Astrocyte Modulation of Neural Circuit Function and Behavior

项目总结：总体 “神经中枢神经胶质细胞的功能是什么？答案仍然未知，而且可能仍未解决 直到科学家们找到直接的方法来攻击它。(Ramon y Cajal，1901)。这个预言 事实证明是准确的。星形胶质细胞是大脑中最丰富的细胞类型之一，长期以来一直被认为 主要作为被动支持细胞。在过去的二十年里，研究表明星形胶质细胞起着关键作用。 在神经系统发育、功能和疾病中的作用。然而，一个重大悬而未决的问题是 神经科学是星形胶质细胞如何在健康的条件下整合不同的神经元信号，调节神经 在多个时间和空间尺度上的电路结构和功能，以及反常激发和分子 输出会影响感觉运动行为，并导致疾病。这支U19团队的总体目标--研究 脑回路计划的建议是通过开发更深层次的机制来解决这一根本问题 了解星形胶质细胞在神经回路操作、复杂行为和脑计算中的作用 理论。主要讨论两个问题：1)星形胶质细胞如何在时间和空间上整合 来自不同类型的局部神经元和投射神经元的分子信号在感觉运动行为中被激活。 2)星形胶质细胞如何将这些信息转换为功能输出，从而调节神经电路结构和 在不同的空间和时间尺度上发挥作用。提出了一个多学科的、综合的努力来解决 这些问题只能通过研究人员与独特的和 互补的专业知识。一种集功能、解剖和遗传学于一体的创新多尺度方法 将利用理论建模进行分析。这种方法包括定量的行为分析， 细胞和分子动力学的大规模成像，针对细胞类型的特定操作，高 吞吐量组学技术、基因图谱、蛋白质工程、机器学习和计算 模特儿。通过将实验和理论方法、分子、细胞和电路机制相结合 将确定星形胶质细胞通过哪些影响神经回路并促进复杂的行为和 脑计算理论。作为该项目的一部分开发的实验和数据分析工具将是 对于更广泛的神经科学界来说，这是无价的。

Project Summary: Overall “What is the function of glial cells in neural centers? The answer is still not known, and it may remain unsolved for many years to come until scientists find direct methods to attack it.” (Ramon y Cajal, 1901). This prophecy turned out to be accurate. Astrocytes, one of the most abundant cell types in the brain, have long been thought of as primarily passive support cells. Over the past two decades, studies indicate that astrocytes play pivotal roles in nervous system development, function, and diseases. However, a major unresolved issue in neuroscience is how astrocytes integrate diverse neuronal signals under healthy conditions, modulate neural circuit structure and function at multiple temporal and spatial scales, and how aberrant excitation and molecular output influences sensorimotor behavior and contributes to disease. The overall goal of this U19 Team-Research BRAIN Circuit Program proposal is to address this fundamental issue by developing a deeper mechanistic understanding of astrocytes’ roles in neural circuit operation, complex behaviors, and brain computation theories. Two overarching questions will be addressed: 1) How do astrocytes temporally and spatially integrate molecular signals from the diverse types of local and projection neurons activated during sensorimotor behaviors. 2) How do astrocytes convert this information into functional outputs that modulate neural circuit structure and function at different spatial and temporal scales. A multidisciplinary, comprehensive effort is proposed to address these questions that can only be completed through close collaboration between researchers with unique and complementary expertise. An innovative multi-scale approach integrating functional, anatomical, and genetic analyses with theoretical modeling will be leveraged. This approach involves quantitative behavioral assays, large-scale imaging of cellular and molecular dynamics, targeted cell-type-specific manipulations, high- throughput omic techniques, genetic profiling, protein engineering, machine learning, and computational modeling. By integrating experimental and theoretical approaches, molecular, cellular, and circuit mechanisms will be determined through which astrocytes influence neural circuits and contribute to complex behaviors and brain computation theories. The experimental and data analysis tools developed as part of this project will be invaluable for the broader neuroscience community.