Linking Fast Timescale Neuron-Astrocyte Communication to Neural Circuit Function and Behavior

项目摘要：项目2-连接快速时间尺度神经元-星形胶质细胞与神经细胞的通讯 电路功能和行为 神经科学中一个基本但尚未解决的问题是非神经细胞如何与 影响神经元的功能，并潜在地影响动物的行为。星形胶质细胞处于一种独特的 调节神经回路功能的位置。它们普遍存在于所有中枢神经系统区域，表达的受体为 神经递质、神经调节剂和神经肽延伸了高度分支的过程，这些过程与 突触和其他中枢神经系统元件，并可以作为一个合胞体运作，部分原因是他们的缝隙连接耦合。 这些结构和功能特性使它们能够调节突触的可塑性和神经元的兴奋性。 事实上，来自多个物种和中枢神经系统区域的实验证据现在表明，星形胶质细胞调节 慢时标和快时标上的神经回路功能和行为。然而，星形胶质细胞究竟是如何 对环境中的复合分子信号的响应以及它们复杂的激发模式 神经回路功能对快速时标(亚秒到分钟)的影响尚不清楚。该项目将 检验星形胶质细胞瞬变的异质性可以通过时间整合来理解的假设 它们所处环境中的时变分子信号。此前的研究也表明，星形胶质细胞 至少在两种不同的模式下运行：1)单独运行，2)作为合体运行。然而，这些不同因素的相关性 神经回路功能的化学激发形式仍然是个谜。该项目的第二个假设是 不同的活动模式起着不同的生理作用，使星形胶质细胞能够影响神经回路 以及不同时间尺度上的行为。该项目提出了四个主要目标来解决这些问题，作为 团队主动性。目标1将确定局部神经元的分子信号如何与星形胶质细胞兴奋有关。目标 2重点阐明投射神经元传递的神经调节剂信号如何影响星形胶质细胞的活动。目标 3将确定星形胶质细胞功能的靶向操作(例如，它们检测、暂时整合、 传递或响应细胞外信号)调节它们的兴奋模式、神经电路功能和 行为。Aim 4将生成所研究的神经元-星形胶质细胞回路的多层、多水平图谱。这些 数据将从涉及感觉运动处理的一组常见的小鼠皮质区域中使用 基于奖励的定量行为分析。对这些数据的计算分析和建模将用于 识别控制星形胶质细胞兴奋的变量，细胞内在参数限制这一活动，不同 活动模式，以及受这些星形细胞特征影响的神经元特性。总而言之，功能性和 本项目的解剖学研究将a)提供有关星形胶质细胞(单独或 作为一个联合体)响应、整合和调节神经回路功能(项目1和2)；b)指导 用于询问神经元-星形胶质细胞的新型遗传编码指标和干预工具的开发 活体内电路(项目2、3和4)；c)告知、测试和改进预测神经元-星形胶质细胞电路模型 传感器运动处理(项目1、2和数据科学资源核心)。

Project Summary: Project 2 - Linking Fast Timescale Neuron-Astrocyte Communication to Neural Circuit Function and Behavior A fundamental yet unresolved question in neuroscience is how non-neuronal cells communicate with the surrounding neurons, influence their function, and potentially affect animal behavior. Astrocytes are in a unique position to modulate neural circuit function. They are ubiquitous in all CNS regions, express receptors for neurotransmitters, neuromodulators, and neuropeptides, extend highly ramified processes that interact with synapses and other CNS elements, and can operate as a syncytium partly due to their gap junctional coupling. These structural and functional properties enable them to modulate synaptic plasticity and neuronal excitability. Indeed, experimental evidence from multiple species and CNS regions now suggests that astrocytes modulate neural circuit function and behavior on both slow and fast timescales. Nevertheless, precisely how astrocytes respond to the composite molecular signals in their environment and how their intricate excitation patterns influence neural circuit function on fast timescales (sub-seconds to minutes) remains unclear. This Project will test the hypothesis that the heterogeneity of astrocyte transients can be understood by the temporal integration of the time-varying molecular signals in their environment. Previous studies have also suggested that astrocytes operate in at least two different modes: 1) Individually, and 2) as a syncytium. Yet, the relevance of these various forms of chemical excitation for neural circuit function remains a mystery. This Project's second hypothesis is that the different activity modes serve distinct physiological roles, enabling astrocytes to influence neural circuits and behavior on different timescales. This Project proposes four major Aims to tackle these issues as part of a team initiative. Aim 1 will determine how molecular signaling by local neurons relates to astrocyte excitation. Aim 2 focuses on elucidating how neuromodulator signaling by projection neurons influences astrocyte activity. Aim 3 will determine how targeted manipulation of astrocyte function (e.g., their ability to detect, temporally integrate, communicate, or respond to extracellular signals) modulates their excitation patterns, neural circuit function, and behavior. Aim 4 will generate a multilayer, multilevel atlas of the investigated neuron-astrocyte circuits. These data will be acquired from a common set of mouse cortical regions involved in sensorimotor processing using a reward-based quantitative behavioral assay. Computational analyses and modeling of this data will be used to identify variables controlling astrocyte excitation, cell-intrinsic parameters constraining this activity, distinct activity modes, and neuronal properties affected by these astrocytic features. Together, the functional and anatomical studies of this Project will a) provide foundational information about how astrocytes (individually or as a syncytium) respond to, integrate, and modulate neural circuit function (Projects 1 and 2); b) guide the development of novel genetically encoded indicators and interventional tools to interrogate neuron-astrocyte circuits in vivo (Projects 2, 3, and 4); c) inform, test, and refine predictive neuron-astrocyte circuit models of sensorimotor processing (Projects 1, 2, and Data Science Resource Core).