Hyperexcitable arousal circuits drive sleep instability during aging

• Published in: Science (American Association for the Advancement of Science) Vol. 375; no. 6583; p. eabh3021
• Main Authors: Li, Shi-Bin, Damonte, Valentina Martinez, Chen, Chong, Wang, Gordon X., Kebschull, Justus M., Yamaguchi, Hiroshi, Bian, Wen-Jie, Purmann, Carolin, Pattni, Reenal, Urban, Alexander Eckehart, Mourrain, Philippe, Kauer, Julie A., Scherrer, Grégory, de Lecea, Luis
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 25.02.2022
• Subjects: Ablation; Aging; Aging (Individuals); Aminopyridines - pharmacology; Animal models; Animals; Arousal; Brain; Channels; Circuits; Cognitive ability; CRISPR; CRISPR-Cas Systems; Depolarization; Destabilization; Disruption; Electroencephalography; Electromyography; Excitability; Female; Firing pattern; Fragmentation; Gene expression; Gene sequencing; Geriatrics; Hypothalamic Area, Lateral - physiopathology; KCNQ1 protein; KCNQ2 Potassium Channel - genetics; KCNQ2 Potassium Channel - metabolism; KCNQ2 protein; KCNQ3 Potassium Channel - genetics; KCNQ3 Potassium Channel - metabolism; Male; Mathematical models; Mice; Narcolepsy; Narcolepsy - genetics; Narcolepsy - physiopathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural networks; Neural Pathways; Neurons; Neurons - physiology; Older people; Optogenetics; Orexins; Orexins - physiology; Patch-Clamp Techniques; Pharmacology; Phylogeny; Potassium channels (voltage-gated); Recording; RNA-Seq; Sleep; Sleep and wakefulness; Sleep Deprivation - physiopathology; Sleep disorders; Sleep Quality; snRNA; Stability; Stimulation; Translation; Wakefulness
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abh3021

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. In humans, the deterioration of sleep quality during aging is one of the most prevalent complaints. In an animal model, Li et al . found that aging correlated with enhanced spontaneous activity of wake-promoting brain areas during sleep (see the Perspective by Jacobson and Hoyer). Hypocretin-expressing neurons were more active during sleep, raising the chances of brief arousals and thus causing sleep to be more fragmented. The excitability of hypocretin neurons in aged brain tissue was heightened, possibly because of decreased expression of a subpopulation of potassium channels. Aging-related sleep fragmentation may therefore be due to altered intrinsic excitability of arousal-promoting neurons. —PRS Down-regulation of potassium channels causes hyperexcitability of hypocretin neurons and leads to age related fragmentation of sleep.