Mouse microglial cell RNA sequencing for "Local cues establish and maintain region-specific phenotypes of basal ganglia microglia" project

Microglia play critical roles in CNS injury responses, tissue homeostasis, and can alsomodulate neuronal function and synaptic connectivity. In contrast to astrocytes andoligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sacprogenitors and are widely considered to be equivalent throughout the CNS. However, littleis known about the features of deep brain microglia, such as those residing within the basalganglia (BG). Here, we show that microglial anatomical features, lysosome content, andmembrane properties differ significantly across BG nuclei. In addition, transcriptomesequencing revealed prominent differences in gene expression between midbrain andcortical microglia. Region-specific phenotypes of BG microglia emerged during the secondpostnatal week and were re-established following genetic or pharmacological microglialablation and repopulation in the adult, indicating that local cues play an ongoing role inshaping microglial diversity. Together, these observations demonstrate that microglia inthe healthy brain exist along a spectrum of distinct functional states and these data providea critical foundation for defining microglial contributions to BG circuit function.

小胶质细胞（Microglia）在中枢神经系统（Central Nervous System, CNS）的损伤应答、组织稳态维持中发挥关键作用，同时还可调控神经元功能与突触连接。与源自多祖细胞库的星形胶质细胞（Astrocytes）和少突胶质细胞（Oligodendrocytes）不同，小胶质细胞起源于卵黄囊祖细胞（Yolk Sac Progenitors），且此前学界普遍认为其在整个中枢神经系统中功能均质一致。然而，目前对于深部脑区小胶质细胞的特征——例如定位于基底神经节（Basal Ganglia, BG）内的小胶质细胞——仍所知甚少。本研究发现，基底神经节各核团的小胶质细胞在解剖学特征、溶酶体（Lysosome）含量以及膜特性上均存在显著差异。此外，转录组测序（Transcriptome Sequencing）结果显示，中脑（Midbrain）与皮层小胶质细胞（Cortical Microglia）的基因表达模式存在显著差异。基底神经节小胶质细胞的区域特异性表型于出生后第二周显现，并在成年个体经遗传或药理学手段完成小胶质细胞清除与再定植后得以重建，这表明局部微环境信号持续参与塑造小胶质细胞的多样性。综上，本研究结果证实，健康大脑内的小胶质细胞以一系列独特的功能状态谱系存在；本研究数据为阐明小胶质细胞对基底神经节环路功能的调控贡献提供了重要的研究基础。