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

• 批准号: 10088048
• 负责人: Jason Daniel Buenrostro
• 金额: $ 155.86万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-05 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088048
• 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 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; Lead; Link; Macaca; Maps; Mediating; Methods; Modeling; Molecular; Motor Activity; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleus Accumbens; Parkinson Disease; Pathogenesis; 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; base; 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

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.

项目摘要 人类基底神经节（BG）是皮层下区域的集合，其多样的专门细胞类型 影响运动控制，情绪调节，习惯形成和更高的认知。最近的进步 单细胞转录组和表观基因组测序已彻底改变了我们系统定义的能力 跨复杂组织的细胞类型和状态，达到足够水平的吞吐量和鲁棒性 可以部署到大脑组织区域，例如灵长类动物BG。但是，迄今为止，尽管BG的核心作用 许多神经退行性和神经精神疾病的细胞类型，它们在人类中的分子定义 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是一种新型的高分辨率空间技术，幻灯片序列，以及一种共同概况的新方法 转录和ATAC签名称为share-seq，系统地识别和解剖映射细胞 猕猴BG的类型。我们将使用这些相同的方法来表征一个细胞类型的多样性 一组200后人类大脑，这是一个前所未有的大型样本量，可以丰富我们的理解 在这组临床相关的大脑区域中，个体间差异。然后，我们将使用这些数据构建 灵长类动物中四种主要BG细胞类型的功能性询问的新病毒工具。在一起，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性定义联系起来，并为这种细胞类型建立框架 整个人大脑的表征。