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).

项目概要：项目2-将快速时间尺度神经元-星形胶质细胞通信与神经元 电路功能和行为 神经科学中一个尚未解决的基本问题是非神经元细胞如何与神经元细胞进行通信。 周围的神经元，影响它们的功能，并可能影响动物的行为。星形胶质细胞是一种独特的 调节神经回路功能的位置。它们普遍存在于所有CNS区域，表达 神经递质，神经调质和神经肽，延伸高度分歧的过程， 突触和其他CNS元件，并且部分由于它们的间隙连接偶联而可以作为合胞体操作。 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 神经回路功能和行为在慢和快的时间尺度上。然而，星形胶质细胞 对环境中复合分子信号的反应以及它们复杂的激发模式 在快速时间尺度（亚秒到分钟）上影响神经回路功能仍然不清楚。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。 时变分子信号的变化。先前的研究也表明星形胶质细胞 以至少两种不同的模式操作：1）单独地，和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兴奋形式仍然是一个谜。本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， 以及不同时间尺度下的行为该项目提出了四个主要目标，以解决这些问题，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的兴奋相关。目的 2集中于阐明投射神经元的神经调质信号传导如何影响星形胶质细胞活性。目的 3将确定星形胶质细胞功能的靶向操纵（例如，他们的能力，检测，时间积分， 通信，或响应细胞外信号）调节其兴奋模式，神经回路功能， 行为目标4将产生一个多层次，多层次的图集的研究神经元星形胶质细胞电路。这些 数据将从参与感觉运动处理的一组常见的小鼠皮层区域获得， 基于奖励的定量行为分析。这些数据的计算分析和建模将用于 确定控制星形胶质细胞兴奋的变量，约束这种活动的细胞内在参数， 活动模式和受这些星形胶质细胞特征影响的神经元特性。功能和 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 开发新的遗传编码指标和干预工具，以询问神经元-星形胶质细胞 体内神经回路（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）。