A cellular atlas of the primate and human basal ganglia

项目摘要 人类基底神经节（BG）是皮质下区域的集合，其多样的特化细胞类型 影响运动控制、情绪调节、习惯形成和高级认知。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 细胞类型和复杂组织的状态，达到足够的吞吐量和鲁棒性水平， 可以部署到大的脑组织区域，如灵长类动物BG。然而，迄今为止，尽管BG发挥了核心作用， 许多神经退行性疾病和神经精神疾病中的细胞类型，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 RNAseq，一种新的高分辨率空间技术，Slide-seq，以及一种联合分析的新方法 转录和ATAC签名，称为SHARE-seq，以系统地识别和解剖学定位细胞 类型在猕猴BG。我们将使用这些相同的方法来表征细胞类型的多样性， 一组200个死后的人脑，一个前所未有的大样本量，将丰富我们的理解 在临床上相关的大脑区域中个体间的差异。然后我们将利用这些数据 新的病毒工具，用于灵长类动物中四种主要BG细胞类型的功能询问。在一起，这项工作 将提供BG细胞类型的全面和高分辨率的分子表征， 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 在整个人类大脑中进行表征。

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.