University of Zürich - Institute of Pharmacology and Toxicology Section of Psychopharmacology and Sleep Research

Aeschbach D., Cajochen C., Landolt H.P., Borbély A.A.

Homeostatic sleep regulation in habitual short sleepers (sleep episode < 6 h, n = 9) and long sleepers (>9 h, n = 7) was investigated by studying their sleep structure and sleep electroencephalogram (EEG) during baseline conditions and after prolonging their habitual waking time by 24 h. In each sleep episode, total sleep time was >3 h longer in the long sleepers than in the short sleepers. Sleep deprivation decreased sleep latency and rapid eye movement (REM) density in REM sleep more in long sleepers than in short sleepers. The enhancement of EEG slow-wave activity (SWA; spectral power density in the 0.75- 4.5 Hz range) in non-REM sleep after sleep loss was larger in long sleepers (47%) than in short sleepers (19%). This difference in the SWA response was predicted by the two-process model of sleep regulation on the basis of the different sleep durations. The results indicate that short sleepers live under a higher "non-REM sleep pressure" than long sleepers. However, the two groups do not differ with respect to the homeostatic sleep regulatory mechanisms.

Am. J. Physiol. 270 (1996): R41-R53.

Deboer T., Tobler I.

To asses the influence of photoperiod on sleep regulation EEG, EMG, and cortical temperature were continuously recorded for two baseline days and after 4 h sleep deprivation in Djungarian hamsters adapted to a short photoperiod (light dark 8:16). Comparison to previous data collected in a long photoperiod (light:dark 16:8) showed several major effects of photoperiod: 1. A prominent change in the 24-h distribution, duration and number of vigilance state episodes, whereas the total amount of sleep and waking was unchanged; 2. Cortical temperature was 0.7°C lower in the short photoperiod; 3. There was a significant negative correlation between cortical temperature and the frequency of REM sleep episodes; and 4. Absolute EEG power density showed a marked reduction in the short photoperiod. After sleep deprivation EEG slow-wave activity (mean power density 0.75-4.0 Hz) in NREM sleep showed a remarkably similar increase in both photoperiods demonstrating the robustness of the homeostatic regulation of sleep. Cortical temperature remained above baseline values after sleep deprivation in the short photoperiod whereas a negative rebound was present in the long photoperiod. Our results support the hypothesis that cortical temperature has a strong influence on REM sleep propensity and indicate the possibility of an optimum cortical temperature for recovery sleep after sleep deprivation. The lower EEG power density in the short photoperiod may contribute to energy conservation.

J. Comp. Physiol. A 179 (1996): 483-492.

Deboer T., Tobler I.

Sleep, daily torpor, and hibernation have been considered to be homologous processes. However, in the Djungarian hamster, daily torpor is followed by an increase in slow-wave activity (SWA; electroencephalogram power density 0.75-4.0 Hz) that is similar to the increase observed after sleep deprivation. A positive correlation was found between torpor episode length and the subsequent increase in SWA, which was highest when SWA was assumed to increase with a saturating exponential function. Thus the increase in SWA propensity during daily torpor followed similar kinetics as during waking, supporting the hypothesis that when the animal is in torpor it is incurring a sleep debt. An alternative hypothesis, proposing that the mode of arousal causes the subsequent SWA increase, was tested by warming the animals during emergence from daily torpor. Irrespective of mode of arousal, more non-rapid eye movement (NREM) sleep and a similar SWA increase was found after torpor. The data are compatible with a putative neuronal restorative function for sleep associated with the expression of SWA in NREM sleep. During torpor, when brain temperature is low, this function is inhibited, whereas the need for restoration accumulates. Recovery takes place only after return to euthermia.

Am. J. Physiol. 40 (1996): R1364-R1371.

Driver H.S., Dijk D.J., Werth E., Biedermann K., Borbély A.A.

Cyclic changes in hormones, body temperature, and metabolic rate characterize the menstrual cycle. To investigate whether these changes are associated with changes in sleep and the sleep electroencephalogram (EEG), a total of 138 sleep episodes from 9 women with no premenstrual syndrome symptoms were recorded every second night throughout one ovulatory menstrual cycle and analyzed in relation to menstrual phase. Ovulation and menstrual cycle stage were confirmed by measurements of temperature, urinary LH, and midluteal plasma levels of estrogen and progesterone. No significant variation across the menstrual cycle was observed for subjective ratings of sleep quality and mood as well as for objective measures of total sleep time, sleep efficiency, sleep latency, rapid eye movement sleep latency, and slow wave sleep. In nonrapid eye movement sleep, EEG power density in the 14.25-15.0 hertz band, which corresponds to the upper frequency range of the sleep spindles, exhibited a large variation across the menstrual cycle, with a maximum in the luteal phase. The data show that in healthy young women, sleep spindle frequency activity varies in parallel with core body temperature, whereas homeostatic sleep regulatory mechanisms, as indexed by the time course of EEG slow wave activity are not substantially affected by the menstrual cycle.

