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. In this study, we used next generation RNA-sequencing to explore effects of age on transcriptome changes between sleep and sleep deprivation in medial prefrontal cortex. 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. Gene ontology analysis revealed differential age-effects on certain pathways. Compared to young mice, many of the wake-active functions were similarly induced by sleep deprivation in old mice, whereas many of the sleep-active pathways were attenuated in old mice. We found similar magnitude of changes in a number of synaptic homeostasis genes (Fos, Arc, and Bdnf) induced by sleep deprivation, suggesting intact synaptic upscaling 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-related genes  when compared to young mice, and enrichment analysis using cell-type specific markers indicated up-regulation of microglia and oligodendrocyte genes in old mice. Moreover, gene sets of the two cell types showed age-specific sleep/wake regulation. This study indicates alteration of molecular changes with sleep in old mice.

睡眠异常在衰老进程中十分普遍。已有研究证实，睡眠对大脑功能发挥着重要作用，而睡眠剥夺与神经系统疾病的发病风险增加密切相关。本研究采用下一代RNA测序（next generation RNA-sequencing）技术，探究衰老对小鼠内侧前额叶皮层（medial prefrontal cortex）内睡眠与睡眠剥夺状态下转录组变化的影响。与年轻小鼠相比，老年小鼠睡眠/觉醒状态间发生显著差异的基因数量减少了30%，且整体上差异表达基因的变化幅度更小。基因本体（Gene Ontology, GO）分析显示，特定信号通路受衰老的影响存在差异。相较于年轻小鼠，老年小鼠体内多数觉醒相关功能可被睡眠剥夺同等诱导激活，但多数睡眠相关通路的激活程度在老年小鼠中被削弱。我们发现，睡眠剥夺诱导的多个突触稳态基因（包括Fos、Arc及Bdnf）的表达变化幅度与年轻小鼠无显著差异，这提示衰老过程中长期觉醒状态下的突触向上缩放功能保持完整。然而，睡眠激活的生物学过程，如DNA修复、突触发生及轴突导向，对衰老影响较为敏感。与年轻小鼠相比，老年小鼠体内免疫相关基因的表达水平升高；采用细胞类型特异性标志物进行的富集分析显示，老年小鼠小胶质细胞（microglia）与少突胶质细胞（oligodendrocyte）相关基因呈现上调表达。此外，这两类细胞的基因集表现出衰老特异性的睡眠/觉醒表达调控模式。本研究表明，衰老小鼠睡眠相关的分子变化模式发生了改变。