Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Departments of Computational Medicine and Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
Nature. 2023 Dec;624(7991):333-342. doi: 10.1038/s41586-023-06818-7. Epub 2023 Dec 13.
The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell types and their positions within individual anatomical structures remain incompletely known. To construct a comprehensive atlas of cell types in each brain structure, we paired high-throughput single-nucleus RNA sequencing with Slide-seq-a recently developed spatial transcriptomics method with near-cellular resolution-across the entire mouse brain. Integration of these datasets revealed the cell type composition of each neuroanatomical structure. Cell type diversity was found to be remarkably high in the midbrain, hindbrain and hypothalamus, with most clusters requiring a combination of at least three discrete gene expression markers to uniquely define them. Using these data, we developed a framework for genetically accessing each cell type, comprehensively characterized neuropeptide and neurotransmitter signalling, elucidated region-specific specializations in activity-regulated gene expression and ascertained the heritability enrichment of neurological and psychiatric phenotypes. These data, available as an online resource ( www.BrainCellData.org ), should find diverse applications across neuroscience, including the construction of new genetic tools and the prioritization of specific cell types and circuits in the study of brain diseases.
哺乳动物大脑的功能依赖于不同特化细胞类型的特化和空间定位。然而，细胞类型的分子特征及其在单个解剖结构内的位置仍然不完全清楚。为了构建每个脑结构的细胞类型综合图谱，我们将高通量单细胞 RNA 测序与 Slide-seq（一种最近开发的具有近细胞分辨率的空间转录组学方法）进行配对，在整个小鼠脑中进行。这些数据集的整合揭示了每个神经解剖结构的细胞类型组成。在中脑、后脑和下丘脑，细胞类型多样性显著较高，大多数簇需要至少三种离散的基因表达标记的组合才能对其进行独特定义。使用这些数据，我们开发了一种用于遗传访问每个细胞类型的框架，全面表征神经肽和神经递质信号传递，阐明了活性调节基因表达的特定区域特征，并确定了神经和精神疾病表型的遗传富集。这些数据可作为在线资源（www.BrainCellData.org）获得，应在神经科学的多个领域找到广泛的应用，包括构建新的遗传工具以及在脑疾病研究中优先考虑特定的细胞类型和回路。