J. Clin. Endocrin. Metab. 81 (1996): 728-735.

Landolt H.P., Dijk D.J., Achermann P., Borbély A.A.

The effect of age on sleep and the sleep EEG was investigated in middle-aged men (mean age: 62.0 y) and in young men (mean age: 22.4 y). Even though the older men reported a higher number of nocturnal awakenings, subjective sleep quality did not differ. Total sleep time, sleep efficiency, and slow wave sleep were lower in the middle-aged, while stage 1 and wakefulness after sleep onset were higher. The difference in wakefulness within nonREM-REM sleep cycles was most pronounced in the third and fourth cycle. In the older men, EEG power density in nonREM sleep was reduced in frequencies below 14.0 Hz, whereas in REM sleep age-related reductions were limited to the delta-theta (0.25-7.0 Hz) and low alpha (8.25-10.0 Hz) band. Slow-wave activity (SWA, power density in the 0.75-4.5 Hz range) decreased in the course of sleep in both age groups. The between-group difference in SWA diminished in the course of sleep, whereas the difference in activity in the frequency range of sleep spindles (12.25-14.0 Hz) increased. It is concluded that frequency and state specific changes occur as a function of age, and that the sleep dependent decline in SWA and increase in sleep spindle activity are attenuated with age.

Brain Res. 738 (1996): 205-212.

Landolt H.P., Roth C., Dijk D.J., Borbély A.A.

The effect of a moderate dose of ethanol (0.55 g/kg of body weight), administered six hours before scheduled bedtime, on performance, nocturnal sleep and the sleep electroencephalogram (EEG) was investigated in ten healthy, middle-aged men (mean age: 61.6±0.9 years). By the beginning of the sleep episode breath-ethanol concentrations had declined to zero in all subjects. Compared to the control condition (mineral water), sleep was perceived as more superficial. Sleep efficiency, total sleep time, stage 1 and REM sleep were reduced. In the second half of the sleep episode, wakefulness exhibited a twofold increase. EEG power density in low delta frequencies was enhanced in nonREM sleep (1.25-2.5 Hz) and REM sleep (1.25-1.5 Hz). In slow wave sleep (SWS, i.e., stages 3+4), power density was increased not only in the low frequency range (1.25-1.5, 2.25-4.0, 4.5-5.0 Hz), but also within the alpha (8.25-9.0 Hz) and sigma (12.25-13.0 Hz) band. The data demonstrate that late afternoon ethanol intake in middle-aged men disrupts sleep consolidation, affects the sleep stage distribution and alters the sleep EEG.

J. Clin. Psychopharmacol. 16 (1996): 428-436.

Neuner-Jehle M., Denizot J.P., Borbély A.A., Mallet J.

We report on the characterization of the novel rat brain protein dendrin which is encoded by the brain-specific transcript 464, On immunoblots, two protein variants (81 kD, 89 kD) were identified in cytosolic and membraneous protein fractions, The variants are most abundant in the hippocampus, notably in apical dendrites of CA1 pyramidal cells, Dendritic and perikaryal immunolabelling is apparent in neurons of the cerebral cortex, dentate gyrus, subiculum, amygdala, and preoptic areas, In cortical and hippocampal dendrites, electron-dense immunoreaction is associated with the endoplasmic reticulum, the plasma membrane, and spine heads, An association of dendrin with polyribosomes and the presence of its mRNA in dendrites both provide evidence for dendritic mRNA translation, In the rat forebrain, dendrin expression is altered after an extended period of wakefulness, Twenty-four-hour sleep deprivation decreases the mRNA and protein concentrations of both variants in subcortical forebrain plus midbrain areas by 24 +/- 11% (P < 0.05) and 40 +/- 14% (P < 0.1), respectively, as measured relative to p-actin mRNA and neural actin, In the cerebral cortex and hippocampus, the relative mRNA level remains unchanged whereas the cortical protein concentration is reduced by 42 +/- 10% (P < 0.05). Thus, dendrin belongs to a new class of dendritic proteins whose expression is differentially modulated by prolonged behavioral activity.

J. Neurosci. Res. 46 (1996): 138-151.

Schwierin B., Borbély A.A., Tobler I.

To study the role of adenosine in sleep regulation, the adenosine A(1) receptor agonist N-6-cyclopentyladenosine (CPA) and the antagonist caffeine were administered to rats. Intraperitoneal (i.p.) CPA 1 mg/kg but not 0.1 mg/kg, suppressed rapid-eye-movement (REM) sleep and enhanced electroencephalographic (EEG) slow-wave activity (power density 0.75-4.0 Hz) in non-REM sleep. The latter effect was remarkably similar to the response to 6-h sleep deprivation. The effects persisted when CPA-induced hypothermia was prevented. Caffeine (10 and 15 mg/kg i.p.) elicited a dose-dependent increase in waking followed by a prolonged increase of slow-wave activity in non-REM sleep. The combination of caffeine (15 mg/kg) and sleep deprivation caused less increase in slow-wave activity than sleep deprivation alone, indicating that caffeine may reduce the buildup of sleep pressure during waking. The results are consistent with the involvement of adenosine in the regulation of non-REM sleep.

