前列腺素D2与睡眠调节

前列腺素D2（PGD2）是目前已知最有潜力的内源性促睡眠物质之一。鼠脑脊液（CSF）中PGD2浓度与睡眠－觉醒周期一致,呈现节律性改变,并且随睡眠剥夺期间嗜睡倾向增加而增加,催化PGH2转变为PGD2的特生酶有两种：Lipocalin型前列腺素D合成酶（L－PGDS）和脾型PGDS。L－PGDS主要在大脑蛛网膜和脉络丛产生,并分泌入CSF。L－PGDS和PGD2在脑室系统、蛛网膜下腔及细胞外间隙中循环,循环中的PGD2可与前脑头端基底腹内侧面的化学感受器中的前列腺素D2受体（DPR）相互作用,通过活化具有腺苷A2a受体的元以产生促进睡眠的信号。PGD2敏感区内DPR的活化可导致腹侧视前区（VLPO）内神经元的活化,其可通过抑制结节乳头核（TMN）而促进睡眠。相反,PGE2在维持大脑清醒状态下起主要作用。PGD2和PGE2的平衡对正常睡眠－觉醒周期的维持十分关键。     

CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness.

To evaluate the function of widely distributed central chemoreceptors during sleep and wakefulness in the rat, we focally stimulate single chemoreceptor sites during naturally occurring sleep-wake cycles by microdialysis of artificial cerebrospinal fluid equilibrated with 25% CO2. In retrotrapezoid nucleus, this increased ventilation (tidal volume) by 24% only in wakefulness (Li A, Randall M, and Nattie E. J Appl Physiol 87: 910-919, 1999). In caudal medullary raphé, it increased ventilation (frequency) by 15-20% only in sleep (Nattie EE and Li A. J Appl Physiol 90: 1247-1257, 2001). Here, in nucleus tractus solitarius (NTS), focal acidification significantly increased ventilation by 11% in sleep and 7% in wakefulness rostrally (n = 5) and by 16% in sleep and 28% in wakefulness caudally (n = 5). The sleep-wake cycle was unaltered. Dialysis with 5% CO2 had no effect. Dialysis with 50% CO2 caudally did not further stimulate ventilation but did disrupt sleep. Central chemoreceptors in the NTS affect breathing in both sleep and wakefulness. The threshold for arousal in caudal NTS is greater than that for the stimulation of breathing.     

Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats

Considerable evidence suggests that receptor-mediated excitation and inhibition of brainstem pedunculopontine tegmental (PPT) neurons are critically involved in the regulation of sleep-wake states. However, the molecular mechanisms operating within the PPT-controlling sleep-wake states remain relatively unknown. This study was designed to examine sleep-wake state-associated extracellular-signal-regulated kinase 1 and 2 (ERK1/2) transduction changes in the PPT of freely moving rats. The results of this study demonstrate that the levels of ERK1/2 expression, phosphorylation, and activity in the PPT increased with increased amount of time spent in sleep. The sleep-associated increases in ERK1/2 expression, phosphorylation, and activity were not observed in the cortex, or in the immediately adjacent medial pontine reticular formation. The results of regression analyses revealed significant positive relationships between the levels of ERK1/2 expression, phosphorylation, and activity in the PPT and amounts of time spent in slow-wave sleep, rapid eye movement sleep, and total sleep. Additionally, these regression analyses revealed significant negative relationships between the levels of ERK1/2 expression, phosphorylation, and activity in the PPT and amounts of time spent in wakefulness. Collectively, these results, for the first time, suggest that the increased ERK1/2 signaling in the PPT is associated with maintenance of sleep via suppression of wakefulness.     

Chloramphenicol decreases brain glucose utilization and modifies the sleep-wake cycle architecture in rats

We studied the effects of chloramphenicol on brain glucose utilization and sleep-wake cycles in rat. After slightly anaesthetized animals were injected with [18F]fluoro-2-deoxy-D-glucose, we acquired time-concentration curves from three radiosensitive beta microprobes inserted into the right and left frontal cortices and the cerebellum, and applied a three-compartment model to calculate the cerebral metabolic rates for glucose. The sleep-wake cycle architecture was analysed in anaesthetic-free rats by recording electroencephalographic and electromyographic signals. Although chloramphenicol is a well-established inhibitor of oxidative phosphorylation, no compensatory increase in glucose utilization was detected in frontal cortex. Instead, chloramphenicol induced a significant 23% decrease in the regional cerebral metabolic rate for glucose. Such a metabolic response indicates a potential mismatch between energy supply and neuronal activity induced by chloramphenicol administration. Regarding sleep-wake states, chloramphenicol treatment was followed by a 64% increase in waking, a 20% decrease in slow-wave sleep, and a marked 59% loss in paradoxical sleep. Spectral analysis of the electroencephalogram indicates that chloramphenicol induces long-lasting modifications of delta-band power during slow-wave sleep.     

