Dexmedetomidine Alleviates Sleep Rhythm Abnormalities in Chronic Sleep-Deprived Mice via Modulation of SIK3/HDAC4/5 Signalling

Background: Sleep deprivation (SD) often disrupts normal sleep patterns, leading to anxiety-like behaviours and cognitive impairments. Dexmedetomidine (DEX), a highly selective α-2 adrenergic agonist, has been reported to improve postoperative sleep quality and alleviate cognitive deficits. Evidence indicates that DEX can regulate the expression of histone deacetylase 5 (HDAC5), a substrate of the sleep-regulating molecule salt-inducible kinase 3 (SIK3). However, its specific role and the underlying mechanisms in regulating sleep structure remain unclear. This study aims to examine DEX's effects and potential mechanisms in regulating sleep structure in sleep-deprived mice.

Methods: C57BL/6J mice were subjected to chronic sleep deprivation (CSD) for 20 h (from 5 to 1 PM the next day), followed by administration of DEX at 1 and 3 PM daily for 7 consecutive days. Emotional behaviours were evaluated using the open-field test. Sleep patterns were assessed during the recovery period using EEG/EMG. Golgi-Cox staining was used to determine neuronal dendritic damage. Western blotting was employed to detect the SIK3/HDAC4/5 pathway-related protein levels.

Results: CSD disrupted the sleep structure of mice during the recovery period and induced anxiety-like behaviour and neuronal dendritic damage. DEX administration alleviated the above effects caused by CSD. Mechanistically, DEX activated SIK3/HDAC4/5 signalling in CSD mice, while inhibition of SIK3 with a specific inhibitor attenuated DEX's effects on the pathway activation.

Conclusion: DEX can alleviate sleep rhythm disturbances caused by CSD in mice possibly via modulation of the SIK3/HDAC4/5 pathway, thereby improving anxiety-like behaviours and cognitive function.

SIK3/HDAC4/5; dexmedetomidine; sleep deprivation; sleep structure.