Dynamic Striatal Astrocyte-Neuron Interactions: An Integrated Experimental and Computational Study

项目概要/摘要 星形胶质细胞占哺乳动物脑细胞的一半。从多个大脑中收集证据 提示星形胶质细胞通过其细胞内Ca 2+信号传导，调节和调节神经元 在单细胞和网络范围级别以及从毫秒到天的广泛时间尺度上的活动 几个星期星形胶质细胞Ca 2+信号的改变也与多种脑部疾病有关，包括 亨廷顿氏病、阿尔茨海默氏病、强迫症、中风和癫痫。然而，在这方面， 要揭示星形胶质细胞对大脑功能的作用还有很多工作要做。首先，缺乏 用于星形胶质细胞数据分析和解释的基于实验的复杂计算方法， 可以帮助指导新的，假设驱动的和严格的实验。其次，缺乏数据， 星形胶质细胞-神经元相互作用已经在具有行为的单一模型脑回路中仔细探索过。 读数我试图通过探索纹状体中星形胶质细胞-神经元的相互作用来在这两个主题上取得进展 使用实验和计算方法。 本研究旨在阐明纹状体星形胶质细胞和神经元之间的生理相互作用， 神经回路在目标1中，实验和计算方法将被整合到原位研究纹状体 星形胶质细胞Ca 2+信号传导及其对神经元兴奋性的影响。为此，星形胶质细胞 Ca 2+活性将被扰乱原位使用基因敲入和化学发生的方法。在目标2中， 将开发一种光遗传学工具，并用于瞬时刺激纹状体星形胶质细胞原位Ca 2+反应， 在体内，并研究其对神经元活动和行为的影响。从这些结果将提供很多 需要深入了解星形胶质细胞-神经元在与行为相关的特征明确的大脑回路中的通讯 和神经系统疾病。此外，这些研究将为未来的研究提供两套工具：一种新的 用于星形胶质细胞操作的光遗传学工具和星形胶质细胞的实验验证的数学模型， 神经元相互作用

Project Summary/Abstract Astrocytes comprise up to half of mammalian brain cells. Accumulating evidence from multiple brain circuits suggests that astrocytes, through their intracellular Ca2+ signaling, regulate and modulate neuronal activity on single-cell and network-wide levels and on a broad range of timescales—from milliseconds to days and weeks. Altered astrocyte Ca2+ signaling has also been implicated in a variety of brain disorders, including Huntington’s Disease, Alzheimer’s Disease, obsessive-compulsive disorder, stroke, and epilepsy. However, much remains to be done to uncover how astrocytes contribute to brain function. First, there is a shortage of experimentally based, sophisticated computational approaches for astrocyte data analysis and interpretation that could aid in guiding new, hypothesis-driven and rigorous experiments. Second, there is a dearth of data where astrocyte-neuron interactions have been explored carefully in a single model brain circuitry with behavioral readouts. I seek to make inroads in both of these topics by exploring astrocyte-neuron interactions in the striatum using experimental and computational approaches. This study proposes to elucidate the physiological interplay between astrocytes and neurons in striatal neural circuits. In Aim 1, experimental and computational approaches will be integrated to study in situ striatal astrocyte Ca2+ signaling and its effect on neuronal excitability on timescales of seconds. For this aim, astrocyte Ca2+ activity will be perturbed in situ using genetic knock-in and chemogenetic approaches. In Aim 2, an optogenetic tool will be developed and used to transiently stimulate striatal astrocyte Ca2+ responses in situ and in vivo, and investigate its effects on neuronal activity and behavior. The results from these will provide much needed insight into astrocyte-neuron communication in a well-characterized brain circuit relevant to behavior and neurological diseases. In addition, these studies will result in two sets of tools for future research: a novel optogenetic tool for astrocyte manipulation and an experimentally-verified mathematical model of astrocyte- neuron interactions.