Eur. J. Pharmacol. 300 (1996): 163-171.

Tobler I., Gaus S.E., Deboer T., Achermann P., Fischer M., Rülicke T., Moser M., Oesch B., McBride P.A., Manson J.C.

There is a wealth of data supporting a central role for the prion protein (PrP) in the neurodegenerative prion diseases of both humans and other species, yet the normal function of PrP, which is expressed at the cell surface of neurons and glial cells, is unknown. It has been speculated that neuropathology may be due to loss of normal function of PrP. Here we show that in mice devoid of PrP there is an alteration in both circadian activity rhythms and sleep patterns. To our knowledge, this is the first null mutation that has been shown to affect sleep regulation and our results indicate that the pathology of at least one of the inherited prion diseases, fatal familial insomnia, where there is a profound alteration in sleep and the daily rhythms of many hormones, may be related to the normal function of the prion protein.

Nature 380 (1996): 639-642.

Tobler I., Schwierin B.

Behavioural sleep was assessed for 152 nights in 5 adult, 2 immature and 1 juvenile giraffes at a zoological garden, using continuous time-lapse video recording. Sleep occurred while the giraffes were standing (SS) and in recumbency (RS). Paradoxical sleep (PS) was recognized by the peculiar positioning of the head on the croup and by phasic events. The 24-h sleep profile had a main bimodal nocturnal sleep period between 20.00 and 07.00 hours, with a trough between 02.00 and 04.00 hours, and several short naps between 12.00 and 16.00 hours. Total sleep time (TST), excluding the juvenile, was 4.6 h, whereby PS comprised only 4.7%. TST was not age dependent, but the lowest amount of RS and the highest amount of SS occurred in the oldest and the two oldest animals, respectively. Sleep was fragmented, as indicated by the predominance of RS episodes lasting less than 11 min. Sleep cycle duration was very variable with most values between 1 and 35 min (when no waking or RS was allowed within PS episodes), or 6-35 min (when the criteria for ending a PS episode allowed 1-2 min interruptions by RS). There were several indications for sleep regulation: (i) RS and SS complemented each other to yield a relatively stable daily value of TST; (ii) sleep was redistributed on nights following a day when the giraffes spent a few hours in an outside enclosure. The first peak of the bimodal sleep profile was absent and RS was more prominent in the second half of the night compared with nights following days spent in the barn; and (iii) napping was followed by a minor reduction of RS and an increase in SS in the subsequent night compared with nights following days without naps.

J. Sleep Res. 5 (1996): 21-32.

Werth E., Achermann P., Borbély A.A.

To investigate the brain topography of the human sleep EEG along the antero-posterior axis, spectra (0.25-25 Hz; 1-Hz bins) were computed from all-night EEG recordings (n=20 subjects) obtained from an anterior (F3-C3) and a posterior (P3-O1) derivation. State-dependent and frequency-dependent topographic differences were observed. In NREMS, power in the anterior derivation was higher than in the posterior derivation in the 2-Hz bin, and lower in the 4-10-Hz bins. In REMS, a posterior dominance was present in most bins below 18 Hz. The 2-6-Hz bins exhibited an antero-posterior shift of power over consecutive NREMS episodes. Consistent shifts of power were also present within NREMS episodes. The results suggest that anterior and posterior cortical regions may be differently involved in the sleep process.

Neuroreport 8 (1996): 123-127.

Werth E., Dijk D.J., Achermann P., Borbély A.A.

Increasing sleep pressure is associated with highly predictable changes in the dynamics of the sleep EEG. To investigate whether also the effects of reduced sleep pressure can be accounted for by homeostatic mechanisms, nighttime sleep following an evening nap was recorded in healthy, young men. In comparison to the baseline night, sleep latency in the post-nap night was prolonged, REM sleep latency was reduced, and EEG power density in nonREM sleep was decreased in the delta and theta band. The buildup of both EEG slow-wave activity (SWA; power density in the 0.75-4.5 Hz range) and spindle frequency activity (SFA; power density in the 12.25- 15.0 Hz range) in nonREMS episodes was diminished (SWA: episodes 1-3; SFA: episode 1). The typical declining trend of SWA over consecutive nonREM sleep episodes was attenuated. The time course of SWA could be closely simulated with a homeostatic model of sleep regulation, although some discrepancies in its level and buildup were apparent. We conclude that homeostatic mechanisms can largely account for the dynamics of the sleep EEG under conditions of reduced sleep pressure.

Am. J. Physiol. 271 (1996): R501-R510.