Functional, Structural and Molecular Decoding of Astrocyte-Neuron Interaction

项目摘要 在我们几十年来对中枢神经系统（CNS）和病理生理学的追求中， 关于毁灭性的神经和精神疾病，研究几乎完全集中在一个特定的 一种"脑细胞"，神经元。然而，神经元在大脑中并不单独起作用。因此，我们可以从以下方面获益匪浅： 了解神经元和其他非神经元细胞，特别是神经胶质细胞之间的相互作用。作为最 大量的神经胶质细胞，星形胶质细胞形成广泛和密切的协会与神经元在整个 CNS。普遍的假设是星形胶质细胞对CNS神经元起被动的支持作用。 然而，包括我们自己的研究在内的越来越多的证据支持星形胶质细胞的功能多样性， 调节不同的神经回路以及复杂行为的各个方面。尽管在这方面取得了进展， 方向，星形胶质细胞和不同的细胞之间相互作用的多样性和特异性的机制， 神经元的数量仍然难以捉摸。在这个建议中，我们的目标是建立一个星形胶质细胞的多维模型- 通过解决一系列基本问题来研究前额叶回路中的神经元相互作用：星形胶质细胞如何 调节单个脑区内与各种行为系统相关的离散神经元亚群？可以 星形胶质细胞根据局部信号区分来自不同神经元集合的突触？如果是的话， 编码星形胶质细胞-神经元相互作用特异性的分子通路和结构基础？我们 拟议的研究将整合最先进的技术，用于星形胶质细胞的遗传/化学遗传操作， 信号传导和自由行为小鼠神经元活动的体内Ca2+成像，以揭示功能相互作用 星形胶质细胞和神经元之间的联系。我们还将开发新的工具和分析平台， 星形胶质细胞突起和突触界面的结构动力学和细胞类型特异性蛋白质组 离散的神经元集合。这项研究的完成将产生新的，关键的见解的复杂性， 星形胶质细胞-神经元相互作用在功能、结构和蛋白质组水平上的异质性， 前所未有的深度。重要的是，星形胶质细胞和神经元的生理和分子异常 与许多神经和精神疾病有关，如阿尔茨海默病，帕金森病， 疾病、自闭症谱系障碍和癫痫。因此，拟议的研究将有很大的潜力， 激发针对星形胶质细胞-神经元相互作用的新型疗法的开发，以治疗多种疾病 大脑紊乱

PROJECT SUMMARY In our decades-long pursuit of understanding the central nervous system (CNS) and the pathophysiology of devastating neurological and psychiatric conditions, research has nearly exclusively focused on one particular kind of “brain cell,” the neuron. However, neurons do not act alone in the brain. Thus, much is to be gained from understanding the interplay between neurons and other non-neuronal cells, particularly glial cells. As the most abundant glial cells, astrocytes form extensive and intimate associations with neurons throughout the entire CNS. The prevailing assumption has been that astrocytes perform a passive supportive role for CNS neurons. However, accumulating evidence including our own studies have supported a functional versatility of astrocytic regulation in different neural circuits as well as diverse aspects of complex behaviors. Despite progress in this direction, the mechanisms underlying the diversity and specificity of interaction between astrocytes and distinct neuron populations remains elusive. In this proposal, we aim to establish a multidimensional model of astrocyte- neuron interaction in the prefrontal circuit by addressing a series of fundamental questions: How do astrocytes regulate discrete neuronal subpopulations linked to various behavioral systems within a single brain region? Can astrocytes discriminate between synapses from distinct neuronal ensembles based on local signals? If so, what are the molecular pathways and structural basis encoding the specificity of astrocyte-neuron interaction? Our proposed research will integrate state-of-the-art techniques for genetic/chemogenetic manipulation of astrocytic signaling and in vivo Ca2+ imaging of neuronal activities in freely behaving mice to reveal the functional interaction between astrocytes and neurons. We will also generate new tools and analysis platforms that will unveil the structural dynamics and cell-type specific proteomes at the interface between astrocytic processes and synapses of discrete neuronal ensembles. The completion of this study will yield novel, critical insights into the complexity and heterogeneity of astrocyte-neuron interaction on the functional, structural, and proteomic levels with an unprecedented depth. Importantly, physiological and molecular abnormalities of both astrocytes and neurons are implicated in numerous neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, autism spectrum disorders and epilepsy. Thus, the proposed research will have a great potential to inspire the development of novel therapeutics targeted at astrocyte-neuron interaction to treat a wide range of brain disorders.