Research reportSleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals
Introduction
Located in the suprachiasmatic nuclei (SCN) of the hypothalamus, the main pacemaker of the mammalian circadian system drives the daily variations of most behavioral and physiological variables. The SCN pacemaker is primarily synchronized to the daily light–dark cycle, thereby providing 24-h temporal cues to the organism that are in synchrony with the external environment [23]. Like many other bodily functions, the sleep–wake cycle is regulated by both homeostatic and circadian processes. The relationships between the sleep–wake cycle and the circadian pacemaker systems, however, appear to be complex because the two systems influence each other to modulate the daily temporal organization. Besides providing circadian signals to brain areas controlling sleep, the SCN pacemaker may also participate in the regulation of the vigilance state [13]. Conversely, changes in the activity–rest state are capable of altering circadian function [29], [43], [44], [45] as well as the response of the circadian pacemaker to light [27], [34].
Sleep deprivation reduces the phase-shifting effect of light in hamsters [28], suggesting that acute changes in sleep homeostasis can alter circadian regulation. On the one hand, sleep deprivation increases hypothalamic serotonin (5-HT) turnover [4] and 5-HT release in the SCN [20]. In addition, changes in serotonergic activity are known to alter photic phase-resetting via 5-HT projections to the SCN [6], [33], [35]. As previously suggested [28], it is therefore possible that changes in 5-HT activity mediate the effects of sleep deprivation on photic phase-resetting. On the other hand, sleep deprivation reduces glucose utilization in several brain areas, including the ventromedial hypothalamus [17]. Moreover, a decrease in glucose availability can affect photic phase-resetting [10], partly through the ventromedial hypothalamus [9]. These data raise the possibility that changes in brain glucose and/or serotonergic function mediate the effects of sleep deprivation on photic phase-resetting.
In this context, a series of experiments were undertaken to try to unravel how sleep deprivation may modulate the responses of the circadian timing system to light. First, we investigated whether sleep deprivation affects the phase-shifting effects of light in mice. Second, we tested whether changes in brain 5-HT activity play a role in mediating the effects of sleep deprivation on the circadian system. Third, we also investigated whether changes in glucose metabolism modify light-induced phase-shifts in sleep-deprived animals, and whether the ventromedial hypothalamus is involved in mediating the impact of sleep deprivation on the circadian timing system.
Section snippets
Animals
Eight-week-old male C57BL/6JI mice were purchased from Iffa-Credo (Font Saint Landry, Brussels, Belgium) and housed singly in cages equipped with running wheels (diameter 11 cm) for the continuous recording of wheel-running activity using the Chronobiology Kit® (Stanford Software Systems, Stanford, CA, USA). Mice were maintained in a temperature-controlled room (23±1°C) and exposed to a daily light–dark cycle of 12L:12D. During the light phase, white fluorescent lamps provided a light intensity
Sleep deprivation, stress and response to a light pulse
To evaluate possible changes of phase-shifting in sleep-deprived mice, the onset of the nocturnal pattern of locomotor activity was analyzed by a two-way ANOVA between the treatment (sleep deprivation, immobilization or control) and the lighting conditions (darkness or light pulse). Behavioral phase-shifts were markedly modified by the treatment (F(2,30)=13.7; P<0.001) and the lighting conditions (F(1,30)=91.7; P<0.001). Furthermore, there was a significant treatment×lighting conditions
Discussion
The present findings indicate that (1) light-induced phase-delays in mice are reduced by sleep deprivation, but not by stress-induced immobilization; and (2) sleep deprivation may modulate the responses of the pacemaker to light by increasing hypothalamic 5-HT and by altering metabolic function, via the ventromedial hypothalamus.
Sleep deprivation has no phase-shifting effects by itself in constant darkness. This result obtained in mice is generally consistent with previous reports that mice
Acknowledgements
This work was supported by NIH grants AG-11412 and HL-96015 (F.W.T.), the Belgian National Fund for Scientific Research (O.V.R. and F.W.T.), and by a Post-doctoral fellowship from Université Libre de Bruxelles (E.C.). We thank Dr. B.M. Bergmann for helpful comments on the experimental design. Portions of this work were presented in abstract form at the International Congress on Chronobiology, Washington, DC, August 1999.
References (47)
- et al.
Neuropeptide Y in the arcuate nucleus is modulated by alterations in glucose utilization
Brain Res.
(1993) - et al.
