The aging brain: sleep, the circadian clock and exercise.

Aging is a multifactorial process likely stemming from damage accumulation and/or a decline in maintenance and repair mechanisms in the organisms that eventually determine their lifespan. In our review, we focus on the morphological and functional alterations that the aging brain undergoes affecting sleep and the circadian clock in both human and rodent models. Although both species share mammalian features, differences have been identified on several experimental levels, which we outline in this review. Additionally, we delineate some challenges on the preferred analysis and we suggest that a uniform route is followed so that findings can be smoothly compared. We conclude by discussing potential interventions and highlight the influence of physical exercise as a beneficial lifestyle intervention, and its effect on healthy aging and longevity. We emphasize that even moderate age-matched exercise is able to ameliorate several aging characteristics as far as sleep and circadian rhythms are concerned, independent of the species studied.

Effects of Chronic Dim-light-at-night Exposure on Sleep in Young and Aged Mice.

Dim-light-at-night (DLAN) exposure is associated with health problems, such as metabolic disruptions, immunological modulations, oxidative stress, sleep problems, and altered circadian timing. Neurophysiological parameters, including sleep patterns, are altered in the course of aging in a similar way. Here, we investigated the effect of chronic (three months) DLAN exposure (12 L:12 Dim-light, 75:5 lux) on sleep and the sleep electroencephalogram (EEG), and rest-activity behavior in young (6-month-old, n = 9) and aged (18- n = 8, 24-month-old, n = 6) C57BL/6J mice and compared with age-matched controls (n = 11, n = 9 and n = 8, respectively). We recorded the EEG and electromyogram continuously for 48-h and conducted a 6-h sleep-deprivation. A delay in the phase angle of entrainment of locomotor activity and daily vigilance state rhythms was apparent in mice following DLAN exposure, throughout the whole age spectrum, rendering sleep characteristics similar among the three age DLAN groups and significantly different from the age-matched controls. Notably, slow-wave-activity in NREM sleep (SWA, EEG power density in 0.5-4.0 Hz) was differentially altered in young and aged DLAN mice. Particularly, SWA increased as a function of age, which was further accentuated following DLAN exposure. However, this was not found in the young DLAN animals, which were characterized by the lowest SWA levels. Concluding, long-term DLAN exposure induced more pronounced alterations in the sleep architecture of young mice, towards an aging phenotype, while it enhanced age-associated sleep changes in the older groups. Our data suggest that irrespective of age, chronic DLAN exposure deteriorates sleep behavior and may consequently impact general health.

Chronic high-caloric diet accentuates age-induced sleep alterations in mice.

Obesity and sleep disturbances comprise major health problems which are likely interrelated. Diet-induced obesity in young mice has been demonstrated to lead towards an altered sleep homeostasis. In the current study, we investigated the effect of chronic (12 weeks) high-caloric diet (HCD, 45% fat) consumption on sleep and the sleep electroencephalogram (EEG) in young and older mice (6-month-old, n = 9; 18-month-old, n = 8 and 24-month-old, n = 4) and compared with age-matched controls on normal chow (n = 11, n = 9 and n = 9 respectively). Half of the 24-month-old mice did not cope well with HCD, therefore this group has a lower n and limited statistical power. We recorded EEG and the electromyogram for continuous 48-h and performed a 6-h sleep deprivation during the second day. In aged HCD fed mice (18 months old) compared to young, an aging effect was still evident, characterized by decreased waking and increased NREM sleep in the dark period, decreased REM sleep during the light period, as well as increased slow-wave-activity (SWA, EEG power in NREM sleep in 0.5-4.0 Hz). Additionally, aged HCD treated mice showed increased NREM sleep and decreased waking, compared to age-matched controls, denoting an enhanced aging phenotype in the sleep architecture. Notably, an overall increase was found in the slow component of SWA (0.5-2.5 Hz) in aged HCD fed mice compared to age-matched controls. Our data suggest that the effect of aging is the dominant variable irrespective of diet. However, a synergistic effect of aging and diet is noted indicating that chronic HCD consumption exacerbates age-associated sleep alterations.

