Circadian Rhythms and Sleep

Research

Our group is involved in fundamental 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). Recently, 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). In 2006 a European Union grant was obtained for further research in this area (Enough sleep link). http://www.enoughsleep.fi/

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) 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 seperately by a sleep homeostatic and a circadian component (Fig 3. Deboer et al, 2004, Neuroscience).

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 addition we can perform normal sleep-wake experiments and EEG analysis in rodents investigating the effect of sleep deprivation, jet-lag, different light-dark conditions, mutations or pharmacological interventions.

• 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.
• Deboer T, Détári L, Meijer JH (2007) Long term effects of sleep deprivation on the mammalian circadian pacemaker. Sleep 30: 257-262.

Collaborators

• Dr. GJ Lammers, Neurology, Leiden University Medical Center, The Netherlands.
• Dr. AMJM van den Maagdenberg, Human Genetics, Leiden University Medical Center, The Netherlands
• Dr. S Overeem, Neurology, Radboud University Nijmegen Medical Center, The Netherlands.
• Prof. Dr. I Tobler, Pharmacology and Toxicology, University of Zurich, Zwitserland
• Prof. Dr. L Détári, Physiology and Neurobiology, Eötvös Loránd University, Hungary

Background

Sleep is regulated by homeostatic and circadian processes. In mammals sleep homeostasis is reflected by EEG slow-wave activity (SWA, EEG power density between ~1-4 Hz) in NREM 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 (Figure 4). Mathematical models, simulating the homeostatic response, have been applied successfully in human, rat and mouse. The circadian process is controlled by a pacemaker located in the SCN and provides the homeostatic process with a circadian framework.