Fundamental astrocyte biology in intact neural circuits

完整神经回路中的基本星形胶质细胞生物学

• 批准号: 9923775
• 负责人: Baljit Khakh
• 金额: $ 100.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9923775
• 关键词: Adult; Astrocytes; Award; Basal Ganglia; Biology; Blood Vessels; Brain; Brain Diseases; Brain Injuries; Cells; Corpus striatum structure; Data; Databases; Development; Disease; Environment; Evaluation; Excision; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Functional disorder; Glues; Goals; Homeostasis; Ions; Laboratories; Lead; Maintenance; Mental disorders; Molecular; Neuraxis; Neurobiology; Neuroglia; Neurons; Neurosciences; Neurotransmitters; Physicians; Physiological; Process; Regulation; Research; Resources; Role; Scientist; Signal Transduction; Synapses; Synaptic Transmission; Testing; Therapeutic; Training; Withdrawal; Work; excitotoxicity; in vivo; insight; nervous system disorder; neural circuit; neurovascular coupling; next generation; novel; novel therapeutics; operation; programs; relating to nervous system; synaptogenesis; tool

A central goal of neurobiology is to understand how the brain forms, stores, retrieves, modifies and encodes information, and to determine how these operations go awry in neurological and psychiatric diseases. The focus of this application is astrocytes, a type of glia. Long considered simply the brain's glue, astrocytes are emerging as important regulators of neuronal function. Astrocytes are ubiquitous, highly branched cells that tile the entire central nervous system, making contacts with neurons and blood vessels, and serving diverse roles. Established roles include ion homeostasis, neurotransmitter clearance, synapse formation/removal, synaptic modulation and contributions to neurovascular coupling. Deciphering and exploiting the physiological roles of astrocytes in the brain is one of the major open questions in neuroscience. This R35 application seeks to exploit technical and conceptual advances made with R01, R21 and DP1 awards and combine them into a single nimble, long-term research program to systematically explore and comprehensively understand the fundamental biology of astrocytes within adult vertebrate intact neural circuits with the compass-driven goal of exploiting this information for advancing new therapies. In this context, we define dysfunction as astrocyte process withdrawal from synapses or altered astrocyte signaling, including trophic support, to synapses. Such dysfunctions would alter established astrocyte roles including neurotransmitter clearance, synapse regulation and maintenance. This in turn would alter the timing of synaptic transmission and microcircuit function, contribute to excitotoxicity and perhaps trigger synapse removal. By exploiting novel experimental tools and concepts generated as part of DP1 and R21 awards, and by applying them to the exemplar striatal microcircuitry studied as part of successive R01 awards, we will determine how astrocytes regulate intact neural microcircuits in vivo. We will test the overarching hypothesis that astrocytes represent a hitherto largely overlooked mechanism in neural circuit function and in neurological disorders. As part of these efforts, we will utilize, and if necessary develop, state-of-the-art tools for molecular, cellular and circuit levels of evaluation. As described herein, our long-term programmatic goal, therefore, is to deliver pivotal molecular, physiological and mechanistic insights on astrocyte contributions to brain function and disease, laying the groundwork for therapeutic advances to occur. We will continue to share openly our database resources and tools in order to enable additional advances by others. In addition, the research program represents an outstanding opportunity and laboratory environment for training the next generation of scientists and physician-scientists.

神经生物学的一个中心目标是了解大脑是如何形成、储存、提取、修改和 对信息进行编码，并确定这些操作在神经学和精神病学上是如何出错的 疾病。这一应用的重点是星形胶质细胞，这是一种胶质细胞。长期以来被简单地认为是大脑的 胶，星形胶质细胞正在成为神经元功能的重要调节者。星形胶质细胞无处不在， 高度分枝的细胞，覆盖整个中枢神经系统，与神经元和血液接触 船只，并服务于不同的角色。既定的角色包括离子动态平衡、神经递质 清除、突触形成/移除、突触调节和对神经血管偶联的贡献。 破译和开发星形胶质细胞在大脑中的生理作用是主要的开放之一 神经科学中的问题。这个R35应用程序寻求利用技术和概念上的进步 与R01、R21和DP1奖项一起制作，并将它们合并为一个灵活的长期研究 计划系统地探索和全面了解生物的基础生物学 成年脊椎动物体内的星形胶质细胞具有完整的神经回路，并以指南针驱动的目标来利用这一点 关于推进新疗法的信息。在此背景下，我们将功能障碍定义为星形胶质细胞突起 退出突触或改变星形胶质细胞信号，包括营养支持，到突触。是这样的 功能障碍会改变星形胶质细胞的既定角色，包括神经递质清除、突触 管理和维护。这反过来又会改变突触传递和微电路的时间 功能，有助于兴奋性毒性，并可能触发突触移除。通过利用小说 作为DP1和R21奖项的一部分生成的实验工具和概念，并通过将它们应用于 作为连续R01奖的一部分，样本纹状体微电路研究，我们将确定如何 星形胶质细胞在体内调节完整的神经微电路。我们将检验最重要的假设 星形胶质细胞代表了一种迄今在很大程度上被忽视的神经回路功能和 神经紊乱。作为这些努力的一部分，我们将利用，并在必要时开发最先进的技术 用于分子、细胞和电路水平评估的工具。正如这里所描述的，我们的长期 因此，计划的目标是提供关键的分子、生理和机制方面的见解 星形胶质细胞对脑功能和疾病的贡献，为治疗进展奠定了基础 发生。我们将继续公开共享我们的数据库资源和工具，以实现更多 其他人的预付款。此外，研究计划代表着一个绝佳的机会和 培养下一代科学家和内科科学家的实验室环境。