Irene Tobler

Sleep EEG in the rat as a function of prior waking

Delta activity in non-REM sleep and theta activity in REM sleep in the rat were computed for an 8 h baseline period and for the recovery period after 3, 6, 12 and 24 h sleep deprivation (SD). Delta activity showed a decreasing trend in all schedules and was enhanced as a function of prior waking. Theta activity and REM sleep were increased after 24 h SD.

Effect of sleep deprivation on sleep and EEG power spectra in the rat

EEG power spectra of the rat were computed for consecutive 4-s epochs of the daily light period and matched with the scores of the vigilance states. Sleep was characterized by a progressive decline of low frequency spectral values (i.e. slow wave activity) in non-rapid eye movement (non-REM) sleep, and a progressive increase in the amount of REM sleep. During recovery from 24-h total sleep deprivation (TSD) the following changes were observed: an increase of slow wave activity in non REM sleep with a persisting declining trend; an enhancement of theta activity (7.25-10.0 Hz) both in REM sleep and waking; a decrease of non-REM sleep and an increase of REM sleep. In addition, a slow wave EEG pattern prevailed in the awake and behaving animal during the initial recovery period. In selective sleep deprivation paradigms, either REM sleep or slow wave activity in non-REM sleep was prevented during a 2-h period following upon 24-h TSD. During both procedures, non-REM sleep spectra in the lowest frequency band showed no increase. There was no evidence for a further enhancement of slow wave activity after its selective deprivation. The results indicate that: (1) slow wave activity in non-REM sleep and theta activity in REM sleep may reflect sleep intensity; and (2) REM sleep and active waking, the two states with dominant theta activity, may be functionally related.

TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription

Production of TNF-α and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-α and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-α on the circadian timing system. TNF-α is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-α on clock genes is shared by IL-1β, but not by IFN-α, and IL-6. Furthermore, TNF-α interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-α is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-α and IL-1β, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.

Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations.

Gene targeted mice can be used as models to investigate the mechanisms underlying sleep regulation. Three commonly used background strains for gene targeting (129/Ola, 129/SvJ and C57BL/6J) were subjected to 4-h and 6-h sleep deprivation (SD), and their sleep and sleep EEG were continuously recorded. The two-process model of sleep regulation has predicted the time course of slow-wave activity (SWA) in nonREM sleep after several sleep-wake manipulations in humans and the rat [3] [9]. We tested the capacity of the model to predict SWA in nonREM sleep on the basis of the temporal organization of sleep in mice. The strains differed in the amount and distribution of sleep and the time course of SWA. After spontaneous waking episodes of 10-30 min as well as after SD, SWA was invariably increased. Simulations of the time course of SWA were successful for 129/SvJ and C57BL/6J, but were not satisfactory for 129/Ola. Since the time constants are assumed to reflect the dynamics of the physiological processes involved in sleep regulation, the results provide a basis for the use of gene targeted mice to investigate the underlying mechanisms.

Diazepam-induced changes in sleep: Role of the α1 GABAA receptor subtype

Ligands acting at the benzodiazepine (BZ) site of γ-aminobutyric acid type A (GABAA) receptors currently are the most widely used hypnotics. BZs such as diazepam (Dz) potentiate GABAA receptor activation. To determine the GABAA receptor subtypes that mediate the hypnotic action of Dz wild-type mice and mice that harbor Dz-insensitive α1 GABAA receptors [α1 (H101R) mice] were compared. Sleep latency and the amount of sleep after Dz treatment were not affected by the point mutation. An initial reduction of rapid eye movement (REM) sleep also occurred equally in both genotypes. Furthermore, the Dz-induced changes in the sleep and waking electroencephalogram (EEG) spectra, the increase in power density above 21 Hz in non-REM sleep and waking, and the suppression of slow-wave activity (SWA; EEG power in the 0.75- to 4.0-Hz band) in non-REM sleep were present in both genotypes. Surprisingly, these effects were even more pronounced in α1(H101R) mice and sleep continuity was enhanced by Dz only in the mutants. Interestingly, Dz did not affect the initial surge of SWA at the transitions to sleep, indicating that the SWA-generating mechanisms are not impaired by the BZ. We conclude that the REM sleep inhibiting action of Dz and its effect on the EEG spectra in sleep and waking are mediated by GABAA receptors other than α1, i.e., α2, α3, or α5 GABAA receptors. Because α1 GABAA receptors mediate the sedative action of Dz, our results provide evidence that the hypnotic effect of Dz and its EEG “fingerprint” can be dissociated from its sedative action.

