫颈脑沟通的发生将有助于对基本机制的重要见解 暴发ETOH暴露后突触功能障碍。拟议的研究很重要，因为成功 完成将导致识别非神经元过程对预防和逆转至关重要 暴饮暴食后神经元回路重塑。一个研究人员的跨学科团队 酒精，星形胶质细胞，串行部分电子显微镜和电生理学领域的专业知识将 进行这个创新的项目。