Single-cell variations of circadian clock and immune gene expression in microglia and neurodegeneration

We investigated the diurnal rhythmicity of gene expression in microglia, the resident macrophages of the brain, in health and disease. Using RNA sequencing and single-cell analysis by RNAscope, we examined wild-type mice and the R6/2 transgenic mouse model of Huntington’s disease (HD). Our findings suggest context-dependent rhythmic gene expression in microglia, exhibiting substantial variability between individual cells and brain regions over 24 hours. Notably, we observed loss of rhythmic gene expression of key clock genes in microglia from symptomatic but not presymptomatic R6/2 mice. Moreover, we identified de novo 24-hour rhythmic gene expression and altered diurnal patterns of immune-related genes associated with neurodegenerative diseases in microglia from symptomatic R6/2 mice. Our findings suggest circadian reprogramming of microglia in the context of neurodegeneration.