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

将快速时间尺度神经元-星形胶质细胞通信与神经回路功能和行为联系起来

• 批准号: 10461226
• 负责人: Axel Nimmerjahn
• 金额: $ 44.59万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461226
• 关键词: Adult; Affect; Anatomy; Animal Behavior; Animals; Astrocytes; Atlases; Behavior; Behavioral; Behavioral Assay; Blood Vessels; Brain; Brain region; Cells; Chemicals; Communication; Computer Analysis; Computer Models; Coupled; Coupling; Data; Data Science Core; Data Set; Development; Elements; Environment; Fiber; Foundations; Gap Junctions; Genetic; Giant Cells; Goals; Heterogeneity; Individual; Intervention; Ions; Link; Maps; Measurement; Microscopy; Modeling; Molecular; Mus; Neuroglia; Neuromodulator; Neurons; Neuropeptides; Neurosciences; Neurotransmitter Receptor; Pattern; Physiological; Positioning Attribute; Process; Property; Regulation; Rewards; Role; Signal Transduction; Synapses; Synaptic plasticity; Task Performances; Techniques; Testing; Time; base; cellular imaging; cholinergic; experimental study; extracellular; in vivo; in vivo imaging; molecular dynamics; multiplexed imaging; neural circuit; neural patterning; neuronal excitability; neuroregulation; noradrenergic; novel; predictive modeling; receptor; relating to nervous system; spatiotemporal; tool

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).

项目摘要：项目 2 - 将快速时间尺度神经元-星形胶质细胞通讯与神经元联系起来 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元细胞如何与 围绕神经元，影响其功能，并可能影响动物行为。星形胶质细胞具有独特的 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，表达受体 神经递质、神经调节剂和神经肽，扩展了与相互作用的高度分支的过程 突触和其他中枢神经系统元件，并且可以作为合胞体运作，部分原因是它们的间隙连接耦合。 这些结构和功能特性使它们能够调节突触可塑性和神经元兴奋性。 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 慢速和快速时间尺度上的神经回路功能和行为。然而，星形胶质细胞究竟如何 对其环境中的复合分子信号及其复杂的激发模式做出反应 在快速时间尺度（亚秒到分钟）上影响神经回路功能仍不清楚。该项目将 检验星形胶质细胞瞬变的异质性可以通过时间积分来理解的假设 环境中随时间变化的分子信号。先前的研究还表明星形胶质细胞 至少以两种不同的模式运行：1）单独，2）作为合胞体。然而，这些不同的相关性 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 不同的活动模式具有不同的生理作用，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。作为解决这些问题的一部分，该项目提出了四个主要目标 团队主动性。目标 1 将确定局部神经元的分子信号传导如何与星形胶质细胞兴奋相关。目的 图 2 重点阐明投射神经元的神经调节信号传导如何影响星形胶质细胞的活动。目的 3 将确定如何有针对性地操纵星形胶质细胞功能（例如，它们检测、暂时整合、 沟通或响应细胞外信号）调节其兴奋模式、神经回路功能，以及 行为。目标 4 将生成所研究的神经元-星形胶质细胞回路的多层、多级图集。这些 数据将从参与感觉运动处理的一组共同的小鼠皮质区域获取，使用 基于奖励的定量行为分析。该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、限制这种活动的细胞内在参数、不同的 活动模式以及受这些星形胶质细胞特征影响的神经元特性。功能性和 该项目的解剖学研究将 a) 提供有关星形胶质细胞（单独或 作为合胞体）响应、整合和调节神经回路功能（项目 1 和 2）； b) 指导 开发新的基因编码指标和介入工具来询问神经元星形胶质细胞 体内电路（项目 2、3 和 4）； c) 告知、测试和完善预测神经元-星形胶质细胞回路模型 感觉运动处理（项目 1、2 和数据科学资源核心）。