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; 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 青春期的暴饮暴食可促进持久的认知缺陷和较高的酒精使用障碍的发病率 成年。使用青少年暴饮暴食（ETOH）的大鼠模型的研究表明了长期缺陷 海马神经元结构，功能和行为；但是，基本机制不好 理解。与CA1海马神经元电路功能的变化一致，青少年ETOH暴露 导致星形胶质细胞反应性和已知为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体内平衡 环突触星形胶质细胞过程（PAP），可以通过各种接触来进行双向通信 调节突触传播的介导和分泌的信号传导因子。另外，行为 星形胶质细胞/突触通信的相关性开始通过令人兴奋的新进步出现 星形胶质细胞参与行为弹性，恐惧学习和遥不可及的记忆，并有助于工作 药物暴露后的记忆缺陷。当前的数据表明，ETOH诱导的持久性 未成熟的树突状棘（即兴奋性突触输入的位点）与副孢子突触相关 脱钩。根据初步数据，研究人员预测，PAP接近突触的破坏 损害神经元到胃细胞信号传导和星形胶质细胞调节突触稳态的能力。 因此，该应用的总体目的是阐明eTOH诱导的副突触的破坏 耦合和神经元 - 胃细胞串扰有助于长期突触功能变化。实现这一目标 目标将使研究人员达到其长期目标，即确定细胞和分子 可能为预防和逆转突触功能障碍和逆转而提供新的治疗方法的机制 重复的青少年ETOH暴露后AUD的出现。中心假设是重复 青少年ETOH暴露会触发Pap突触的脱钩和星形胶质细胞神经元的持久变化 相声。该项目背后的理由是了解驱动EtOH诱导的新型介体 适应不良的星形胶质细胞神经元串扰将为突触的基础机制提供关键的见解 青少年ETOH暴露后功能障碍。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 青少年乙醇暴露后的神经元电路功能障碍。一个跨学科的调查员团队 以及在青少年酒精，星形胶质细胞和电生理学领域具有专业知识的顾问 这个创新的项目。