The day‐night differences in cognitive and anxiety‐like behaviors of mice after chronic sleep restriction

Abstract Animal behavioral tests are often conducted during the day. However, rodents are nocturnal animals and are primarily active at night. The aim of this study was to determine whether there are diurnal changes in cognitive and anxiety‐like performance of mice following chronic sleep restriction (SR). We also investigated whether this phenotypic difference is related to the diurnal variation of glymphatic clearance of metabolic wastes. Mice received 9‐day SR by the use of the modified rotating rod method, followed by the open field, elevated plus maze, and Y‐maze tests conducted during the day and at night, respectively. Brain β‐amyloid (Aβ) and tau protein levels, the polarity of aquaporin4 (AQP4), a functional marker of the glymphatic system, and glymphatic transport ability were also analyzed. SR mice exhibited cognitive impairment and anxiety‐like behaviors during the day, but not at night. AQP4 polarity and glymphatic transport ability were higher during the day, with lower Aβ 1‐42 , Aβ 1‐40 , and P‐Tau levels in the frontal cortex. These day‐night differences were totally disrupted after SR. These results reveal the diurnal changes in behavioral performance after chronic SR, which may be related to circadian control of AQP4‐mediated glymphatic clearance of toxic macromolecules from the brain.