GSE204769
Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination [Trem2KO]
Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination occurring in these diseases. Here, we present a high-resolution snRNA-seq analysis of gene expression changes across all brain cells in this model. We define signatures of prototypic responses to demyelination and remyelination for each cell type, including anti-stress, anti-oxidant-, metabolic-, hypoxia-, IFN-, and IL-33-driven responses, and validate them at the protein level and in IL-33R-deficient mice. We identify related transcription regulators underpinning these pathways, including STAT3, NF-?B, OLIG1 and MAFB. Furthermore, snRNA- seq data provide novel insights into how various brain cell types connect and interact, defining complex circuitries previously unknown to impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency impacts the oligodendrocyte responses to demyelination. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelination and remyelination. Overall design: Single nucleus RNA-seq analysis of cortex and corpus callosum from WT and TREM2 knockout  mice treated with or without cuprizone. Three experimental groups were set up in each genotype: a) demyelination (5-week CPZ treatment); b) remyelination (5-week CPZ treatment, followed by 2-week regular chow); c) control (regular chow throughout the time course)