Age attenuates the transcriptional changes that occur with sleep in the medial prefrontal cortex

Sleep abnormalities are common with aging. Studies show that sleep plays important roles in brain functions, and loss of sleep is associated with increased risks for neurological diseases. Here, we used RNA sequencing to explore effects of age on transcriptome changes between sleep and sleep deprivation (SD) in medial prefrontal cortex and found that transcriptional changes with sleep are attenuated in old. In particular, old mice showed a 30% reduction in the number of genes significantly altered between sleep/wake and, in general, had smaller magnitudes of changes in differentially expressed genes compared to young mice. Gene ontology analysis revealed differential age effects on certain pathways. Compared to young mice, many of the wake‐active functions were similarly induced by SD in old mice, whereas many of the sleep‐active pathways were attenuated in old mice. We found similar magnitude of changes in synaptic homeostasis genes (Fos, Arc, and Bdnf) induced by SD, suggesting intact synaptic upscaling on the transcript level during extended wakefulness with aging. However, sleep‐activated processes, such as DNA repair, synaptogenesis, and axon guidance, were sensitive to the effect of aging. Old mice expressed elevated levels of immune response genes when compared to young mice, and enrichment analysis using cell‐type‐specific markers indicated upregulation of microglia and oligodendrocyte genes in old mice. Moreover, gene sets of the two cell types showed age‐specific sleep/wake regulation. Ultimately, this study enhances understanding of the transcriptional changes with sleep and aging, providing potential molecular targets for future studies of age‐related sleep abnormalities and neurological disorders.