过度兴奋的唤醒回路导致衰老过程中的睡眠不稳定。
Hyperexcitable arousal circuits drive sleep instability during aging.
机构信息
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305, USA.
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
出版信息
Science. 2022 Feb 25;375(6583):eabh3021. doi: 10.1126/science.abh3021.
Abstract
Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness. Aged Hcrt neurons showed hyperexcitability with lower KCNQ2 expression and impaired M-current, mediated by KCNQ2/3 channels. Single-nucleus RNA-sequencing revealed adaptive changes to Hcrt neuron loss in the aging brain. Disruption of genes in Hcrt neurons of young mice destabilized sleep, mimicking aging-associated sleep fragmentation, whereas the KCNQ-selective activator flupirtine hyperpolarized Hcrt neurons and rejuvenated sleep architecture in aged mice. Our findings demonstrate a mechanism underlying sleep instability during aging and a strategy to improve sleep continuity.
摘要
睡眠质量随年龄增长而下降；然而，潜在的机制仍然难以捉摸。我们发现，过度兴奋的下丘脑泌素/食欲素（Hcrt/OX）神经元在衰老过程中导致睡眠碎片化。在老年小鼠中，Hcrt 神经元表现出更频繁的神经元活动期，驱动觉醒期，光遗传学激活 Hcrt 神经元引起更长时间的觉醒。老年 Hcrt 神经元表现出兴奋性增加，KCNQ2 表达降低，M 电流受损，由 KCNQ2/3 通道介导。单细胞 RNA 测序揭示了衰老大脑中 Hcrt 神经元丢失的适应性变化。年轻小鼠 Hcrt 神经元中 基因的破坏会破坏睡眠的稳定性，模拟与衰老相关的睡眠碎片化，而 KCNQ 选择性激活剂氟吡汀使 Hcrt 神经元超极化，并恢复老年小鼠的睡眠结构。我们的研究结果表明了衰老过程中睡眠不稳定的一种机制，以及一种改善睡眠连续性的策略。
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