Our group is involved in research on sleep regulation with emphasis on the interaction between the circadian clock and sleep regulatory mechanisms. Research is mainly approached in rats and mice applying long-term recordings of the electroencephalogram (EEG) sometimes in combination with neuronal activity in the suprachiasmatic nucleus (SCN) of the hypothalamus, the location of the circadian clock in mammals, on the multi-unit and single-unit level together with behavioral techniques to record daily rest-activity patterns.
With these techniques we have been able to show that multiunit activity within the SCN responds to changes in vigilance state (waking, non-rapid eye movement sleep, rapid eye movement sleep) with changes in firing rate (Fig 1. Deboer et al, 2003, Nature Neuroscience). In addition, we were able to show that sleep deprivation has a long lasting depressing effect on multi-unit firing rate in the SCN (Fig 2. Deboer et al, 2007, Sleep). Ongoing research investigates how sleep influences the functioning of the circadian clock.
The consequences of aging on sleep and the interaction between sleep and the circadian clock are now subject of the STW grant “On TIME”,
In recent research we have focused on developing a sleep deprivation method, published in the journal SLEEP in 2010 (Yasenkov and Deboer, Sleep 33: 631-641) to disentangle sleep homeostatic mechanisms from circadian regulatory mechanisms in rodents (see also Background below). This will enable us to separate the two processes on different regulatory levels (from gene to behavior) in future experiments.
Fig. 1. The time course of suprachiasmatic nucleus (SCN) neuronal activity (top) and electroencephalogram slow-wave activity (EEG power density between 1..0-4.0 Hz, bottom) at the transition from NREM to REM sleep, NREM sleep to waking and waking to NREM sleep in the two minutes before and after the state transition. (Figure from Deboer et al, 2003, Nature Neuroscience).
Fig. 2. A 48-h record of suprachiasmatic nuclei neuronal activity, slow-wave activity and vigilance states (W=waking, N=NREM sleep, R=REM sleep) of an individual animal. The first 24 h is the baseline recording starting at rest onset, followed by 6-h sleep deprivation and 18 h recovery. Note the decrease in electrical activity between CT 6-12 on the experimental day compared with the baseline control day (Figure from Deboer et al, 2007, Sleep).
In collaboration with the Neurology Department (GJ Lammers, S Overeem) of the LUMC we have been able to show that hypocretin/orexin, a substance centrally involved in sleep-wake consolidation and produced by the lateral hypothalamus, is regulated separately by a sleep homeostatic and a circadian component (Fig 3. Deboer et al, 2004, Neuroscience). Lack of hypocretin/orexin is the major cause of narcolepsy in humans.
Fig 3. A Combined data of hypocretin-1 levels in cerebrospinal fluid (CSF) of suprachiasmatic nuclei lesioned (SCN-x) and sham-lesioned control animals under constant dim red light conditions. The data are double plotted for clarity. The gray background indicates subjective night where the control animals are most active. The fluctuation in CSF hypocretin-1 was significant across the circadian day in the control animals, but not in the SCN-x animals. B. The effect of sleep deprivation (SD) on hypocretin levels in CSF of SCN-x and sham-lesioned control animals. SD data are in bar number 3. Asterisks indicate a significant increase in hypocretin-1 compared with samples taken before the start of SD (bar number 2) or 24 h before the end of SD (bar number 1).
In an ongoing collaboration with Human Genetics (AMJM van den Maagdenberg) and Neurology (MD Ferrari) of the LUMC we investigate sleep regulation in a calcium channel mutation migraine mouse model (R192Q knock-in mice).
In a recent pharmacological study we investigated the effects of methylphenidate on sleep in mice. Methylphenidate is a preferred treatment for ADHD in adults and children. In mice, methylphenidate caused a delay in the sleep-wake cycle together with an increase of waking in the dark period due to prolonged waking episodes. Combined with other techniques in the neurophysiology group we can conlude that methylpenidate alters the circadian clock consistent with alterations that would promote sleep-onset insomnia.
In addition, we can perform sleep-wake experiments and EEG analysis in rodents to investigate the effect of sleep deprivation, jet-lag, different light-dark conditions, mutations or pharmacological interventions.
Selected publications (here is the complete list)
- Deboer T, Vansteensel MJ, Détári L, Meijer JH (2003) Sleep states alter neuronal activity of the suprachiasmatic nucleus. Nat Neurosci 6: 1086-1090.
- Deboer T, Overeem S Visser NAH, Duindam H, Frölich M, Lammers GJ, Meijer JH (2004) Convergence of circadian and sleep regulatory mechanisms on hypocretin-1. Neurosci 129: 727-732.
- Jenni OG, Deboer T, Achermann P (2006) Development of rest-activity patterns in human infants. Infant Behavior & Development 29: 143-152.
- Deboer T, Détári L, Meijer JH (2007) Long term effects of sleep deprivation on the mammalian circadian pacemaker. Sleep 30: 257-262.
- VanOosterhout FFTO, Michel S, Deboer T, Houben T, VandeVen RCG, Albus H, Westerhout J, Vansteensel MJ, Ferrari MD, VandenMaagdenberg AMJM, Meijer JH (2008) Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice. Ann Neurol. 64: 315-324.
- Deboer T (2009) Sleep and sleep homeostasis in constant darkness in the rat. J Sleep Res 18: 357-364.
- Krauchi K, Deboer T (2010) The interrelationship between sleep regulation and thermoregulation. Front Biosci 15: 604-625.
- Yasenkov R, Deboer T (2011) Interrelations and circadian changes of EEG frequencies under baseline conditions and constant sleep pressure in the rat. Neurosci 180: 212-221.
- Dr. GJ Lammers, Neurology, Leiden University Medical Center, The Netherlands.
- Dr. AMJM van den Maagdenberg, Human Genetics, Leiden University Medical Center, The Netherlands
- Prof. Dr. MD Ferrari, Neurology, Leiden University Medical Center, The Netherlands
- Dr. S Overeem, Neurology, Radboud University Nijmegen Medical Center, The Netherlands.
- Dr. OG Jenni, Kinderspital Zurich, University of Zurich, Switzerland.
- Prof Dr. P Achermann, Institute of Pharmacology and Toxicology, University of Zurich, Switzerland.
- K Krauchi, Centre for Chronobiology, Psychiatric University Clinic, University of Basel, Switzerland.
- Prof. Dr. C Colwell, Psychiatry and Biobehavioral Sciences, Brain Research Institute, UCLA, USA.
- Prof. Dr. L Détári, Physiology and Neurobiology, Eötvös Loránd University, Hungary
In the two-process model of sleep regulation (Borbély, 1982 Human Neurobiol 1: 195-204; Daan et al., 1984 Am J Physiol 246: R161-R178) sleep is regulated by homeostatic and circadian processes (Figure 4). In mammals sleep homeostasis (Process S) is reflected by EEG slow-wave activity (SWA, EEG power density between ~1-4 Hz) in NREM sleep. The level of S rises during waking and declines during sleep. In all mammalian species investigated, SWA increases as a function of prior waking duration and in several species a dose-response relationship between waking duration and subsequent SWA was established. Mathematical models, simulating the homeostatic response, have been applied successfully in human, rat and mouse. The circadian process (Process C) is controlled by a pacemaker located in the SCN and provides the homeostatic process with a circadian framework.