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: 10409565
• 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/10409565
• 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(OEF/OIF)研究报告称 退伍军人酗酒和酒精使用障碍(AUD)的风险增加。 38%的受访陆军现役军人在2008至2011年间从OEF/OIF部署返回 据报道酗酒。此外，年龄在20岁到25岁之间的退伍军人患癌症的可能性是男性的2.21倍 大量饮酒，患澳门氏症的可能性是46岁或以上同龄人的2.24倍，概述了 年轻退伍军人中酗酒的普遍程度。重要的是，超过50%的受访男性 甚至在部署之前就报告了危险的狂欢饮酒。尽管反复酗酒被认为是 患有急性和长期的认知障碍，并增加发展为AUD的可能性，潜在的 机制还不是很清楚。 使用一种名为慢性间歇性酒精暴露(CIE)的狂饮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。我们已经证明了，不谋而合 随着CA1区神经元回路功能的改变，过量乙醇(Etoh)暴露导致慢性 已知参与突触重建的星形胶质细胞分泌信号因子的失调。星形胶质细胞 通过突触周围星形胶质细胞突起(PAPs)严格调节突触活动和离子动态平衡， 允许通过各种接触中介的和分泌的信令因子进行双向通信 调节突触传递。此外，星形胶质细胞/突触交流的行为相关性是 开始出现令人兴奋的新进展，表明星形胶质细胞参与行为弹性， 害怕学习，并在药物暴露后导致工作记忆缺陷。 我们目前的数据表明，乙醇诱导的未成熟树突棘(即 兴奋性突触输入)在时空上与PAP-突触去耦合有关。我们预测， PAP接近突触会影响星形胶质细胞调节突触动态平衡的能力。因此， 这项应用的总体目标是阐明乙醇是如何诱导星形胶质细胞功能和 突触-突触耦合有助于突触网络的长期变化。实现这一目标将 使我们能够达到我们的长期目标，即确定细胞和分子机制 提示预防和逆转突触功能障碍和AUD出现的新疗法 在反复暴饮暴食酒精后。我们的中心假设是，反复暴饮乙醇会触发 星形胶质细胞信号的异常和PAP-突触邻近性的破坏导致突触的持续性缺陷 结构和动态平衡。这个项目背后的基本原理是理解星形胶质细胞的破坏 功能和PAP-突触通讯的发生将有助于对潜在机制的关键洞察 暴饮性酒精暴露后的突触功能障碍。由于研究的成功，所提出的研究具有重要意义。 这项工作的完成将导致识别对预防和逆转 酗酒暴露后神经元回路重塑。一个由多个学科组成的调查小组 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 开展这一创新项目。