Astrocyte Modulation of Neural Circuit Function and Behavior

项目概要：总体 “神经胶质细胞在神经中枢的功能是什么？答案仍然不得而知，它可能仍然没有解决 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 被证明是准确的。星形胶质细胞是大脑中最丰富的细胞类型之一， 作为主要的被动支持细胞。在过去的二十年里，研究表明星形胶质细胞发挥着关键作用 在神经系统发育、功能和疾病中的作用。然而，一个尚未解决的主要问题是， 神经科学是星形胶质细胞如何在健康条件下整合不同的神经信号，调节神经元信号， 电路结构和功能在多个时间和空间尺度，以及如何异常激发和分子 输出影响感觉运动行为并导致疾病。U19团队研究的总体目标 脑回路计划的建议是通过开发一个更深层次的机制来解决这个根本问题。 了解星形胶质细胞在神经回路运作、复杂行为和大脑计算中的作用 理论两个首要问题将得到解决：1）星形胶质细胞如何在时间和空间上整合 来自感觉运动行为期间激活的不同类型的局部和投射神经元的分子信号。 2)星形胶质细胞如何将这些信息转化为调节神经回路结构的功能输出， 在不同的时空尺度上发挥作用。建议开展多学科的综合努力， 这些问题只能通过研究人员之间的密切合作来完成， 补充专业知识。一种创新的多尺度方法，整合了功能，解剖和遗传 将利用理论模型进行分析。该方法涉及定量行为分析， 细胞和分子动力学的大规模成像，靶向细胞类型特异性操作，高 通量组学技术，遗传分析，蛋白质工程，机器学习和计算 建模通过整合实验和理论方法，分子，细胞和电路机制， 将确定星形胶质细胞通过哪些影响神经回路，并有助于复杂的行为， 大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 对更广泛的神经科学界来说是无价的。

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.