美国斯坦福大学
研究人员发现，过度兴奋的下丘脑素/orexin（Hcrt/OX）神经元在衰老过程中驱动睡眠碎片化。在老年小鼠中，Hcrt神经元表现出更频繁的驱动唤醒的神经元活动时期，而且Hcrt神经元的光遗传学激活引起了更长时间的唤醒。老年Hcrt神经元表现出过度兴奋性，KCNQ2表达较低，M电流受损，并由KCNQ2/3通道介导。
单核RNA测序显示了衰老大脑中Hcrt神经元损失的适应性变化。年轻小鼠Hcrt神经元中Kcnq2/3基因的中断破坏了睡眠的稳定性，模拟了衰老相关的睡眠片段化，而KCNQ选择性激活剂flupirtine使Hcrt神经元超极化并使老年小鼠的睡眠结构恢复活力。这些研究结果证明了衰老过程中睡眠不稳定的机制和改善睡眠连续性的策略。
据悉，睡眠质量随着年龄的增长而下降；然而，其基本机制仍然难以捉摸。
附：英文原文
Title: Hyperexcitable arousal circuits drive sleep instability during aging
Author: Shi-Bin Li, Valentina Martinez Damonte, Chong Chen, Gordon X. Wang, Justus M. Kebschull, Hiroshi Yamaguchi, Wen-Jie Bian, Carolin Purmann, Reenal Pattni, Alexander Eckehart Urban, Philippe Mourrain, Julie A. Kauer, Grégory Scherrer, Luis de Lecea
Issue&Volume: 2022-02-25
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 Kcnq2/3 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.
DOI: abh3021
Source: https://www.science.org/doi/10.1126/science.abh3021