Mapping the cellular and molecular organization of mouse cerebral aging by single-cell transcriptome imaging

The enormous cellular diversity and complex tissue organization of the brain have hindered systematic characterization of its age-related changes in cellular and molecular architecture and mechanistic understanding of its functional decline and degeneration during aging. Here we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified the changes in gene expression and spatial organization of major cell types in these regions over the lifespan of mice. We observed more pronounced changes in the composition, gene expression and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly within the white matter of the corpus callosum, and identified both similarities and differences in cell activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain. Nuclei of 2 young (4 week old) and 2 aged (90 week old) mice were isolated by fluorescence-activated cell sorting (FACS) according to the presence of Hoeschst signal and analyzed using 10X Genomics snRNA-seq.

大脑拥有极为丰富的细胞多样性与复杂的组织架构，这极大阻碍了学界对其衰老相关细胞及分子结构变化开展系统性表征，也制约了人们对衰老过程中大脑功能衰退与退行性病变机制的深入理解。本研究借助空间分辨单细胞转录组测序（spatially resolved single-cell transcriptomics）技术，构建了小鼠额叶皮层与纹状体衰老的高分辨率细胞图谱，并量化了小鼠整个生命周期内，上述两个脑区主要细胞类型的基因表达与空间组织模式的动态变化。我们观察到，相较于神经元，非神经元细胞在组成、基因表达及空间组织层面的变化幅度显著更高。本研究数据揭示了衰老过程中胶质细胞与免疫细胞激活的分子与空间特征，该特征在胼胝体白质区域尤为突出，并鉴定出衰老与系统性炎症刺激所诱导的细胞激活模式的共性与差异。上述研究结果为解析大脑衰老相关的功能衰退与炎症反应提供了关键认知。本研究通过荧光激活细胞分选（FACS），基于Hoechst信号分选了2只年轻（4周龄）与2只老年（90周龄）小鼠的脑组织细胞核，并采用10X Genomics 单细胞核RNA测序（snRNA-seq）完成后续分析。