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

项目摘要/摘要 星形胶质细胞占哺乳动物脑细胞的一半。从多个大脑中积累证据 电路提示，星形胶质细胞通过其细胞内的钙信号，调节和调节神经元 单细胞和全网络水平上的活动，以及从毫秒到天数的广泛时间范围 还有几个星期。星形胶质细胞钙信号的改变也与多种脑部疾病有关，包括 亨廷顿病、阿尔茨海默病、强迫症、中风和癫痫。然而， 要弄清星形胶质细胞对大脑功能的贡献，还有很多工作要做。首先，有一个短缺的 基于实验的复杂计算方法，用于星形胶质细胞数据分析和解释 可以帮助指导新的、假设驱动的和严格的实验。其次，数据匮乏， 星形胶质细胞-神经元的相互作用已经在一个单一的脑回路模型中被仔细地研究过， 读数。我试图通过探索纹状体中星形胶质细胞与神经元的相互作用来研究这两个主题。 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，将结合实验和计算方法来原位研究纹状体 星形胶质细胞钙信号及其对秒级神经元兴奋性的影响。为了达到这个目的，星形细胞 利用基因敲入和化学发生的方法，CA2的活性将被原位干扰。在Aim 2中，一个 将开发并使用光遗传工具来瞬时刺激纹状体星形胶质细胞原位和 在体内，并研究其对神经元活动和行为的影响。这些结果将提供更多 需要深入了解与行为相关的脑回路中星形胶质细胞-神经元的通讯 以及神经系统疾病。此外，这些研究将为未来的研究带来两套工具：一种新颖的 用于操纵星形胶质细胞的光遗传工具和实验验证的星形胶质细胞数学模型- 神经元的相互作用。

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.