A cellular atlas of the primate and human basal ganglia

灵长类动物和人类基底神经节的细胞图谱

基本信息

批准号：
10527335
负责人：
Fei Chen
金额：
$ 170.66万
依托单位：
BROAD INSTITUTE, INC.
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：
2020-12-05 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527335
关键词：
ATAC-seq Adult Affect Anatomy Area Atlases Autopsy Basal Ganglia Biological Assay Brain Brain region Cell Nucleus Cells Chromatin Cognition Collection Complex Corpus striatum structure Data Data Analyses Data Set Development Disease Disease Progression Dopamine Dorsal Enhancers Epigenetic Process Equipment and supply inventories Female Functional disorder Gene Expression Gene Expression Profile Generations Genetic Transcription Genomics Globus Pallidus Habits Human Huntington Disease Individual Injections Link Macaca Maps Mediating Methods Modeling Molecular Motor Activity Mus Nerve Degeneration Neurodegenerative Disorders Neurons Nucleus Accumbens Parkinson Disease Pathogenesis Predisposition Primates Resolution Role Sample Size Sampling Slide Specificity Structure Structure of subthalamic nucleus Substantia nigra structure Surveys Target Populations Technology Thinking Tissues Variant Ventral Tegmental Area Viral Work XCL1 gene brain tissue causal variant cell type clinically relevant emotion regulation epigenome genome wide association study human subject human tissue inter-individual variation male motor control neuropsychiatric disorder nonhuman primate novel novel strategies putamen reconstruction tool transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY The human basal ganglia (BG) are a collection of subcortical regions whose diverse, specialized cell types influence motor control, emotional regulation, habit formation, and higher cognition. Recent advances in single-cell transcriptome and epigenome sequencing have revolutionized our ability to systematically define cell types and states across complex tissues, reaching sufficient levels of throughput and robustness to be deployable to large brain tissue regions like the primate BG. However, to date, despite the central role of BG cell types in many neurodegenerative and neuropsychiatric diseases, their molecular definitions in the human and primate are distinctly lacking. Here, we propose to use a combination of high-throughput single-nucleus RNAseq, a novel high-resolution spatial technology, Slide-seq, and a new approach to jointly profile transcription and ATAC signatures called SHARE-seq, to systematically identify and anatomically map cell types across the macaque BG. We will use these same methods to characterize cell type diversity across a set of 200 postmortem human brains, an unprecedentedly large sample size that will enrich our understanding of inter-individual variation in this clinically relevant set of brain regions. We will then use these data to build new viral tools for the functional interrogation of four principal BG cell types in the primate. Together, this work will provide a comprehensive and high-resolution molecular characterization of BG cell types, provide tools for linking these molecular definitions to functional ones, and establish a framework for such cell type characterization across the entire human brain.

项目概要人类基底神经节 (BG) 是皮层下区域的集合，其具有多种、特化的细胞类型影响运动控制、情绪调节、习惯形成和更高的认知。最近的进展单细胞转录组和表观基因组测序彻底改变了我们系统定义的能力复杂组织中的细胞类型和状态，达到足够水平的吞吐量和鲁棒性可部署到灵长类动物 BG 等大型脑组织区域。然而，迄今为止，尽管 BG 发挥着核心作用，许多神经退行性疾病和神经精神疾病的细胞类型，它们在人类中的分子定义和灵长类动物明显缺乏。在这里，我们建议使用高通量单核的组合 RNAseq，一种新颖的高分辨率空间技术，Slide-seq，以及一种联合分析的新方法称为 SHARE-seq 的转录和 ATAC 签名，用于系统地识别和解剖细胞图谱猕猴 BG 的类型。我们将使用这些相同的方法来表征整个细胞类型的多样性一组 200 个死后人类大脑，前所未有的大样本量将丰富我们的理解这组临床相关的大脑区域的个体间差异。然后我们将使用这些数据来构建用于对灵长类动物中四种主要 BG 细胞类型进行功能询问的新病毒工具。共同完成这项工作将提供 BG 细胞类型的全面且高分辨率的分子表征，为将这些分子定义与功能定义联系起来，并为此类细胞类型建立框架整个人脑的表征。