A cellular atlas of the primate and human basal ganglia

项目总结 人的基底节(BG)是皮质下区域的集合，其不同的特化细胞类型 影响运动控制、情绪调节、习惯养成和高级认知。的最新进展 单细胞转录组和表观基因组测序已经彻底改变了我们系统定义 跨复杂组织的细胞类型和状态，达到足够的吞吐量和稳健性水平，以 可以部署到像灵长类动物BG这样的大脑组织区域。然而，到目前为止，尽管英国天然气公司发挥了核心作用 多种神经退行性疾病和神经精神疾病的细胞类型及其在人类中的分子定义 和灵长类明显缺乏。在这里，我们建议使用高通量单核组合 RNAseq，一种新的高分辨率空间技术，Slide-seq和联合剖面的新方法 转录和ATAC签名称为Share-Seq，用于系统地识别和解剖定位细胞 恒河猴BG的类型。我们将使用相同的方法来表征细胞类型的多样性 一套200个人脑的身体，史无前例的大样本将丰富我们的理解 这组临床上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 用于对灵长类动物四种主要BG细胞类型进行功能询问的新病毒工具。共同努力，这项工作 将提供全面和高分辨率的BG细胞类型的分子表征，为 将这些分子定义与功能定义联系起来，并为这种细胞类型建立一个框架 整个人脑的特征。

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.