Abstract
Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3′,5′-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1–4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.
Highlights
Life evolved in an environment of periodic recurrence of light and darkness
A complete Prkg1 knock-out leads to premature death at approximately 6 weeks of age, presumably due to smooth muscle dysfunction [20]
We confirmed Cre activity in the suprachiasmatic nuclei (SCN) by X-Gal staining of ROSA26 Cre reporter (R26R) reporter mice and abolition of PRKG1 expression in the SCN of Prkg1BKO mice by immunohistochemistry (Fig. 1D) and used these mutants to assess the influence of PRKG1 on circadian rhythmicity
Summary
Life evolved in an environment of periodic recurrence of light and darkness. These steady changes have led to the incorporation of daily biological rhythms in order to schedule biochemical processes to their optimal phase during the 24 hours of a day. Sleep is mainly controlled by two mechanisms: A homeostatic component regulates need and intensity of sleep according to the time spent awake or asleep, whereas a circadian component schedules sleep and wakefulness to the appropriate times within one day [1]. Delta power is high at the onset of sleep and consecutively decreases as animals rest. For the circadian process in rodents, reliable information on the internal period length of the autonomous clock mechanism and the ability of the clock to adapt to changes in lighting schedules can be obtained by recording wheel-running activity. Deciphering the molecular base of sleep is difficult because the contributions of the homeostatic and circadian processes are not easy to separate
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