Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice

• Published in: Journal of cerebral blood flow and metabolism 2024-09, Vol.44 (9), p.1515-1531
• Main Authors: Deng, Saiyue, Hu, Yusi, Chen, Simiao, Xue, Yang, Yao, Di, Sun, Qian, Nedergaard, Maiken, Wang, Wei, Ding, Fengfei
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Cognition - physiology; Glymphatic System - metabolism; Glymphatic System - physiopathology; Male; Mice; Mice, Inbred C57BL; Sleep Deprivation - metabolism; Sleep Deprivation - physiopathology
• ISSN: 0271-678X; 1559-7016; 1559-7016
• DOI: 10.1177/0271678X241230188

Accumulating evidence shows that most chronic neurological diseases have a link with sleep disturbances, and that patients with chronically poor sleep undergo an accelerated cognitive decline. Indeed, a single-night of sleep deprivation may increase metabolic waste levels in cerebrospinal fluid. However, it remains unknown how chronic sleep disturbances in isolation from an underlying neurological disease may affect the glymphatic system. Clearance of brain interstitial waste by the glymphatic system occurs primarily during sleep, driven by multiple oscillators including arterial pulsatility, and vasomotion. Herein, we induced sleep fragmentation in young wildtype mice and assessed the effects on glymphatic activity and cognitive functions. Chronic sleep fragmentation reduced glymphatic function and impaired cognitive functions in healthy mice. A mechanistic analysis showed that the chronic sleep fragmentation suppressed slow vasomotion, without altering cardiac-driven pulsations. Taken together, results of this study document that chronic sleep fragmentation suppresses brain metabolite clearance and impairs cognition, even in the absence of disease. Graphical Abstract Deng et al. found that chronic sleep fragmentation of 30 days significantly suppressed glymphatic influx, which was mirrored by cognitive decline. In vivo two-photon imaging in the awake state revealed that slow vasomotion rather than cardiac driven pulsations was suppressed in chronic sleep fragmented mice. Therefore, vascular dysfunction induced by sleep disturbance might impair brain metabolic waste clearance and increase the risk of developing dementia.