Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB^hi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

脱髓鞘是多发性硬化症、白质脑病、脑血管病和多种神经退行性疾病的标志。铜宗小鼠模型被广泛用于模拟这些疾病中发生的脱髓鞘和髓鞘再生。在这里，我们对该模型中所有脑细胞的基因表达变化进行了高分辨率单核 RNA 测序 (snRNA-seq) 分析。我们定义了脱髓鞘相关的少突胶质细胞 (DOL) 和髓鞘再生相关的 MAFB ^hi小胶质细胞，以及具有代谢改变、氧化应激和干扰素反应特征的星形胶质细胞和血管细胞。此外，snRNA-seq 提供了关于脑细胞类型如何连接和相互作用的见解，定义了影响脱髓鞘和髓鞘再生的复杂电路。作为一个说明性的例子，TREM2 缺陷引起的小胶质细胞扰动间接损害了 DOL 的诱导。总而言之，这项研究为未来研究脱髓鞘疾病的机制提供了丰富的资源。