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：
10394911
负责人：
Marsa Taheri
金额：
$ 7.73万
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/10394911
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.

项目摘要/摘要星形胶质细胞堆积多达一半的哺乳动物脑细胞。从多个大脑积累证据圆圈表明，星形胶质细胞通过其细胞内CA2+信号传导调节和调节神经元从毫秒到几天，在单细胞和网络范围的水平以及广泛的时间尺度上的活动和几周。在多种脑部疾病中也暗示了星形胶质细胞CA2+信号传导的改变，包括亨廷顿氏病，阿尔茨海默氏病，强迫症，中风和癫痫病。然而，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，缺乏用于星形胶质细胞数据分析和解释的实验，基于实验的，复杂的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，有数据死亡星形胶质细胞 - 神经元相互作用已在具有行为的单个模型脑电路中仔细探索读数。我试图通过探索纹状体中的星形胶质细胞互动来侵入这两个主题使用实验和计算方法。这项研究提出的建议阐明纹状体中星形胶质细胞和神经元之间的物理相互作用神经回路。在AIM 1中，将集成实验和计算方法以研究原位纹状体星形胶质细胞CA2+信号传导及其对秒时尺度神经元刺激的影响。为此，星形胶质细胞 Ca2+活性将使用遗传敲入和化学遗传学方法来扰动。在AIM 2中将开发和用于瞬时刺激纹状体星形胶质细胞Ca2+反应的原位和体内，研究其对神经元活性和行为的影响。这些结果将提供很多需要深入了解与行为相关的良好表征大脑电路中的星形胶质细胞通信和神经疾病。此外，这些研究将为未来研究提供两组工具：一种新颖星形胶质细胞操纵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。