Unilateral vibrissae stimulation during waking induces interhemispheric EEG asymmetry during subsequent sleep in the rat.

To test the theory that sleep is a regional, use‐dependent process, rats were subjected to unilateral sensory stimulation during waking. This was achieved by cutting the whiskers on one side, in order to reduce the sensory input to the contralateral cortex. The animals were kept awake for 6 h in an enriched environment to activate the cortex contralateral to the intact side. Whiskers are known to be represented in the barrel field of the contralateral somatosensory cortex and their stimulation during exploratory behavior results in a specific activation of the projection area. In the 6 h recovery period following sleep deprivation, spectral power of the nonrapid eye‐movement (NREM) sleep EEG in the 0.75–6.0 Hz range exhibited an interhemispheric shift towards the cortex that was contralateral to the intact whiskers. The results support the theory that sleep has a regional, use‐dependent facet.

The effect of 3-h and 6-h sleep deprivation on sleep and EEG spectra of the rat

Vigilance states and EEG power density of the rat were determined after a 3- or 6-h sleep deprivation (SD) in the beginning of the 12-h light period. In comparison to baseline, non-rapid eye movement (REM) sleep showed a delayed and transitory increase after 3 h SD, and an immediate and persistent increase after 6 h SD. REM sleep was not affected. In non-REM sleep, EEG power density in the low-frequency range (0.75-6.0 Hz) was markedly enhanced after 6 h SD, but not significantly increased after 3 h SD. In REM sleep EEG activity in the 5-6 Hz band was increased after 6 h SD. We conclude that in the early part of the light period, 3 h waking prolongs non-REM sleep, whereas 6 h waking also enhances non-REM sleep intensity.

Sleep homeostasis in the rat: Simulation of the time course of EEG slow-wave activity

According to the two-process model of sleep regulation, a homeostatic Process S increases during waking and declines during sleep. For humans, the time course of S has been derived from the changes in EEG slow-wave activity (SWA; spectral power density in the 0.75-4.0 Hz range) during sleep. We tested the applicability of the model to sleep in the rat. The simulation was based on the vigilance states for consecutive 8-s epochs of a 96-h experiment in 9 animals. The level of S was made to decrease in epochs of non-REM sleep (NREMS), and to increase in epochs of waking or REM sleep according to exponential functions. By optimizing the initial value and the time constants of S, a close fit between the hourly values of SWA in NREMS and of S was obtained. The biphasic time course of SWA during baseline, its enhancement in the initial recovery period after 24-h sleep deprivation, and its subsequent prolonged undershoot were present in the simulation. We conclude that sleep homeostasis as conceptualized in the two-process model may be a general property of mammalian sleep.

Sleep Initiation and Initial Sleep Intensity: Interactions of Homeostatic and Circadian Mechanisms:

Sleep initiation and sleep intensity in humans show a dissimilar time course. The propensity of sleep initiation (PSI), as measured by the multiple sleep latency test, remains at a relatively constant level throughout the habitual period of waking or exhibits a midafternoon peak. When waking is extended into the sleep period, PSI rises rapidly within a few hours. In contrast, sleep intensity, as measured by electroencephalographic slow-wave activity during naps, shows a gradual increase during the period of habitual waking. In the two-process model of sleep regulation, it corresponds to the rising limb of the homeostatic Process S. We propose that PSI is determined by the difference between Process S and the threshold H defining sleep onset, which is modulated by the circadian process C. In contrast to a previous version of the model, the parameters of H (amplitude, phase, skewness) differ from those of threshold L, which defines sleep termination. The present model is able to simulate the time course of PSI under baseline conditions as well as following recovery sleep after extended sleep deprivation. The simulations suggest that during the regular period of waking, a circadian process coun teracts the increasing sleep propensity induced by a homeostatic process. Data obtained in the rat indicate that during the circadian period of predominant waking, a circadian process prevents a major intrusion of sleep.

All-night spectral analysis of the sleep EEG in untreated depressives and normal controls

Sleep was recorded in nine drug-free depressive patients and nine age- and sex-matched normal control subjects. All-night spectral analysis of the sleep electroencephalogram (EEG) showed a significantly reduced power density in the 0.25-2.50 Hz band in the depressive group. Power density values integrated over the entire frequency range (0.25-25.0 Hz) exhibited for both groups a decreasing trend over the first three non-REM/REM sleep cycles. In each cycle depressives had lower values than controls. The results are consistent with hypothesis that the build-up of a sleep-dependent process is deficient in the sleep regulation of depressive patients.