TY - JOUR
T1 - Hyperexcitable arousal circuits drive sleep instability during aging
AU - Li, Shi Bin
AU - Damonte, Valentina Martinez
AU - Chen, Chong
AU - Wang, Gordon X.
AU - Kebschull, Justus M.
AU - Yamaguchi, Hiroshi
AU - Bian, Wen Jie
AU - Purmann, Carolin
AU - Pattni, Reenal
AU - Urban, Alexander Eckehart
AU - Mourrain, Philippe
AU - Kauer, Julie A.
AU - Scherrer, Grégory
AU - de Lecea, Luis
N1 - Publisher Copyright:
© 2022 American Association for the Advancement of Science. All rights reserved.
PY - 2022/2/25
Y1 - 2022/2/25
N2 - 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.
AB - 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.
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U2 - 10.1126/science.abh3021
DO - 10.1126/science.abh3021
M3 - Article
C2 - 35201886
AN - SCOPUS:85125216113
SN - 0036-8075
VL - 375
JO - Science
JF - Science
IS - 6583
M1 - eabh3021
ER -