Daily rhythms of the sleep-wake cycle

ABSTRACT: The amount and timing of sleep and sleep architecture (sleep stages) are determined by several factors, important among which are the environment, circadian rhythms and time awake. Separating the roles played by these factors requires specific protocols, including the constant routine and altered sleep-wake schedules. Results from such protocols have led to the discovery of the factors that determine the amounts and distribution of slow wave and rapid eye movement sleep as well as to the development of models to determine the amount and timing of sleep. One successful model postulates two processes. The first is process S, which is due to sleep pressure (and increases with time awake) and is attributed to a 'sleep homeostat'. Process S reverses during slow wave sleep (when it is called process S'). The second is process C, which shows a daily rhythm that is parallel to the rhythm of core temperature. Processes S and C combine approximately additively to determine the times of sleep onset and waking. The model has proved useful in describing normal sleep in adults. Current work aims to identify the detailed nature of processes S and C. The model can also be applied to circumstances when the sleep-wake cycle is different from the norm in some way. These circumstances include: those who are poor sleepers or short sleepers; the role an individual's chronotype (a measure of how the timing of the individual's preferred sleep-wake cycle compares with the average for a population); and changes in the sleep-wake cycle with age, particularly in adolescence and aging, since individuals tend to prefer to go to sleep later during adolescence and earlier in old age. In all circumstances, the evidence that sleep times and architecture are altered and the possible causes of these changes (including altered S, S' and C processes) are examined.     

Adjustment of the Sleep-Wake Cycle to Small (1-2h) Changes in Schedule

Changes of schedules larger than 3 h, such as jet lag and shift work, require an adjustment period of several days to resynchronize the sleep-wake cycle and several weeks to resynchronize other circadian rhythms to the new schedule. Initial studies on adaptation to small changes of schedule (1-2 h) found that the sleep-wake cycle adapts to the new schedule in less than 48 h, and such modifications are generally not studied because they may be confounded by a potential masking effect. This article summarizes the few published studies on Daylight Saving Time (DST) and sleep during weekends, two examples of small changes in schedule. There are individual differences in adaptation to daylight saving time, while some persons adjust immediately; other persons require more than 2 weeks. During weekends, people tend to go to bed and wake up later, and to extend their sleep. Delay and extension of sleep depend on factors such as shift of work during weekdays and chronotype (morningness-eveningness). Both DST and sleep during weekends offer the opportunity to study adaptation of the sleep-wake cycle in recurrent, social conditions. Studying these phenomena is also relevant to some socioeconomic issues, like the reportedincrease of traffic accidents and complaints from the population during daylight saving time; or the possible decrease in productivity and absenteeism during the 'Blue Monday'.     

Human salivary eicosanoids: circadian variation

A circadian rhythm in the concentrations of prostaglandins (PG) E2, PGF2, PGI2 (measured as 6-keto-PGF1 alpha), immunoreactive h hydroxyeicosatetraenoic acids and immunoreactive 6-sulfidopeptide containing leukotrienes in human mixed saliva was observed. The rhythm reflected changes in the absolute amounts of these compounds in saliva. Under usual sleep-wake cycles a single peak occurred during sleep with maximal levels at 5:00 AM; the amplitude of the peak varied for each product. The rhythm was sleep-dependent and a shift occurred when the sleep-wake cycles were displaced. Basal levels of these eicosanoids were maintained even without sleep.     

Effects of sleep-wake state on the genioglossus vs.diaphragm muscle response to CO(2) in rats.

