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.

阿富汗持久自由行动和伊拉克自由行动的研究报告指出， 战斗退伍军人酗酒和酒精使用障碍（AUD）的风险增加。 2008年至2011年期间，38%的陆军现役成员从“持久自由行动”/“伊拉克和黎凡特国际组织”部署返回。 报告说他酗酒此外，20至25岁的退伍军人有2.21倍的可能性 酗酒和2.24倍更有可能有一个澳元比同龄人46岁或以上，概述了 年轻退伍军人中酗酒的流行率。重要的是，超过50%的受访男性 甚至在部署前就报告了危险的酗酒行为尽管反复酗酒 患有急性和长期认知障碍，并有可能发展为AUD， 机制还不太清楚。 使用一种称为慢性间歇性乙醇暴露（CIE）的大鼠酗酒模型进行的研究表明， 海马神经元结构、功能和行为的长期缺陷。我们已经证明，巧合的是， 随着CA 1海马神经元回路功能的改变，酒精（EtOH）暴露导致慢性 已知参与突触重塑的星形胶质细胞分泌的信号传导因子的失调。星形细胞 通过它们的突触周星形胶质细胞过程（PAP）紧密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传导因子进行双向通信， 调节突触传递。此外，星形胶质细胞/突触通讯的行为相关性是 令人兴奋的新进展开始显示星形胶质细胞参与行为弹性， 恐惧学习，并导致药物暴露后的工作记忆缺陷。 我们目前的数据表明，EtOH诱导的未成熟树突棘（即， 兴奋性突触输入）与PAP-突触解耦时空相关。我们预测， PAP接近突触损害星形胶质细胞调节突触稳态的能力。因此，我们认为， 本申请的总体目的是阐明EtOH诱导的星形胶质细胞功能的破坏 PAP-突触耦合有助于突触网络的长期变化。实现这一目标将 使我们能够实现我们的长期目标，即确定可能导致癌症的细胞和分子机制。 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 在反复暴饮乙醇后死亡我们的中心假设是反复的酒精暴露会触发 异常星形胶质细胞信号传导和PAP-突触接近的破坏，导致突触 结构和体内平衡。这个项目背后的基本原理是， 功能和PAP-突触通讯的发生将有助于深入了解潜在的机制 酒精过量后的突触功能障碍该研究取得了成功，具有重要意义 完成将导致识别对预防和逆转神经系统疾病至关重要的非神经元过程。 酒精中毒后神经回路重塑一个跨学科的研究团队， 在酒精，星形胶质细胞，连续切片电子显微镜和电生理学领域的专业知识将 开展这一创新项目。