A multi-modal, brain-wide atlas of astrocyte diversity across developmental stages and model species

跨发育阶段和模型物种的星形胶质细胞多样性的多模式、全脑图谱

基本信息

批准号：
10677211
负责人：
Margaret Elizabeth Schroeder
金额：
$ 4.77万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677211
关键词：
Acute Address Adolescent Adult Aging Architecture Astrocytes Atlases Automobile Driving BRAIN initiative Basic Science Biological Brain Brain Diseases Brain region Calcium Calcium Channel Callithrix Cataloging Cell Nucleus Cells Censuses Cognitive Science Collaborations Communities Complex Computational Technique Computing Methodologies Cues Data Development Disease Embryo Equipment Etiology Evolution Fellowship Functional disorder Genes Genetic Transcription Glutamates Goals Health Heterogeneity Image Ion Channel Knowledge Laboratories Maps Massachusetts Mental disorders Microscopy Modeling Molecular Molecular Profiling Morphologic artifacts Morphology Motor Cortex Mus Neurodevelopmental Disorder Neuroglia Neurons Neurosciences Neurotransmitter Receptor Pathogenesis Pathway Analysis Pattern Physiological Play Population Postdoctoral Fellow Preparation Primates Printing Process Property Resource Development Rodent Role Sampling Signal Transduction Slice Synapses Synaptic Transmission Techniques Technology Training Translational Research United States National Institutes of Health brain cell cell type differential expression in silico member multimodality nanoscale neonate neuron component neuronal circuitry next generation nonhuman primate postnatal development protein expression sequencing platform single nucleus RNA-sequencing single-cell RNA sequencing species difference transcriptomics young adult

项目摘要

PROJECT SUMMARY Astrocytes influence neuronal circuit assembly and function and have been shown to respond, modulate, and drive disease pathogenesis. Despite this, relatively little is known about astrocyte diversity across brain regions, development, and species. However, recent single-cell RNA sequencing studies demonstrate that astrocytes have significant transcriptomic heterogeneity across the brain. Detailed molecular and cellular characterization of these subpopulations is needed to determine whether molecularly-defined astrocyte subpopulations serve distinct functions in both health and disease. Thus, the goal of this project is to use cutting-edge techniques to characterize the transcriptomic, structural, and functional diversity of astrocyte subpopulations across developmental stages and disease-relevant brain regions in the mouse and marmoset brain. By conducting a detailed analysis of over 70,000 astrocyte nuclei across eight brain regions in the young adult marmoset, I have discovered striking regional heterogeneity among astrocytes, particularly between cortical and subcortical regions. In this proposal, I aim to make three significant advances: a) map the evolution of astrocyte regional heterogeneity across development, b) compare this heterogeneity between rodent and non-human primate species, and c) characterize the functional identities of transcriptomically distinct astrocyte subtypes. To address the first two of these, I will conduct single-nucleus RNA sequencing of four brain regions in the embryo, neonate, juvenile, and adolescent marmoset and mouse. To address the third, I will use expansion microscopy to assess whether molecularly-defined astrocyte subtypes have distinct morphologies, ensheathment of synapses, and/or configuration of ion channels at the nanoscale. Additionally, I will image astrocyte calcium dynamics, considered key components of signaling processes used by astrocytes to regulate neuronal networks, in acute brain slices from both mouse and marmoset to characterize the functional diversity of transcriptomically-defined astrocyte subtypes. The proposed study will mark the first cross-species, cross-development, cross-region molecular profile of brain cells using consistent experimental and computational methodology, and will create new knowledge about the development of astrocyte heterogeneity across brain regions in rodents and non-human primates. Importantly, this detailed molecular and cellular characterization of astrocyte subpopulations will facilitate their precise manipulation for basic and translational research on neurodevelopmental and psychiatric disorders. I will carry out this project in the labs of Dr. Guoping Feng and Dr. Ed Boyden in the Brain and Cognitive Sciences Department at the Massachusetts Institute of Technology. The Feng and Boyden labs contain all required equipment for the proposed project. All necessary training regarding required laboratory and computational techniques will be provided by senior lab members or through collaboration with other labs in BCS and external collaborators. The Feng and Boyden labs, BCS, and MIT offer exceptional scientific and professional development resources to facilitate my successful transition into a postdoctoral fellowship.

项目概要星形胶质细胞影响神经元回路的组装和功能，并已被证明可以做出反应、调节和驱动疾病的发病机制。尽管如此，人们对大脑各区域星形胶质细胞的多样性知之甚少，发展、物种。然而，最近的单细胞 RNA 测序研究表明星形胶质细胞整个大脑具有显着的转录组异质性。详细的分子和细胞表征需要对这些亚群进行分析来确定分子定义的星形胶质细胞亚群是否可以发挥作用在健康和疾病中具有不同的功能。因此，该项目的目标是利用尖端技术表征星形胶质细胞亚群的转录组、结构和功能多样性小鼠和狨猴大脑的发育阶段和疾病相关的大脑区域。通过进行我对年轻成年狨猴八个大脑区域的 70,000 多个星形胶质细胞核进行了详细分析发现星形胶质细胞之间存在显着的区域异质性，特别是皮质和皮质下之间地区。在这个提案中，我的目标是取得三个重大进展：a）绘制星形胶质细胞区域的进化图发育过程中的异质性，b) 比较啮齿类动物和非人类灵长类动物之间的异质性种，c) 表征转录组上不同的星形胶质细胞亚型的功能特性。致地址其中前两个，我将对胚胎、新生儿、幼年和青春期的狨猴和小鼠。为了解决第三个问题，我将使用膨胀显微镜来评估分子定义的星形胶质细胞亚型是否具有不同的形态、突触鞘和/或纳米级离子通道的配置。此外，我将对星形胶质细胞钙动力学进行成像，考虑在急性脑切片中，星形胶质细胞用于调节神经元网络的信号传导过程的关键组成部分来自小鼠和狨猴的特征，以表征转录组定义的星形胶质细胞的功能多样性亚型。拟议的研究将标志着第一个跨物种、跨开发、跨区域的分子研究使用一致的实验和计算方法对脑细胞进行分析，并将创造新的关于啮齿动物和非人类大脑区域星形胶质细胞异质性发展的知识灵长类动物。重要的是，星形胶质细胞亚群的这种详细的分子和细胞特征将促进神经发育和精神病学基础和转化研究的精确操作失调。我将在冯国平博士和埃德·博伊登博士的大脑和认知实验室进行这个项目麻省理工学院科学系。冯和博伊登实验室包含所有拟议项目所需的设备。有关所需实验室和实验室的所有必要培训计算技术将由高级实验室成员提供或通过与 BCS 的其他实验室合作提供和外部合作者。 Feng 和 Boyden 实验室、BCS 和 MIT 提供卓越的科学和专业发展资源，以促进我成功过渡到博士后奖学金。