Caffeine increases light responsiveness of the mouse circadian pacemaker.

Caffeine is the most commonly used psychoactive stimulant worldwide. It reduces sleep and sleepiness by blocking access to the adenosine receptor. The level of adenosine increases during sleep deprivation, and is thought to induce sleepiness and initiate sleep. Light-induced phase shifts of the rest-activity circadian rhythms are mediated by light-responsive neurons of the suprachiasmatic nucleus (SCN) of the hypothalamus, where the circadian clock of mammals resides. Previous studies have shown that sleep deprivation reduces circadian clock phase-shifting capacity and decreases SCN neuronal activity. In addition, application of adenosine agonists and antagonists mimics and blocks, respectively, the effect of sleep deprivation on light-induced phase shifts in behaviour, suggesting a role for adenosine. In the present study, we examined the role of sleep deprivation in and the effect of caffeine on light responsiveness of the SCN. We performed in vivo electrical activity recordings of the SCN in freely moving mice, and showed that the sustained response to light of SCN neuronal activity was attenuated after 6 h of sleep deprivation prior to light exposure. Subsequent intraperitoneal application of caffeine was able to restore the response to light. Finally, we performed behavioural recordings in constant conditions, and found enhanced period lengthening during chronic treatment with caffeine in drinking water in constant light conditions. The data suggest that increased homeostatic sleep pressure changes circadian pacemaker functioning by reducing SCN neuronal responsiveness to light. The electrophysiological and behavioural data together provide evidence that caffeine enhances clock sensitivity to light.

Circadian modulation of sleep in rodents.

Sleep is regulated by circadian and homeostatic processes. The sleep homeostat keeps track of the duration of prior sleep and waking and determines the intensity of sleep. In mammals, the homeostatic process is reflected by the slow waves in the non-rapid eye movement (NREM) sleep electroencephalogram (EEG). The circadian process is controlled by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus and provides the sleep homeostat with a circadian framework. This review summarizes the changes in sleep obtained after different chronobiological interventions (changes in photoperiod, light availability, and running wheel availability), the influence of mutations or lesions in clock genes on sleep, and research on the interaction between sleep homeostasis and the circadian clock. Research in humans shows that the period of consolidated waking during the day is a consequence of the interaction between an increasing homeostatic sleep drive and a circadian signal, which promotes waking during the day and sleep during the night. In the rat, it was shown that, under constant homeostatic sleep pressure, with similar levels of slow waves in the NREM sleep EEG at all time points of the circadian cycle, still a small circadian modulation of the duration of waking and NREM sleep episodes was observed. Under similar conditions, humans show a clear circadian modulation in REM sleep, whereas in the rat, a circadian modulation in REM sleep was not present. Therefore, in the rat, the sleep homeostatic modulation in phase with the circadian clock seems to amplify the relatively weak circadian changes in sleep induced by the circadian clock. Knowledge about the interaction between sleep and the circadian clock and the circadian modulation of sleep in other species than humans is important to better understand the underlying regulatory mechanisms.

Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock.

Aging is associated with a deterioration of daily (circadian) rhythms in physiology and behavior. Deficits in the function of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) have been implicated, but the responsible mechanisms have not been clearly delineated. In this report, we characterize the progression of rhythm deterioration in mice to 900 d of age. Longitudinal behavioral and sleep-wake recordings in up to 30-month-old mice showed strong fragmentation of rhythms, starting at the age of 700 d. Patch-clamp recordings in this age group revealed deficits in membrane properties and GABAergic postsynaptic current amplitude. A selective loss of circadian modulation of fast delayed-rectifier and A-type K+ currents was observed. At the tissue level, phase synchrony of SCN neurons was grossly disturbed, with some subpopulations peaking in anti-phase and a reduction in amplitude of the overall multiunit activity rhythm. We propose that aberrant SCN rhythmicity in old animals--with electrophysiological arrhythmia at the single-cell level and phase desynchronization at the network level--can account for defective circadian function with aging.

Circadian regulation of sleep and the sleep EEG under constant sleep pressure in the rat.

STUDY OBJECTIVE: Sleep is regulated by homeostatic and circadian processes. Slow wave activity (SWA; 1-4 Hz) in the NREM sleep electroencephalogram (EEG) reflects sleep homeostasis. Activity of faster EEG frequencies (10-25 Hz) is thought to be under influence of circadian factors. The relative contribution of both processes to the distribution of sleep and wakefulness and EEG activity in rodents remains uncertain. DESIGN: Continuous EEG recording in rats in constant dark conditions (DD) were performed and a sleep deprivation protocol consisting of 2 h sleep deprivation followed by 2 h of rest (2h/2h) was applied for 48 h to obtain a constant sleep pressure. SETTINGS: Basic sleep research laboratory. PATIENTS OR PARTICIPANTS: Adult male Wistar rats. INTERVENTION: Sleep deprivation. MEASUREMENTS AND RESULTS: Under the 2h/2h protocol, the circadian modulation of waking, NREM and REM sleep was markedly reduced compared to the baseline, affecting the frequency of vigilance state episodes and the duration of REM sleep and waking episodes. In contrast, NREM sleep episode duration still showed a daily modulation. Consecutive 2h values of SWA in NREM sleep were stabile during the 2h\2h protocol, while NREM sleep EEG activity within the higher frequencies (7-25 Hz) still demonstrated strong circadian modulation, which did not differ from baseline. CONCLUSIONS: In rats, the daily modulation of REM sleep is less pronounced compared to NREM sleep and waking. In contrast to SWA, activity in higher frequencies (7-25 Hz) in the NREM sleep EEG have an endogenous circadian origin and are not influenced by sleep homeostatic mechanisms.