Cell-specific effects of acute sleep deprivation on transcriptomic signatures of non-neuronal cells in the mouse hippocampus and prefrontal cortex

Sleep is essential for maintaining cognitive, emotional, metabolic, and immune functions. Although research on sleep homeostasis is traditionally neuron-centric, increasing evidence indicates non-neuronal cells also play critical roles. In this study, we performed transcriptomic analyses of non-neuronal nuclei from the hippocampus and prefrontal cortex of mice subjected to acute sleep deprivation (SD). We found that acute SD induces robust, cell-type- and region-specific transcriptional reprogramming in astrocytes and oligodendrocytes. The most pronounced changes occurred in astrocytes, including downregulation of cholesterol biosynthesis genes in both brain regions, accompanied by region-specific and opposing regulation of genes involved in mitochondrial function and neurodegeneration-related pathways. Notably, genes associated with primary cilia were selectively induced in cortical astrocytes. In oligodendrocytes, acute SD led to downregulation of genes encoding cell-adhesion molecules. Together, these findings provide molecular evidence that non-neuronal cells actively contribute to sleep regulation and suggest novel potential mechanisms that broaden our understanding of sleep homeostasis.