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Functional and Molecular Investigation of Physiological Astrocyte Heterogeneity

生理星形胶质细胞异质性的功能和分子研究

基本信息

批准号：
8983476
负责人：
Hua Chai
金额：
$ 3.47万
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：
2015
资助国家：
美国
起止时间：
2015-09-08 至 2019-09-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8983476
关键词：
Address Adult Astrocytes Brain Brain Diseases Brain Part Brain region Calcium Signaling Cells Corpus striatum structure Coupled Data Disease Distal Electrophysiology (science)Epilepsy Evaluation Excision Fluorescence-Activated Cell Sorting Follow-Up Studies Functional disorder Gene Expression Glial Fibrillary Acidic Protein Glues Heterogeneity Hippocampus (Brain)Huntington Disease Image Individual Investigation Laboratories Mass Spectrum Analysis Membrane Proteins Mental disorders Methods Molecular Monitor Mood Disorders Morphology Mus Names Neuraxis Neuroglia Neurologic Neurons Physiological Physiology Process Property Proteins Proteome Proteomics Reporter Reporter Genes Role Signal Transduction Signaling Molecule Specificity Structure Synaptic Transmission Testing Therapeutic Western Blotting base biocytin brain circuitry calcium indicator insight lucifer yellow mouse model nervous system disorder neuronal circuitry neuropsychiatry novel patch clamp public health relevance reconstruction research study synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): The focus of this application is to systematically explore functional and molecular differences in astrocytes from hippocampal and striatal circuits, and thus obtain a quantitative understanding of astrocyte heterogeneity between these regions. Astrocytes are ubiquitous glial cells that interact with neurons via fine specialised distal extensions called processes. These cells serve a variety of important homeostatic roles within circuits, regulate synapse formation/removal and modulate synaptic transmission. It has generally been assumed that astrocytes are a homogenous "glue" throughout the brain. A significant bottleneck to critically assessing this view has been the lack of data on astrocyte properties in different parts of the brain. Thus we lack information that is necessary to systematically evaluate if astrocytes are functionally diverse within circuits that serve separate functions. The current application seeks to test the hypothesis that astrocytes are diverse in two brain circuitries with distinct functional roles. Specifically, this application seeks to extend insights made in our laboratory that revealed functional differences between striatal and hippocampal astrocytes, and preferential dysfunction of striatal astrocytes in mouse models of Huntington's disease. I will test the hypothesis that astrocytes in the hippocampus and striatum have distinct functional, morphological and molecular properties. This hypothesis gains support from preliminary data shown in the application that I gathered using immunohistochemical analyses of GFAP and Aldh1L1 reporter gene expression in the hippocampus and striatum. Further support comes from ongoing physiological experiments suggesting functional and morphological differences between astrocytes in these two brain regions. I will logically extend these initial findings with three specific aims. The first aim will test the hypothesis that functinal properties of striatal and hippocampal astrocytes differ. The second aim will test the hypothesis that striatal and hippocampal astrocyte morphology and astrocyte network topography differ. The third aim will test the hypothesis that the proteome of hippocampal and striatal astrocytes differ and that this can explain functional differences studied in aims 1 and 2.

描述（由申请人提供）：本申请的重点是系统地探索海马和纹状体回路中星形胶质细胞的功能和分子差异，从而定量了解这些区域之间的星形胶质细胞异质性。星形胶质细胞是普遍存在的神经胶质细胞，其通过称为突起的精细专门的远端延伸与神经元相互作用。这些细胞在神经回路中发挥着各种重要的稳态作用，调节突触的形成/去除和调节突触传递。一般认为，星形胶质细胞是一种均匀的“胶水”，遍布大脑。批判性地评估这一观点的一个重要瓶颈是缺乏关于大脑不同部位星形胶质细胞特性的数据。因此，我们缺乏必要的信息，以系统地评估星形胶质细胞是否在功能不同的电路中发挥不同的功能。本申请试图检验星形胶质细胞在具有不同功能作用的两个脑回路中是不同的这一假设。具体而言，本申请旨在扩展我们实验室的见解，揭示纹状体和海马星形胶质细胞之间的功能差异，以及亨廷顿病小鼠模型中纹状体星形胶质细胞的优先功能障碍。我将检验海马和纹状体中的星形胶质细胞具有不同的功能、形态和分子特性的假设。这一假设得到了初步数据的支持，这些数据是我通过对海马和纹状体中GFAP和Aldh 1 L1报告基因表达的免疫组织化学分析收集的。进一步的支持来自正在进行的生理实验，表明这两个大脑区域中星形胶质细胞之间的功能和形态差异。我将从逻辑上扩展这些初步发现，提出三个具体目标。第一个目标是检验纹状体和海马星形胶质细胞功能特性不同这一假设。第二个目的是检验纹状体和海马星形胶质细胞形态和星形胶质细胞网络拓扑结构不同的假设。第三个目标将测试海马和纹状体星形胶质细胞的蛋白质组不同的假设，这可以解释目标1和2中研究的功能差异。