Different Effects of Sleep Deprivation and Torpor on EEG Slow-Wave Characteristics in Djungarian Hamsters.

It has been shown previously in Djungarian hamsters that the initial electroencephalography (EEG) slow-wave activity (power in the 0.5-4.0 Hz band; SWA) in non-rapid eye movement (NREM) sleep following an episode of daily torpor is consistently enhanced, similar to the SWA increase after sleep deprivation (SD). However, it is unknown whether the network mechanisms underlying the SWA increase after torpor and SD are similar. EEG slow waves recorded in the neocortex during sleep reflect synchronized transitions between periods of activity and silence among large neuronal populations. We therefore set out to investigate characteristics of individual cortical EEG slow waves recorded during NREM sleep after 4 h SD and during sleep after emergence from an episode of daily torpor in adult male Djungarian hamsters. We found that during the first hour after both SD and torpor, the SWA increase was associated with an increase in slow-wave incidence and amplitude. However, the slopes of single slow waves during NREM sleep were steeper in the first hour after SD but not after torpor, and, in contrast to sleep after SD, the magnitude of change in slopes after torpor was unrelated to the changes in SWA. Furthermore, slow-wave slopes decreased progressively within the first 2 h after SD, while a progressive increase in slow-wave slopes was apparent during the first 2 h after torpor. The data suggest that prolonged waking and torpor have different effects on cortical network activity underlying slow-wave characteristics, while resulting in a similar homeostatic sleep response of SWA. We suggest that sleep plays an important role in network homeostasis after both waking and torpor, consistent with a recovery function for both states.

Plasticity of circadian clocks and consequences for metabolism.

The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans.

Design and construction of a silver(I)-loaded cellulose-based wound dressing: trackable and sustained release of silver for controlled therapeutic delivery to wound sites.

Although application of silver nitrate and silver sulfadiazine have been shown to be effective in thwarting infections at burn sites, optimization of the delivery of bioactive silver (Ag(+)) remains as an obstacle due to rapid precipitation and/or insolubility of the silver sources. To circumvent these shortcomings, we have designed a silver(I) complex [Ag(ImD)2]ClO4 (ImD = dansyl imidazole) that effectively increases the bioavailability of Ag(+) and exhibits MIC values of 2.3 and 4.7 µg/mL against E. coli and S. aureus, respectively. This fluorescent silver complex has been incorporated within a robust hydrogel derived from carboxymethyl cellulose that allows slow release of silver. A complete occlusive dressing has finally been constructed with the Ag(ImD)CMC (1% Ag loaded) pad sealed between a sterile mesh gauze (as bottom layer) and a rayon-based surgical tape (as the top layer). Such construction has afforded a dressing that displays sustained delivery of silver onto a skin and soft tissue infection model and causes effective eradication of bacterial loads within 24 h. The transfer of the bioactive silver complex is readily visualized by the observed fluorescence that overlays precisely with the kill zone. The latter feature introduces a unique feature of therapeutic trackability to this silver-donating occlusive dressing.

Supramolecular Assembly of Ag(I) Centers: Diverse Topologies Directed by Anionic Interactions.

Ag(I)-Ag(I) interactions in supramolecular structures have been achieved through the use of structural support from the ligand frames. In structures involving simple ligands like pyridine, strong π-π interaction leads to spatial ordering of the individual [Ag(L)2]+ units. In such structures anions also play a crucial role in dictating the final arrangement of the [Ag(L)2]+ synthons. In order to determine whether the anions can solely dictate the arrangement of the [Ag(L)2]+ synthons in the supramolecular structure, four Ag(I) complexes of 4-pyridylcarbinol (PyOH), namely, [Ag(PyOH)2]X (X = NO3- (1), BF4- (2), CF3SO3- (3), and ClO4- (4)) have been synthesized and structurally characterized. Gradual transformation of the extended structures observed in 1-3 eventually merges into a unique linear alignment of the [Ag(PyOH)2]+ units in 4 along the c axis, a feature that results in strong argentophilic interactions. Complex 4 is sensitive to light and is inherently less stable than the other three analogues. The structural variations in this set of extended assemblies are solely dictated by the anions, since π-π interaction between the substituted pyridine ligands is significantly diminished due to disposition of the -CH2OH substituent at the 4 position and H-bonding throughout the structure.

