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

动态纹状体星形胶质细胞-神经元相互作用：综合实验和计算研究

基本信息

批准号：
10393076
负责人：
Marsa Taheri
金额：
$ 0.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393076
关键词：
Adult Affect Alzheimer&apos s Disease Astrocytes Attenuated BRAIN initiative Behavior Behavioral Biochemical Biological Brain Brain Diseases Brain region Buffers Cells Communication Computer Models Computing Methodologies Corpus striatum structure Coupled Data Data Analyses Electrophysiology (science)Epilepsy Experimental Models Extracellular Space G-Protein-Coupled Receptors Genetic Goals Huntington Disease Hyperactivity Image In Situ Ions Knock-in Mathematics Measurable Measurement Measures Mediating Methods Modeling Modification Mus Na(+)-K(+)-Exchanging ATPase Neuroglia Neurons Obsessive compulsive behavior Obsessive-Compulsive Disorder Outcome Pathway interactions Physiological Pump Receptor Activation Regulation Reporting Rodent Role Serine Signal Transduction Silicon Site Slice Stroke Study models Synapses Testing Time Work attenuation base behavioral outcome brain cell brain circuitry computer framework computer studies experimental study extracellular in vivo innovation insight large scale data mathematical model millisecond nervous system disorder neural circuit neuronal excitability novel novel strategies optogenetics patch clamp predictive modeling response time use tool

项目摘要

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.

项目概要/摘要来自多个脑细胞的证据表明，星形胶质细胞占哺乳动物脑细胞的一半。电路表明星形胶质细胞通过其细胞内 Ca2+ 信号传导调节神经元单细胞和网络范围内的活动以及广泛的时间尺度（从毫秒到天）星形胶质细胞 Ca2+ 信号传导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。要揭示星形胶质细胞如何促进大脑功能还有很多工作要做。首先，星形胶质细胞的短缺。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、假设驱动的严格实验。其次，缺乏数据。星形胶质细胞与神经元的相互作用已经在具有行为学特征的单一大脑电路模型中进行了仔细探索。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中星形胶质细胞和神经元之间的生理相互作用在目标 1 中，将整合实验和计算方法来研究原位纹状体。星形胶质细胞 Ca2+ 信号传导及其对秒级神经元兴奋性的影响为了实现这一目标，星形胶质细胞。在目标 2 中，将使用基因敲入和化学遗传学方法原位扰动 Ca2+ 活性。将开发光遗传学工具并用于瞬时刺激纹状体星形胶质细胞原位 Ca2+ 反应体内，并研究其对神经活动和行为的影响，这些结果将提供很多信息。需要深入了解与行为相关的明确大脑回路中的星形胶质细胞-神经元通信此外，这些研究将为未来的研究带来两套工具：一套新颖的工具。用于星形胶质细胞操作的光遗传学工具和经过实验验证的星形胶质细胞数学模型神经元相互作用。