Expression of clock genes in human peripheral blood mononuclear cells throughout the sleep/wake and circadian cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non-SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five-day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake-time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi-hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

Masking effects of posture and sleep onset on core body temperature have distinct circadian rhythms: results from a 90-min/day protocol

Both recumbency and sleep affect core body temperature (CBT). To characterize their circadian effects and interactions, the authors examined the bedtime temperature drops (TDs) of nine men and eight women (aged 20 to 30) who repeated 90-min sleep-wake cycles over 2.5 days. While awake, subjects were exposed to 50 to 250 lux; while asleep, lights were off. Electroencephalogram-monitored time inbed lasted 30 min during each cycle. Cosinor nonlinear mixed-effects regressions modeled the circadian rhythm of TDs. The circadian maximum of TDs occurred approximately 4 h before the time of circadian CBT minimum, in a model that included the effects of baseline expected CBT, deviations from baseline CBT, time in study, and gender-dependent 24- and 12-h adjustments. Rates of temperature drops were faster during initial periods of lying awake than during periods of initially sleeping. Both rates followed separate circadian rhythms. The circadian maximum of TDs was located near customary nocturnal bedtimes, suggesting its role in fostering sleep during a normal bedtime routine. The apparent deceleration of temperature dropping at sleep onset supports the notion that the sleep onset period has complicated circadian neuroregulatory dynamics. These findings confirm the need for nonlinear models of temperature responses to postural changes and sleep that incorporate circadian variability in these masking effects.     

An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night

Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0 degrees ). Data were segregated according to: (1) circadian phase (60 degrees bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300 degrees , approximately 2300-0300 h in these subjects) than during the biological day (bin 180 degrees , approximately 1500-1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive prior to awakening (changes in sleep efficiency across circadian phase or across the tertiaries), or by the proportion of the varied sleep stages prior to awakenings. This robust endogenous circadian rhythm in sleep inertia may have important implications for people who need to be alert soon after awakening.     

Heart rate variability and body temperature during the sleep onset period

Heart rate variability (HRV) and body temperature during the sleep onset period was examined. The core body temperature and electrocardiogram were recorded continuously beginning 1 h before lights out (LO) until the end of the first rapid eye movement sleep (REM) in 14 young healthy subjects. HRV was calculated by the MemCalc method. The time course changes in body temperature and HRV was analyzed before and after sleep onset, and during the following eight consecutive phases: the 60 min before LO, the 30 min before LO, LO, first stage 2 (sleep onset), first slow wave sleep (SWS), stage 2 just before REM, start of REM, and end of REM. A clear decline was observed in the ratio of the low frequency (LF) to high frequency (HF) component of HRV (LF/HF), normalized LF (LF/(LF + HF)), and body temperature prior to sleep onset both in the time course of the sleep onset period and in the consecutive phases. The HF increased prior to sleep onset in the consecutive phases, while no clear increase was observed in the time course of sleep onset period. Changes in LF/(LF + HF) and LF/HF preceded SWS and REM. These results suggest the existence of a strong coupling between the cardiac autonomic nervous system and body temperature at the sleep onset period that may not be circadian effects. Furthermore, LF/(LF + HF) and LF/HF may possibly anticipate sleep and the onset of each sleep stage.

     

Chronobiological characterization of women with primary vasospastic syndrome: body heat loss capacity in relation to sleep initiation and phase of entrainment

Women with primary vasospastic syndrome (VS), but otherwise healthy, exhibit a functional disorder of vascular regulation (main symptom: cold extremities) and often suffer from difficulties initiating sleep (DIS). Diverse studies have shown a close association between distal vasodilatation before lights off and a rapid onset of sleep. Therefore, we hypothesized that DIS in women with VS could be due to a reduced heat loss capacity in the evening, i.e., subjects are physiologically not ready for sleep. The aim of the study was to elucidate whether women having both VS and DIS (WVD) or not (controls) show different circadian characteristics (e.g., phase delay of the circadian thermoregulatory system with respect to the sleep-wake cycle). Healthy young women (n = 9 WVD and n = 9 control) completed a 40-h constant routine protocol (adjusted to habitual bedtime) before and after an 8-h sleep episode. Skin temperatures [off-line calculated as distal-proximal skin temperature gradient (DPG)] and core body temperature (CBT; rectal) were continuously recorded. Half-hourly saliva samples were collected for melatonin assay and subjective sleepiness was assessed on the Karolinska Sleepiness Scale (KSS). Compared with control, WVD showed no differences in habitual bed times, but a 1-h circadian phase delay of dim light-melatonin onset (hours after lights on: WVD 14.6 +/- 0.3 h; control 13.5 +/- 0.2 h; P = 0.01). Similar phase shifts were observed in CBT, DPG, and KSS ratings. In conclusion, WVD exhibit a phase delay of the endogenous circadian system with respect to their habitual sleep-wake cycle, which could be a cause of DIS.     