Interrelations and circadian changes of electroencephalogram frequencies under baseline conditions and constant sleep pressure in the rat.

Similar to the nap-protocols applied in humans, the repeated short-sleep deprivation protocol in rats stabilizes slow-wave activity (SWA, 0.5-4 Hz) in the non-rapid eye movement (NREM) sleep electroencephalogram (EEG), thus reflecting a constant sleep pressure or sleep homeostatic level, whereas higher frequencies (7-25 Hz) in these conditions preserve their daily rhythm, therefore demonstrating a strong input from an endogenous circadian clock. How different EEG frequencies in rapid eye movement (REM) sleep and waking respond to these constant conditions, how they interrelate to each other within the different vigilance states, and which component of sleep regulation (homeostatic or circadian) is involved, remain unknown. To answer these questions, we applied power spectral analysis and correlation analysis to 1 Hz bin EEG frequency data for different vigilance states in freely moving rats in constant darkness, under baseline conditions and during the repeated short-sleep deprivation protocol. Our analysis suggests that (1) 0.5-5 Hz frequencies in NREM sleep and higher frequencies in REM sleep (above 19 Hz) and waking (above 10 Hz) are sleep-dependent, and thus seem to be under control of the sleep homeostat, while (2) faster frequencies in the NREM sleep EEG (7-25 Hz) and 3-7 Hz activity in the REM sleep EEG are under strong influence of the endogenous circadian clock. Theta activity in waking (5-7 Hz) seems to reflect both circadian and behavior dependent influences. NREM sleep EEG frequencies between 9 and 14 Hz showed both homeostatic and circadian components in their behavior. Thus, frequencies in the EEG of the different vigilance states seem to represent circadian and homeostatic components of sleep regulatory mechanisms, where REM sleep and waking frequency ranges behave similarly to each other and differently from NREM sleep frequencies.

[In time for Beijing: influence of the biological clock on athletic performance]. / Op tijd voor Beijing: invloed van de biologische klok op sportprestaties.

Circadian rhythms are a common characteristic ofmulticellular organisms and evolved as an adaptation to the earth's rotation on its axis. In humans, circadian rhythms are regulated by suprachiasmatic nuclei located at the base of the hypothalamus. The suprachiasmatic nuclei function as a biological clock that controls the daily rhythms of nearly all physiological functions. External light synchronises the endogenous clock to the environmental light-dark cycle. When travelling rapidly across multiple time zones, the endogenous clock must adjust to the new time. During the period of adjustment, many physiological circadian rhythms become desynchronised and jet lag occurs. Few studies have analysed the influence of jet lag on athletic performance. These studies indicate that performance levels can decline during jet lag. This seems to be a result of the desynchronized physiological state and sleep disturbances, leading to suboptimal values of blood pressure, heart rate, body temperature, and muscle strength. We give some advice for athletes who must cross multiple time zones shortly before a competition.

Overlapping numerical cognition impairments in children with chromosome 22q11.2 deletion or Turner syndromes.

Children with one of two genetic disorders (chromosome 22q11.2 deletion syndrome and Turner syndrome) as well typically developing controls, participated in three cognitive processing experiments. Two experiments were designed to test cognitive processes involved in basic aspects numerical cognition. The third was a test of simple manual motor reaction time. Despite significant differences in global intellectual abilities, as measured by IQ tests, performance on the two numerical cognition tasks differed little between the two groups of children with genetic disorders. However, both performed significantly more poorly than did controls. The pattern of results are consistent with the hypothesis that impairments were not due to global intellectual ability but arose in specific cognitive functions required by different conditions within the tasks. The fact that no group differences were found in the reaction time task, despite significant differences in the standardized processing speed measure, further supports the interpretation that specific cognitive processing impairments and not global intellectual or processing speed impairments explain the pattern of results. The similarity in performance on these tasks of children with unrelated genetic disorders counters the view that numerical cognition is under any direct genetic control. Instead, our findings are consistent with the view that disturbances in foundational spatiotemporal cognitive functions contribute to the development of atypical representations and processes in the domains of basic magnitude comparison and simple numerical enumeration.

