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.