Challenging the sleep homeostat does not influence the thermoregulatory system in men: evidence from a nap vs. sleep-deprivation study

The purpose of our study was to understand the relationship between the components of the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) and the thermoregulatory system. This was achieved by comparing the impact of a 40-h sleep deprivation vs. a 40-h multiple nap paradigm (10 cycles with 150/75 min wakefulness/sleep episodes) on distal and proximal skin temperatures, core body temperature (CBT), melatonin secretion, subjective sleepiness, and nocturnal sleep EEG slow-wave activity in eight healthy young men in a "controlled posture" protocol. The main finding of the study was that accumulation of sleep pressure increased subjective sleepiness and slow-wave activity during the succeeding recovery night but did not influence the thermoregulatory system as measured by distal, proximal, and CBT. The circadian rhythm of sleepiness (and proximal temperature) was significantly correlated and phase locked with CBT, whereas distal temperature and melatonin secretion were phase advanced (by 113 +/- 28 and 130 +/- 30 min, respectively; both P < 0.005). This provides evidence for a primary role of distal vasodilatation in the circadian regulation of CBT and its relationship with sleepiness. Specific thermoregulatory changes occur at lights off and on. After lights off, skin temperatures increased and were most pronounced for distal; after lights on, the converse occurred. The decay in distal temperature (vasoconstriction) was significantly correlated with the disappearance of sleep inertia. These effects showed minor and nonsignificant circadian modulation. In summary, the thermoregulatory system seems to be independent of the sleep homeostat, but the circadian modulation of sleepiness and sleep inertia is clearly associated with thermoregulatory changes.     

A compromise phase position for permanent night shift workers: circadian phase after two night shifts with scheduled sleep and light/dark exposure

Night shift work is associated with a myriad of health and safety risks. Phase-shifting the circadian clock such that it is more aligned with night work and day sleep is one way to attenuate these risks. However, workers will not be satisfied with complete adaptation to night work if it leaves them misaligned during days off. Therefore, the goal of this set of studies is to produce a compromise phase position in which individuals working night shifts delay their circadian clocks to a position that is more compatible with nighttime work and daytime sleep yet is not incompatible with late nighttime sleep on days off. This is the first in the set of studies describing the magnitude of circadian phase delays that occurs on progressively later days within a series of night shifts interspersed with days off. The series will be ended on various days in order to take a "snapshot" of circadian phase. In this set of studies, subjects sleep from 23:00 to 7:00 h for three weeks. Following this baseline period, there is a series of night shifts (23:00 to 07:00 h) and days off. Experimental subjects receive five 15 min intermittent bright light pulses (approximately 3500 lux; approximately 1100 microW/cm2) once per hour during the night shifts, wear sunglasses that attenuate all visible wavelengths--especially short wavelengths ("blue-blockers")--while traveling home after the shifts, and sleep in the dark (08:30-15:30 h) after each night shift. Control subjects remain in typical dim room light (<50 lux) throughout the night shift, wear sunglasses that do not attenuate as much light, and sleep whenever they want after the night shifts. Circadian phase is determined from the circadian rhythm of melatonin collected during a dim light phase assessment at the beginning and end of each study. The sleepiest time of day, approximated by the body temperature minimum (Tmin), is estimated by adding 7 h to the dim light melatonin onset. In this first study, circadian phase was measured after two night shifts and day sleep periods. The Tmin of the experimental subjects (n=11) was 04:24+/-0.8 h (mean+/-SD) at baseline and 7:36+/-1.4 h after the night shifts. Thus, after two night shifts, the Tmin had not yet delayed into the daytime sleep period, which began at 08:30 h. The Tmin of the control subjects (n=12) was 04:00+/-1.2 h at baseline and drifted to 4:36+/-1.4 h after the night shifts. Thus, two night shifts with a practical pattern of intermittent bright light, the wearing of sunglasses on the way home from night shifts, and a regular sleep period early in the daytime, phase delayed the circadian clock toward the desired compromise phase position for permanent night shift workers. Additional night shifts with bright light pulses and daytime sleep in the dark are expected to displace the sleepiest time of day into the daytime sleep period, improving both nighttime alertness and daytime sleep but not precluding adequate sleep on days off.     

