Fundamental astrocyte biology in intact neural circuits

神经生物学的一个中心目标是了解大脑如何形成，存储，检索，修改和 编码信息，并确定这些操作是如何在神经和精神病学中出错的， 疾病本申请的重点是星形胶质细胞，一种神经胶质细胞。长期以来被认为是大脑 胶，星形胶质细胞正在成为神经元功能的重要调节因子。星形胶质细胞无处不在， 覆盖整个中枢神经系统的高度分支的细胞，与神经元和血液接触 船舶，并担任不同的角色。已确定的作用包括离子稳态，神经递质 清除、突触形成/去除、突触调节和对神经血管偶联的贡献。 破译和利用星形胶质细胞在大脑中的生理作用是一个主要的开放 神经科学的问题R35的应用旨在利用技术和概念上的进步 与R 01，R21和DP 1奖项和联合收割机，他们成为一个单一的灵活，长期的研究 计划系统地探索和全面了解基础生物学 星形胶质细胞在成年脊椎动物完整的神经回路与指南针驱动的目标，利用这一点， 为推进新疗法提供信息。在这种情况下，我们将功能障碍定义为星形胶质细胞过程 从突触退出或改变星形胶质细胞信号传导，包括营养支持，突触。等 功能障碍将改变已建立的星形胶质细胞的作用，包括神经递质清除，突触 调节和维护。这反过来会改变突触传递和微电路的时间 功能，有助于兴奋性毒性，并可能触发突触消除。通过利用小说 作为DP 1和R21奖项的一部分产生的实验工具和概念，并将其应用于 作为连续R 01奖项的一部分，我们将研究纹状体微电路的范例， 星形胶质细胞在体内调节完整的神经微回路。我们将检验一个总体假设， 星形胶质细胞代表了迄今为止在神经回路功能中被很大程度上忽视的机制， 神经系统疾病作为这些努力的一部分，我们将利用并在必要时发展最先进的 用于分子、细胞和电路级别评估的工具。如本文所述，我们的长期 因此，计划目标是提供关键的分子，生理和机制的见解， 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.我们将继续公开分享我们的数据库资源和工具，以使更多的 其他人的进步。此外，该研究计划代表了一个杰出的机会， 培养下一代科学家和医学科学家的实验室环境。

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.