Technologies of sleep research.

Sleep is investigated in many different ways, many different species and under many different circumstances. Modern sleep research is a multidisciplinary venture. Therefore, this review cannot give a complete overview of all techniques used in sleep research and sleep medicine. What it will try to do is to give an overview of widely applied techniques and exciting new developments. Electroencephalography has been the backbone of sleep research and sleep medicine since its first application in the 1930s. The electroencephalogram is still used but now combined with many different techniques monitoring body and brain temperature, changes in brain and blood chemistry, or changes in brain functioning. Animal research has been very important for progress in sleep research and sleep medicine. It provides opportunities to investigate the sleeping brain in ways not possible in healthy volunteers. Progress in genomics has brought new insights in sleep regulation, the best example being the discovery of hypocretin/orexin deficiency as the cause of narcolepsy. Gene manipulation holds great promise for the future since it is possible not only to investigate the functions of different genes under normal conditions, but also to mimic human pathology in much greater detail.

Convergence of circadian and sleep regulatory mechanisms on hypocretin-1.

Hypocretin is a potential regulator of sleep and wakefulness and its levels fluctuate with the day-night cycle with high levels during the animal's activity period. Whether the daily fluctuations are driven endogenously or by external light cycles is unknown. We investigated the circadian and homeostatic regulation of hypocretin in the absence of environmental light cycles. To this purpose we performed repetitive samplings of cerebrospinal fluid in rats through implanted microcannulas in the cisterna magna and determined hypocretin-1 levels by radioimmunoassay. These experiments were also performed in rats that received a lesion of the suprachiasmatic nucleus (SCN), a major pacemaker for circadian rhythms in mammals. The results showed sustained rhythmicity of hypocretin in constant dim red light in control animals. SCN-lesioned animals showed no circadian rhythms in hypocretin and mean hypocretin levels were remarkably low. The results indicate that the SCN is indispensable for rhythmicity in hypocretin and induces a daily increase in hypocretin levels during the animal's active phase. Additional sleep deprivation experiments were carried out to investigate homeostatic regulation of hypocretin. Hypocretin levels increased in response to sleep deprivation in both control and SCN-lesioned animals, demonstrating that sleep homeostatic control of hypocretin occurs independently from the SCN. Our data indicate that the circadian pacemaker of the SCN and sleep homeostatic mechanisms converge on one single sleep regulatory substance.

Diazepam-induced changes in sleep: role of the alpha 1 GABA(A) receptor subtype.

Ligands acting at the benzodiazepine (BZ) site of gamma-aminobutyric acid type A (GABA(A)) receptors currently are the most widely used hypnotics. BZs such as diazepam (Dz) potentiate GABA(A) receptor activation. To determine the GABA(A) receptor subtypes that mediate the hypnotic action of Dz wild-type mice and mice that harbor Dz-insensitive alpha1 GABA(A) receptors [alpha1 (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 alpha1(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 GABA(A) receptors other than alpha1, i.e., alpha2, alpha3, or alpha5 GABA(A) receptors. Because alpha1 GABA(A) 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.

Sleep in the blind mole rat Spalax ehrenbergi.

