The Influence of Sleep Deprivation on Hippocampal CA1 Gene Expression: Relation to Stress and Aging

Sleep deprivation (SD) in young adults is associated with metabolic, stress and cognitive responses that are also characteristic of brain aging. Given that sleep architecture changes with age, including increased fragmentation and decreased slow wave activity, it seems reasonable to investigate potential molecular relationships between SD and aging in brain tissue. Here, we tested the hypothesis that young rats exposed to 24 or 72 hour SD would respond with stress and aging-like shifts in brain hippocampal CA1 gene expression. SD animals showed blood corticosterone and weight changes consistent with a stress response. Microarray results, validated by Western blot and comparison to prior SD studies, pointed to disruptions in neurotransmission, sleep pressure signaling, and macromolecular synthesis. In a separate experiment, animals exposed to 24 or 72 hour novel environment stress recapitulated nearly one third of the SD transcriptional profile, particularly upregulated apoptotic and immune signaling pathways. Compared to aging (based on three previously published independent hippocampal aging studies), SD transcriptional profiles agreed for neurogenesis and energy pathways. However, immune signaling, glial activity, macromolecular synthesis and neuronal function all showed an SD profile that was, at least in part, opposed by aging. We conclude that while stress and SD have discrete molecular signatures, they do show a subset of highly similar changes. However, the same could not be said of aging and SD, where a similar subset of genes is changed, but in partially divergent directions. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel targets for future SD-countering therapeutics.青年群体的睡眠剥夺（Sleep Deprivation，SD）与代谢、应激及认知反应相关，而这些反应亦是脑衰老的典型特征。鉴于睡眠结构（sleep architecture）随年龄增长发生改变，包括片段化程度升高与慢波活动（slow wave activity）降低，探究脑组织中SD与衰老之间的潜在分子关联具备合理性。本研究针对以下假说开展验证：暴露于24小时或72小时SD的幼年大鼠，其脑海马CA1区（hippocampal CA1）的基因表达会出现应激反应与类衰老的表达偏移。接受SD处理的大鼠出现了血液皮质酮（corticosterone）水平与体重的变化，这些变化符合应激反应的特征。经蛋白质印迹（Western Blot）验证并与既往SD研究比对后，基因芯片（Microarray）结果显示，神经传递、睡眠压力信号通路与大分子合成均出现紊乱。在另一项独立实验中，暴露于24小时或72小时新奇环境应激的大鼠，其转录谱（transcriptional profile）中有近三分之一与SD处理后的转录谱一致，尤其是凋亡与免疫信号通路的上调特征。与衰老状态（基于三项已发表的独立海马衰老研究）相比，SD的转录谱在神经发生（neurogenesis）与能量代谢通路方面与衰老特征相符。但免疫信号通路、神经胶质细胞活性（glial activity）、大分子合成以及神经元功能的SD相关表达谱，至少在部分层面与衰老的表达变化方向相反。本研究得出结论：尽管应激与SD各自拥有独特的分子特征，但二者确实存在一部分高度相似的表达变化。但衰老与SD的关系则并非如此：二者虽有部分相似的差异表达基因，但变化方向存在部分差异。最后，本研究鉴定出突触前囊泡释放（presynaptic vesicular release）与细胞间黏附（intercellular adhesion）的分子特征，可作为未来开发对抗SD治疗手段的新型靶点。