Abstract
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.
Highlights
Multiple microarray studies have examined differences in gene expression in the brains of animals during sleep, wake, and sleep deprivation (SD; for a review, see Mackiewicz, Zimmerman, Shockley, Churchill, & Pack, 2009)
One hypothesis is synaptic homeostasis (Tononi & Cirelli, 2014), that is, synaptic strengthening during wakefulness and down‐ scaling during sleep. Another theory is that endoplasmic reticulum (ER) stress and activation of the unfolded protein response occur during wake, and recovery occurs during sleep (Brown & Naidoo, 2010)
Since circadian‐related functions were enriched by both behavior and age, we examined how the 12 circadian core clock genes (Bmal1/Arntl, Clock, Per1, Per2, Per3, Cry1, Cry2, Nr1d1, Nr1d2, Dbp, Tef, and Hif) were affected by sleep/wake and aging
Summary
Multiple microarray studies have examined differences in gene expression in the brains of animals during sleep, wake, and sleep deprivation (SD; for a review, see Mackiewicz, Zimmerman, Shockley, Churchill, & Pack, 2009). The four functions with most genes (n > 50) showed highly significantly increased expression changes in young mice compared to old (ER stress [p = 8e−5], regulation of transcrip‐ tion [p = 2e−13], MAPK signaling [p = 1e−5], and Kinase activity [p = 2e−12]) (Table S5). As many transcription factors (TFs) differentially regulated by sleep and wake are key factors of neuronal activity and synaptic plas‐ ticity (Alberini, 2009), we directly examined five – Fos, Fosb, Egr, Egr, and Arc. All were highly induced by SD in both ages (q ≤ 6.4e−17), with similar magnitude of change in young (2.6‐ to 7.7‐fold increase) and old (2.8‐ to 11.5‐fold increase) mice. Upregulation of the oli‐ godendrocyte genes during SD was observed in young mice only, while upregulation of the microglia genes during SS was observed in old mice only
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