STUDY OBJECTIVES: The mole rat, Spalax ehrenbergi, is an interesting species for sleep because of its pronounced specialization to a fossorial life. These rodents spend most of their life-time underground, and are less exposed to many of the environmental stimuli and challenges that are common to non-fossorial rodents. A prominent adaptation is their blindness, which is due to an atrophy of the eyes. DESIGN: Continuous 24-h recordings of EEG, EMG and cortical temperature, and EEG spectral analysis were performed in six individuals caught in the wild and adapted to the laboratory for several months. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Total sleep time (52% of recording time) and the amount of REM sleep (8% of recording time) in these subterranean rodents are in the range of values found in the laboratory rat, mouse and hamster recorded under similar conditions. In contrast to these species, the polyphasic sleep-wakefulness distribution in mole rats was more distinct. A predominance of sleep in the dark period was only minor and not present in all individuals, which resembles sleep in the guinea pig. As in all other mammals investigated, the daily time course of EEG slow-wave activity (SWA) in nonREM sleep closely followed the polyphasic sleep-wake pattern and the light-dark preference. The transitions from non REM sleep to REM sleep were characterized, as in other rodents, by a gradual increase in EEG activity in the theta and sigma frequency bands before the transition. However, the power surge in these frequencies massively exceeded that found in other rodents. This feature may be related to adaptations of the brain to the requirements of the subterranean habitat. CONCLUSIONS: It is remarkable that large ecological differences between species within the same order have relatively small effects on many sleep features. The time course of SWA confirmed its predictability on the basis of the previous sleep-wake history.

Light-Induced resetting of the circadian pacemaker: quantitative analysis of transient versus steady-state phase shifts.

The suprachiasmatic nuclei of the hypothalamus contain the major circadian pacemaker in mammals, driving circadian rhythms in behavioral and physiological functions. This circadian pacemaker's responsiveness to light allows synchronization to the light-dark cycle. Phase shifting by light often involves several transient cycles in which the behavioral activity rhythm gradually shifts to its steady-state position. In this article, the authors investigate in Syrian hamsters whether a phase-advancing light pulse results in immediate shifts of the PRC at the next circadian cycle. In a first series of experiments, the authors aimed a light pulse at CT 19 to induce a phase advance. It appeared that the steady-state phase advances were highly correlated with activity onset in the first and second transient cycle. This enabled them to make a reliable estimate of the steady-state phase shift induced by a phase-advancing light pulse on the basis of activity onset in the first transient cycle. In the next series of experiments, they presented a light pulse at CT 19, which was followed by a second light pulse aimed at the delay zone of the PRC on the next circadian cycle. The immediate and steady-state phase delays induced by the second light pulse were compared with data from a third experiment in which animals received a phase-delaying light pulse only. The authors observed that the waveform of the phase-delay part of the PRC (CT 12-16) obtained in Experiment 2 was virtually identical to the phase-delay part of the PRC for a single light pulse (obtained in Experiment 3). This finding allowed for a quantitative assessment of the data. The analysis indicates that the delay part of the PRC-between CT 12 and CT 16-is rapidly reset following a light pulse at CT 19. These findings complement earlier findings in the hamster showing that after a light pulse at CT 19, the phase-advancing part of the PRC is immediately shifted. Together, the data indicate that the basis for phase advancing involves rapid resetting of both advance and delay components of the PRC.

Topography of EEG dynamics after sleep deprivation in mice.

Several recent results show that sleep and sleep regulation are not only global phenomena encompassing the entire brain, but have local features. It is well established that slow-wave activity [SWA; mean electroencephalographic (EEG) power density in the 0.75-4.0 Hz band] in non-rapid eye movement (NREM) sleep is a function of the prior history of sleep and wakefulness. SWA is thought to reflect the homeostatic component of the two-process model of sleep regulation. According to this model, originally formulated for the rat and later extended to human sleep, the timing and structure of sleep are determined by the interaction of a homeostatic Process S and a circadian process. Our aim was to investigate the dynamics of SWA in the EEG of two brain regions (frontal and occipital cortex) after sleep deprivation (SD) in two of the mice strains most often used in gene targeting. C57BL/6J (n = 9) and 129/Ola (n = 8) were recorded during a 24-h baseline day, 6-h SD, and 18-h recovery. Both derivations showed a significant increase in SWA in NREM sleep after SD in both strains. In the first hour of recovery, SWA was enhanced more in the frontal derivation than in the occipital derivation and showed a faster decline. This difference resulted in a lower value for the time constant for the decrease of SWA in the frontal derivation (frontal: 10.9 +/- 2.1 and 6.8 +/- 0.9 h in Ola and C57, respectively; occipital: 16.6 +/- 2.1 and 14.1 +/- 1.5 h; P < 0.02; for each of the strains; paired t-test). Neither time constant differed significantly between the strains. The subdivision of SWA into a slower and faster band (0.75-2.5 Hz and 2.75-4.0 Hz) further highlighted regional differences in the effect of SD. The lower frequency band had a higher initial value in the frontal derivation than in the occipital derivation in both strains. Moreover, in the higher frequency band a prominent reversal took place so that power in the frontal derivation fell below the occipital values in both strains. Thus our results indicate that there may be differences in the brain in the effects of SD on SWA in mice, suggesting regional differences in the dynamics of the homeostatic component of sleep regulation. The data support the hypothesis that sleep has local, use- or waking-dependent features that are reflected in the EEG, as has been shown for humans and the laboratory rat.

