Deep Sleep and Parietal Cortex Gene Expression Changes Are Related to Cognitive Deficits with Age

BackgroundAge-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption's well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep's relationship to cognitive aging. MethodologyWe measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken. Principal FindingsWater maze performance was impaired, and inactive period deep sleep was decreased with age. However, increased deep sleep during the active period was most strongly correlated to maze performance. Transcriptional profiles were strongly associated with behavior and age, and were validated against prior studies. Bioinformatic analysis revealed increased translation and decreased myelin/neuronal pathways. ConclusionsThe F344 rat appears to serve as a reasonable model for some common sleep architecture and cognitive changes seen with age in humans, including the cognitively disrupting influence of active period deep sleep. Microarray analysis suggests that the processes engaged by this sleep are consistent with its function. Thus, active period deep sleep appears temporally misaligned but mechanistically intact, leading to the following: first, aged brain tissue appears capable of generating the slow waves necessary for deep sleep, albeit at a weaker intensity than in young. Second, this activity, presented during the active period, seems disruptive rather than beneficial to cognition. Third, this active period deep sleep may be a cognitively pathologic attempt to recover age-related loss of inactive period deep sleep. Finally, therapeutic strategies aimed at reducing active period deep sleep (e.g., by promoting active period wakefulness and/or inactive period deep sleep) may be highly relevant to cognitive function in the aging community.研究背景：与年龄相关的认知功能缺损会显著降低生活质量，还可能预示严重的神经退行性疾病。尽管睡眠紊乱对认知的负面影响已得到广泛认可，且其发生率随年龄增长而升高，但令人惊讶的是，鲜有研究探讨睡眠与认知衰老之间的关联。 研究方法：我们分别在静息（睡眠增强）与活跃（觉醒增强）阶段，对青年成年及老年F344大鼠（F344 rats）的睡眠时相进行了检测。随后通过莫里斯水迷宫（Morris Water Maze）对实验动物开展行为学评估，并采集其顶叶皮层的基因表达谱。 主要研究结果：随年龄增长，大鼠的莫里斯水迷宫任务表现受损，且静息阶段的深睡时长减少。但活跃阶段的深睡时长增加与迷宫任务表现的相关性最强。转录组谱与行为学表现及年龄均存在显著关联，且该结果已通过既往研究得到验证。生物信息学分析显示，翻译过程相关通路出现上调，而髓鞘/神经元相关通路则出现下调。 研究结论：F344大鼠可作为人类年龄相关常见睡眠结构与认知改变的合理动物模型，其中包括活跃阶段深睡对认知的损害作用。基因芯片（Microarray）分析显示，该睡眠阶段所涉及的生物学过程与其功能相符。由此可见，活跃阶段的深睡存在时间错位，但机制完整，据此可得出以下推论：其一，老年脑组织虽可产生深睡所需的慢波，但其强度弱于年轻脑组织；其二，活跃阶段出现的此类脑活动对认知功能反而具有损害而非益处；其三，活跃阶段的深睡可能是一种认知病理性代偿，用以弥补年龄相关的静息阶段深睡缺失；最后，旨在减少活跃阶段深睡的干预策略（例如通过促进活跃阶段觉醒或静息阶段深睡），或可对老年群体的认知功能产生积极意义。