Mood, alertness, and performance in response to sleep deprivation and recovery sleep in experienced shiftworkers versus non-shiftworkers

Previous studies have shown increased sleepiness and mood changes in shiftworkers, which may be due to sleep deprivation or circadian disruption. Few studies, however, have compared responses of experienced shiftworkers and non-shiftworkers to sleep deprivation in an identical laboratory setting. The aim of this laboratory study, therefore, was to compare long-term shiftworkers and non-shiftworkers and to investigate the effects of one night of total sleep deprivation (30.5 h of continuous wakefulness) and recovery sleep on psychomotor vigilance, self-rated alertness, and mood. Eleven experienced male shiftworkers (shiftwork ≥5 yrs) were matched with 14 non-shiftworkers for age (mean ± SD: 35.7 ± 7.2 and 32.5 ± 6.2 yrs, respectively) and body mass index (BMI) (28.7 ± 3.8 and 26.6 ± 3.4 kg/m(2), respectively). After keeping a 7-d self-selected sleep/wake cycle (7.5/8 h nocturnal sleep), both groups entered a laboratory session consisting of a night of adaptation sleep and a baseline sleep (each 7.5/8 h), a sleep deprivation night, and recovery sleep (4-h nap plus 7.5/8 h nighttime sleep). Subjective alertness and mood were assessed with the Karolinska Sleepiness Scale (KSS) and 9-digit rating scales, and vigilance was measured by the visual psychomotor vigilance test (PVT). A mixed-model regression analysis was carried out on data collected every hour during the sleep deprivation night and on all days (except for the adaptation day), at .25, 4.25, 5.25, 11.5, 12.5, and 13.5 h after habitual wake-up time. Despite similar circadian phase (melatonin onset), demographics, food intake, body posture, and environmental light, shiftworkers felt significantly more alert, more cheerful, more elated, and calmer than non-shiftworkers throughout the laboratory study. In addition, shiftworkers showed a faster median reaction time (RT) compared to non-shiftworkers, although four other PVT parameters did not differ between the groups. As expected, both groups showed a decrease in subjective alertness and PVT performance during and following the sleep deprivation night. Subjective sleepiness and most aspects of PVT performance returned to baseline levels after a nap and recovery sleep. The mechanisms underlying the observed differences between shiftworkers and non-shiftworkers require further study, but may be related to the absence of shiftwork the week prior to and during the laboratory study as well as selection into and out of shiftwork.     

Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (∼20-30 years old) and older people (∼65-75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20-30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation-induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285-311, 2000)     

Expression of Clock Genes in Human Peripheral Blood Mononuclear Cells throughout the Sleep/Wake and Circadian Cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non‐SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five‐day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake‐time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi‐hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.     

DBT affects sleep in both circadian and non-circadian neurons

Sleep is a very important behavior observed in almost all animals. Importantly, sleep is subject to both circadian and homeostatic regulation. The circadian rhythm determines the daily alternation of the sleep-wake cycle, while homeostasis mediates the rise and dissipation of sleep pressure during the wake and sleep period. As an important kinase, dbt plays a central role in both circadian rhythms and development. We investigated the sleep patterns of several ethyl methanesulfonate-induced dbt mutants and discuss the possible reasons why different sleep phenotypes were shown in these mutants. In order to reduce DBT in all neurons in which it is expressed, CRISPR-Cas9 was used to produce flies that expressed GAL4 in frame with the dbt gene at its endogenous locus, and knock-down of DBT with this construct produced elevated sleep during the day and reduced sleep at night. Loss of sleep at night is mediated by dbt loss during the sleep/wake cycle in the adult, while the increased sleep during the day is produced by reductions in dbt during development and not by reductions in the adult. Additionally, using targeted RNA interference, we uncovered the contribution of dbt on sleep in different subsets of neurons in which dbt is normally expressed. Reduction of dbt in circadian neurons produced less sleep at night, while lower expression of dbt in noncircadian neurons produced increased sleep during the day. Importantly, independently of the types of neurons where dbt affects sleep, we demonstrate that the PER protein is involved in DBT mediated sleep regulation.     

