Effects of adolescent ethanol exposure on astrocyte-neuronal crosstalk

青少年乙醇暴露对星形胶质细胞-神经元串扰的影响

• 批准号: 10590098
• 负责人: Mary-Louise Risher
• 金额: $ 21.28万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590098
• 关键词: Acute; Adenosine; Adolescence; Adolescent; Adult; Affect; Agonist; Alcohols; Astrocytes; Attenuated; Behavior; Behavioral; Brain; Central Nervous System; Chronic; Cognitive deficits; Communication; Coupling; Data; Dendritic Spines; Development; Drug Exposure; Electrophysiology (science); Ethanol; Fright; Functional disorder; Future; Glutamates; Goals; High School Student; Hippocampus; Homeostasis; Impaired cognition; Impairment; Incidence; Ions; Knowledge; Learning; Life; Link; Long-Term Effects; Mediating; Mediator; Memory; Memory impairment; Mission; Modeling; Molecular; National Institute on Alcohol Abuse and Alcoholism; Neuroglia; Neurons; Output; Peripheral; Positioning Attribute; Prevention; Process; Rattus; Recording of previous events; Recovery; Regulation; Reporting; Research; Research Personnel; Short-Term Memory; Signal Transduction; Site; Slice; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; United States National Institutes of Health; adolescent alcohol exposure; adolescent binge drinking; alcohol exposure; alcohol use disorder; binge drinking; critical developmental period; critical period; designer receptors exclusively activated by designer drugs; innovation; insight; neuron loss; neuronal circuitry; neurotransmission; novel; prevent; resilience; spatiotemporal; synaptic function; underage drinking

ABSTRACT Adolescent binge drinking promotes enduring cognitive deficits and higher incidence of alcohol use disorder in adulthood. Studies using a rat model of adolescent binge drinking (EtOH) demonstrate long-term deficits in hippocampal neuronal structure, function, and behavior; however, the underlying mechanisms are not well understood. Coincident with changes in CA1 hippocampal neuronal circuit function, adolescent EtOH exposure results in astrocyte reactivity and 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 remote memory, and contribute to working memory deficits following drug exposure. Current data demonstrates that EtOH-induced persistence of immature dendritic spines (i.e. sites of excitatory synaptic input) is spatiotemporally linked with PAP-synaptic decoupling. Based on preliminary data the researchers predict that disruption of PAP proximity to synapses compromises neuron-to-astrocyte signaling and the ability of astrocytes to regulate synaptic homeostasis. Therefore, the overall objective of this application is to elucidate how EtOH-induced disruption of PAP-synaptic coupling and neuron-astrocyte crosstalk contributes to long-term changes in synaptic function. Achieving this objective will allow the researchers to reach their 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 adolescent EtOH exposure. The central hypothesis is that repeated adolescent EtOH exposure triggers PAP-synaptic decoupling and lasting changes in astrocyte-neuronal crosstalk. The rationale behind the project is that understanding the novel mediators that drive EtOH-induced maladaptive astrocyte-neuronal crosstalk will contribute key insight into the mechanisms underlying synaptic dysfunction following adolescent 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 dysfunction following adolescent ethanol exposure. An interdisciplinary team of investigators and consultants with expertise in the field of adolescent alcohol, astrocytes, and electrophysiology will conduct this innovative project.

抽象的 青少年酗酒会导致持久的认知缺陷和酒精使用障碍的发生率更高 成年期。使用青少年酗酒 (EtOH) 大鼠模型进行的研究表明， 海马神经元结构、功能和行为；但底层机制并不完善 明白了。青少年乙醇暴露与 CA1 海马神经元回路功能的变化一致 导致星形胶质细胞反应性和星形胶质细胞分泌的信号因子的慢性失调 参与突触重塑。星形胶质细胞通过其紧密调节突触活动和离子稳态 突触周围星形胶质细胞过程（PAP），允许通过各种接触进行双向通信 调节突触传递的介导和分泌的信号因子。此外，行为 通过令人兴奋的新进展，星形胶质细胞/突触通讯的相关性开始出现 星形胶质细胞参与行为弹性、恐惧学习和远程记忆，并有助于工作 接触药物后记忆力减退。目前的数据表明，EtOH 诱导的持久性 未成熟的树突棘（即兴奋性突触输入位点）与 PAP 突触在时空上相关 脱钩。根据初步数据，研究人员预测 PAP 与突触接近的破坏 损害神经元到星形胶质细胞的信号传导以及星形胶质细胞调节突触稳态的能力。 因此，本申请的总体目标是阐明 EtOH 如何诱导 PAP 突触破坏 耦合和神经元-星形胶质细胞串扰有助于突触功能的长期变化。实现这一点 目标将使研究人员能够实现他们的长期目标，即识别细胞和分子 可能为预防和逆转突触功能障碍的新疗法提供信息的机制 青少年反复接触乙醇后出现 AUD。中心假设是重复 青少年乙醇暴露触发 PAP 突触解耦和星形胶质细胞神经元的持久变化 相声。该项目背后的基本原理是了解驱动 EtOH 诱导的新型介质 适应不良的星形胶质细胞-神经元串扰将有助于深入了解突触背后的机制 青少年乙醇暴露后功能障碍。由于成功，拟议的研究意义重大 完成将导致识别对于预防和逆转至关重要的非神经元过程 青少年乙醇暴露后神经元回路功能障碍。跨学科研究团队 具有青少年酒精、星形胶质细胞和电生理学领域专业知识的顾问将进行 这个创新项目。