Long photoperiod restores the 24-h rhythm of sleep and EEG slow-wave activity in the Djungarian hamster (Phodopus sungorus).

Photoperiod influences the distribution of sleep and waking and electroencephalogram (EEG) power density in the Djungarian hamster. In an experimental procedure combining short photoperiod (SP) and low ambient temperature, the light-dark difference in the amount of sleep was decreased, and the changes in slow-wave activity (SWA) (mean EEG power density between 0.75 and 4.0 Hz) in nonrapid eye movement (NREM) sleep within 24 h were abolished. These findings, obtained in three different groups of animals, suggested that at the lower ambient temperature, the influence of the circadian clock on sleep-wake behavior was diminished. However, it remained unclear whether the changes were due to the photoperiod, ambient temperature, or both. Here, the authors show that EEG and electromyogram recordings in a single group of animals sequentially adapted to a short and long photoperiod (LP) at low ambient temperature (approximately 15 degrees C) confirm that EEG power is reduced in SP. Moreover, the nocturnal sleep-wake behavior and the changes in SWA in NREM sleep over 24 h were restored by returning the animals to LP and retaining ambient temperature at 15 degrees C. Therefore, the effects cannot be attributed to ambient temperature alone but are due to a combined effect of temperature and photoperiod. When the Djungarian hamster adapts to winter conditions, it appears to uncouple sleep regulation from the circadian clock.

Slow waves in the sleep electroencephalogram after daily torpor are homeostatically regulated.

Animals emerging from hibernation or daily torpor show an initial increase in electroencephalogram slow-wave activity (SWA, power density between 0.75 and 4.0 Hz) in non-REM sleep, which subsequently declines. These typical features of sleep following prolonged waking led to the interpretation that the animals incur a sleep deprivation (SD) during torpor. This hypothesis has recently been questioned because the increase in SWA disappears in ground squirrels when sleep deprived immediately following hibernation. Here we show that in Djungarian hamsters subjected to SD immediately after daily torpor a predictable increase in SWA occurs during recovery. This supports the notion that the hamsters must sleep to dissipate the pressure for SWA incurred during torpor. The similarity between sleep after waking and torpor may provide a key for understanding sleep regulation.

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.

Running wheel size influences circadian rhythm period and its phase shift in mice.

Running wheels are widely used in studies on biological rhythms. In mice wheel diameters have ranged from 11 cm to 23 cm. We provided mice with running wheels of two different sizes: 15 cm diameter and 11 cm diameter. The amount of running in the 12-h light:12-h dark condition and the endogenous period of wheel running in constant darkness was determined over 40 days. On the 1st day in constant darkness all animals were exposed to a 15-min light pulse at circadian time 13. The animals in the small wheel ran significantly less both in 12 h light: 12 h dark and constant darkness, and showed a longer endogenous period in constant darkness compared to animals in the large wheel. Moreover, after the light pulse at circadian time 13, mice in the small wheel showed a significantly smaller phase delay in running wheel activity than mice in the larger wheels. The data suggest that the magnitude of a photic phase shift depends on the amount and timing of activity the animals display in relation to this stimulus. It can be concluded that technical features of the running wheel can influence the circadian period of wheel running.