Effects of daytime food intake on memory consolidation during sleep or sleep deprivation

Sleep enhances memory consolidation. Bearing in mind that food intake produces many metabolic signals that can influence memory processing in humans (e.g., insulin), the present study addressed the question as to whether the enhancing effect of sleep on memory consolidation is affected by the amount of energy consumed during the preceding daytime. Compared to sleep, nocturnal wakefulness has been shown to impair memory consolidation in humans. Thus, a second question was to examine whether the impaired memory consolidation associated with sleep deprivation (SD) could be compensated by increased daytime energy consumption. To these aims, 14 healthy normal-weight men learned a finger tapping sequence (procedural memory) and a list of semantically associated word pairs (declarative memory). After the learning period, standardized meals were administered, equaling either ～50% or ～150% of the estimated daily energy expenditure. In the morning, after sleep or wakefulness, memory consolidation was tested. Plasma glucose was measured both before learning and retrieval. Polysomnographic sleep recordings were performed by electroencephalography (EEG). Independent of energy intake, subjects recalled significantly more word pairs after sleep than they did after SD. When subjects stayed awake and received an energy oversupply, the number of correctly recalled finger sequences was equal to those seen after sleep. Plasma glucose did not differ among conditions, and sleep time in the sleep conditions was not influenced by the energy intake interventions. These data indicate that the daytime energy intake level affects neither sleep's capacity to boost the consolidation of declarative and procedural memories, nor sleep's quality. However, high energy intake was followed by an improved procedural but not declarative memory consolidation under conditions of SD. This suggests that the formation of procedural memory is not only triggered by sleep but is also sensitive to the fluctuations in the energy state of the body.     

Energy conservation characterizes sleep in sharks

Sharks represent the earliest group of jawed vertebrates and as such, they may provide original insight for understanding the evolution of sleep in more derived animals. Unfortunately, beyond a single behavioural investigation, very little is known about sleep in these ancient predators. As such, recordings of physiological indicators of sleep in sharks have never been reported. Reduced energy expenditure arising from sustained restfulness and lowered metabolic rate during sleep have given rise to the hypothesis that sleep plays an important role for energy conservation. To determine whether this idea applies also to sharks, we compared metabolic rates of draughtsboard sharks (Cephaloscyllium isabellum) during periods ostensibly thought to be sleep, along with restful and actively swimming sharks across a 24 h period. We also investigated behaviours that often characterize sleep in other animals, including eye closure and postural recumbency, to establish relationships between physiology and behaviour. Overall, lower metabolic rate and a flat body posture reflect sleep in draughtsboard sharks, whereas eye closure is a poorer indication of sleep. Our results support the idea for the conservation of energy as a function of sleep in these basal vertebrates.     

Wavelength-dependent effects of evening light exposure on sleep architecture and sleep EEG power density in men

Light strongly influences the circadian timing system in humans via non-image-forming photoreceptors in the retinal ganglion cells. Their spectral sensitivity is highest in the short-wavelength range of the visible light spectrum as demonstrated by melatonin suppression, circadian phase shifting, acute physiological responses, and subjective alertness. We tested the impact of short wavelength light (460 nm) on sleep EEG power spectra and sleep architecture. We hypothesized that its acute action on sleep is similar in magnitude to reported effects for polychromatic light at higher intensities and stronger than longer wavelength light (550 nm). The sleep EEGs of eight young men were analyzed after 2-h evening exposure to blue (460 nm) and green (550 nm) light of equal photon densities (2.8 x 10(13) photons x cm(-2) x s(-1)) and to dark (0 lux) under constant posture conditions. The time course of EEG slow-wave activity (SWA; 0.75-4.5 Hz) across sleep cycles after blue light at 460 nm was changed such that SWA was slightly reduced in the first and significantly increased during the third sleep cycle in parietal and occipital brain regions. Moreover, blue light significantly shortened rapid eye movement (REM) sleep duration during these two sleep cycles. Thus the light effects on the dynamics of SWA and REM sleep durations were blue shifted relative to the three-cone visual photopic system probably mediated by the circadian, non-image-forming visual system. Our results can be interpreted in terms of an induction of a circadian phase delay and/or repercussions of a stronger alerting effect after blue light, persisting into the sleep episode.     

Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology

Early attempts to characterize free-running human circadian rhythms generated three notable results: 1) observed circadian periods of 25 hours (considerably longer than the now established 24.1- to 24.2-hour average intrinsic circadian period) with sleep delayed to later circadian phases than during entrainment; 2) spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles--the former with an approximately 24.9-hour period, and the latter with a longer (28-68 hour) or shorter (12-20 hour) period; and 3) bicircadian (48-50 hour) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically based model of hypothalamic and brain stem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with observed sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.     

Altered sleep and behavioral activity phenotypes in PER3-deficient mice

Sleep homeostasis and circadian rhythmicity interact to determine the timing of behavioral activity. Circadian clock genes contribute to circadian rhythmicity centrally and in the periphery, but some also have roles within sleep regulation. The clock gene Period3 (Per3) has a redundant function within the circadian system and is associated with sleep homeostasis in humans. This study investigated the role of PER3 in sleep/wake activity and sleep homeostasis in mice by recording wheel-running activity under baseline conditions in wild-type (WT; n = 54) and in PER3-deficient (Per3(-/-); n = 53) mice, as well as EEG-assessed sleep before and after 6 h of sleep deprivation in WT (n = 7) and Per3(-/-) (n = 8) mice. Whereas total activity and vigilance states did not differ between the genotypes, the temporal distribution of wheel-running activity, vigilance states, and EEG delta activity was affected by genotype. In Per3(-/-) mice, running wheel activity was increased, and REM sleep and NREM sleep were reduced in the middle of the dark phase, and delta activity was enhanced at the end of the dark phase. At the beginning of the baseline light period, there was less wakefulness and more REM and NREM sleep in Per3(-/-) mice. Per3(-/-) mice spent less time in wakefulness and more time in NREM sleep in the light period immediately after sleep deprivation, and REM sleep accumulated more slowly during the recovery dark phase. These data confirm a role for PER3 in sleep-wake timing and sleep homeostasis.     

Ozone-induced paradoxical sleep decrease is related to diminished acetylcholine levels in the medial preoptic area in rats

Ozone (O3) produces significant effects on sleep, characterized specially by a decrease in paradoxical sleep (PS) and increase in slow-wave sleep (SWS), which in turn represent a sleep-wake cycle disruption. On the other hand, neuronal activity recorded in the cholinoceptive hypothalamic medial preoptic area (MPO) has been involved in the regulation of sleep. However, there is no direct evidence on the role that acetylcholine (Ach) release in the MPO plays in the sleep-wake cycle. In order to study this relation, we measured the Ach concentration in dialysates collected from MPO in rats exposed to coal-filtered air (clean air) for 48 h and in rats exposed to clean air for 24 h followed by 24-h of O3 exposure to 0.5 ppm. Polygraphic sleep records were taken simultaneously to neurochemical sampling. O3 was employed to disrupt the sleep-wake cycle and relate these changes with concomitant disruptions in Ach concentration dialyzed from MPO. A clear circadian pattern of Ach concentration was observed in dialysates from MPO and also in PS, SWS and wakefulness of rats exposed to filtered air. However, O3 exposure decreased the PS by 65% (Mann-Whitney's U-test, p相似文献   

Diurnal variation in vascular function: role of sleep

Although vascular function is lower in the morning than afternoon, previous studies have not assessed the influence of prior sleep on this diurnal variation. The authors employed a semiconstant routine protocol to study the contribution of prior nocturnal sleep to the previously observed impairment in vascular function in the morning. Brachial artery vascular function was assessed using the flow-mediated dilation technique (FMD) in 9 healthy, physically active males (mean ± SD: 27 ± 9 yrs of age), at 08:00 and 16:00 h following, respectively, 3.29 ± .37 and 3.24 ± .57 h prior sleep estimated using actimetry. Heart rate and systolic and diastolic blood pressures were also measured. The data of the experimental sleep condition were compared with the data of the "normal" diurnal sleep condition, in which FMD measurements were obtained from 21 healthy individuals who slept only during the night, as usual, before the morning test session. The morning-afternoon difference in FMD was 1 ± 4% in the experimental sleep condition compared with 3 ± 4% in the normal sleep condition (p =?.04). This difference was explained by FMD being 3 ± 3% lower in afternoon following the prior experimental sleep (p =?.01). These data suggest that FMD is more dependent on the influence of supine sleep than the endogenous circadian timekeeper, in agreement with our previous finding that diurnal variation in FMD is influenced by exercise. These findings also raise the possibility of a lower homeostatic "set point" for vascular function following a period of sleep and in the absence of perturbing hemodynamic fluctuation.     

Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans

The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain's master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.