Functional and Molecular Investigation of Physiological Astrocyte Heterogeneity

 描述(申请人提供)：本申请的重点是系统地探索来自海马和纹状体回路的星形胶质细胞的功能和分子差异，从而对这些区域之间的星形胶质细胞异质性有一个定量的了解。星形胶质细胞是无处不在的神经胶质细胞，通过被称为突起的精细的特化末端延伸与神经元相互作用。这些细胞在回路中起着各种重要的稳态作用，调节突触的形成/移除和调节突触的传递。一般认为，星形胶质细胞是贯穿整个大脑的同质“粘合剂”。对这一观点进行批判性评估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来系统地评估星形胶质细胞在提供不同功能的回路中是否具有不同的功能。目前的应用试图验证星形胶质细胞在两个具有不同功能角色的大脑回路中存在差异的假设。具体地说，这项申请旨在扩展我们实验室的见解，揭示纹状体和海马区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。我将验证一个假设，即海马体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。这一假设得到了应用程序中显示的初步数据的支持，这些数据是我使用免疫组织化学分析海马区和纹状体中GFAP和ALDH1L1报告基因表达而收集的。进一步的支持来自正在进行的生理实验，这些实验表明这两个脑区的星形胶质细胞在功能和形态上存在差异。我将用三个具体目标从逻辑上扩展这些初步发现。第一个目标将检验纹状体和海马区星形胶质细胞功能特性不同的假设。第二个目标将检验纹状体和海马区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。第三个目标将检验这一假设，即海马区和纹状体星形胶质细胞的蛋白质组不同，这可以解释目标1和2中研究的功能差异。

 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.