Injection with gold thioglucose impairs sensitivity to glucose: evidence that glucose-responsive neurons are important for long-term regulation of body weight
Brain Res.
(1996) - et al.
Serotonin-containing fibers in the suprachiasmatic hypothalamus attenuate light-induced phase delays in mice
Brain Res.
(1997) - et al.
Gold-thioglucose-induced hypothalamic lesions inhibit metabolic modulation of light-induced circadian phase shifts in mice
Brain Res.
(1999) - et al.
Intracarotid glucose selectively increases Fos-like immunoreactivity in paraventricular, ventromedial and dorsomedial nuclei neurons
Brain Res.
(1997) The role of glutamate in the photic regulation of the suprachiasmatic nucleus
Prog. Neurobiol.
(1996)Functional consequences of sustained sleep deprivation in the rat
Behav. Brain Res.
(1995)- et al.
Drug concentrations in mouse brain at pharmacologically active doses of fluoxetine enantiomers
Biochem. Pharmacol.
(1993) - et al.
Instrumental and pharmacological paradoxical sleep deprivation in mice: strain differences
Neuropharmacology
(1980) - et al.
Glucose, insulin and sympathoadrenal activation
J. Auton. Nerv. Syst.
(1987)
Entrainment and phase shifting of circadian rhythms in mice by forced treadmill running
Physiol. Behav.
Behavioral inhibition of light-induced circadian phase resetting is phase and serotonin dependent
Brain Res.
Sleep deprivation can attenuate light-induced phase shifts of circadian rhythms in hamsters
Neurosci. Lett.
Glucose as a regulator of neuronal activity
Adv. Metab. Disord.
A serotonin neurotoxin attenuates the phase-shifting effects of triazolam on the circadian clock in hamsters
Brain Res.
Alterations of blood platelet MAO-B activity and LSD-binding in humans after sleep deprivation and recovery sleep
J. Psychiatr. Res.
Goldthioglucose causes brain norepinephrine and serotonin depletion correlated with increased body weight
Brain Res.
Impact of a sleep debt on metabolic and endocrine function
Lancet
Effects of anxiolytics, diazepam and tandospirone, on immobilization stress-induced hyperglycemia in mice
Life Sci.
The effects of short periods of immobilization on the hamster circadian clock
Brain Res.
Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster
J. Neurosci.
Response curves in circadian periodicity
Sleep deprivation increases brain serotonin turnover in the rat
Neuroreport
Cited by (69)
Sleep homeostasis
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionAdjunctive and alternative treatments of circadian rhythm sleep disorders
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionSleep timing and the circadian clock in mammals: Past, present and the road ahead
2022, Seminars in Cell and Developmental BiologyCitation Excerpt :While the two processes are clearly able to work independently, there is increasing evidence that they also influence each other and that Process S may have more influence over Process C than vice versa. For example, in both humans and rodent models, the magnitude of phase shifts induced by changes in the LD cycle are attenuated during periods of sleep deprivation [79,80]. Although some evidence indicates that clock genes may influence sleep depth and that SWS is modulated by circadian phase, more research is needed to determine if and how the circadian clock influences Process S [81].
Distinct feedback actions of behavioural arousal to the master circadian clock in nocturnal and diurnal mammals
2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Furthermore, serotonin modulates photic resetting differently between nocturnal and diurnal rodents. Serotonergic activation reduces light-induced shifts in nocturnal rodents, while this treatment potentiates light-induced phase-shifts in the diurnal Arvicanthis (Challet et al., 2001; Cuesta et al., 2008). Consistently, a serotonergic activation induced by a single dose of citalopram, a serotonin reuptake inhibitor, increases photic sensitivity of the circadian system in humans (McGlashan et al., 2018).
Circadian and Sleep Metabolomics Across Species
2020, Journal of Molecular BiologySleep homeostasis and the circadian clock: Do the circadian pacemaker and the sleep homeostat influence each other's functioning?
2018, Neurobiology of Sleep and Circadian RhythmsCitation Excerpt :Serotonin levels increase in the SCN during sleep deprivation (Grossman et al., 2000), and serotonin is known to reduce SCN neuronal activity in vitro (Yu et al., 2001). Moreover, impairment of serotonin transmission could partially restore the phase shifting capacity of light (Challet et al., 2001). Serotonin and its agonists has a phase shifting capacity of its own (Prosser et al. 1990).