The effects of sleep on the ventilatory responses to hypercapnia have been well described in animals and in humans. In contrast, there is little information for genioglossus (GG) responses to a range of CO(2) stimuli across all sleep-wake states. Given the notion that sleep, especially rapid eye movement (REM) sleep, may cause greater suppression of muscles with both respiratory and nonrespiratory functions, this study tests the hypothesis that GG activity will be differentially affected by sleep-wake states with major suppression in REM sleep despite excitation by CO(2). Seven rats were chronically implanted with electroencephalogram, neck, GG, and diaphragm electrodes, and responses to 0, 1, 3, 5, 7, and 9% CO(2) were recorded. Diaphragm activity and respiratory rate increased with CO(2) (P < 0.001) across sleep-wake states with significant increases at 3-5% CO(2) compared with 0% CO(2) controls (P < 0.05). Phasic GG activity also increased in hypercapnia but required higher CO(2) (7-9%) for significant activation (P < 0.05). Further studies in 15 urethane-anesthetized rats with the vagi intact (n = 6) and cut (n = 9) showed that intact vagi delayed GG recruitment with hypercapnia but did not affect diaphragm responses. In the naturally sleeping rats, we also showed that GG activity was significantly reduced in non-REM and REM sleep (P < 0.04) and was almost abolished in REM even with stimulation by 9% CO(2) (decrease = 80.4% vs. wakefulness). Such major suppression of GG activity in REM, even with significant respiratory stimulation, may explain why obstructive apneas are more common in REM sleep.     

Diversity and noise effects in a model of homeostatic regulation of the sleep-wake cycle

Recent advances in sleep neurobiology have allowed development of physiologically based mathematical models of sleep regulation that account for the neuronal dynamics responsible for the regulation of sleep-wake cycles and allow detailed examination of the underlying mechanisms. Neuronal systems in general, and those involved in sleep regulation in particular, are noisy and heterogeneous by their nature. It has been shown in various systems that certain levels of noise and diversity can significantly improve signal encoding. However, these phenomena, especially the effects of diversity, are rarely considered in the models of sleep regulation. The present paper is focused on a neuron-based physiologically motivated model of sleep-wake cycles that proposes a novel mechanism of the homeostatic regulation of sleep based on the dynamics of a wake-promoting neuropeptide orexin. Here this model is generalized by the introduction of intrinsic diversity and noise in the orexin-producing neurons, in order to study the effect of their presence on the sleep-wake cycle. A simple quantitative measure of the quality of a sleep-wake cycle is introduced and used to systematically study the generalized model for different levels of noise and diversity. The model is shown to exhibit a clear diversity-induced resonance: that is, the best wake-sleep cycle turns out to correspond to an intermediate level of diversity at the synapses of the orexin-producing neurons. On the other hand, only a mild evidence of stochastic resonance is found, when the level of noise is varied. These results show that disorder, especially in the form of quenched diversity, can be a key-element for an efficient or optimal functioning of the homeostatic regulation of the sleep-wake cycle. Furthermore, this study provides an example of a constructive role of diversity in a neuronal system that can be extended beyond the system studied here.     

Validation of the Chinese Version of the Children’s ChronoType Questionnaire (CCTQ) in school-aged children

ABSTRACT

The Children’s ChronoType Questionnaire (CCTQ) is a valid and reliable measure for assessing prepubertal children aged 4–11 years. The CCTQ is a parent-reported, 27-item questionnaire consisting of sleep-wake parameters for scheduled and free days (16 items), a morningness/eveningness scale (M/E, 10 items), and a five-point, single-item, chronotype score. The CCTQ has been translated into different languages, but a Chinese version is not available. In the present study, we aimed to produce a Chinese version of the CCTQ and test its validity and reliability on school-aged children. A total of 555 children aged 7–11 years were recruited from five primary schools. The parents were told to complete the CCTQ and record their child’s sleep pattern in a 7-day sleep diary. Sixty-six children and their parents were invited to participate in determining the test-retest reliability of the CCTQ over a 2-week interval, and their sleep patterns were assessed using a sleep diary. The internal consistency of the Chinese CCTQ M/E score as measured by Cronbach’s alpha was acceptable (0.74). Regarding the test-retest reliability of the instrument, moderate to strong Spearman’s correlation coefficients were found for most of the CCTQ – sleep-wake items (ρ = 0.52–0.86) and for the CCTQ-M/E total score (ρ = 0.78). For the concurrent validity, Spearman’s correlations between the sleep-wake parameters of the CCTQ and the sleep diary were moderate to high on both the scheduled days (ρ = 0.54 to 0.87) and free days (ρ = 0.36 to 0.60). For the correlations measured with actigraphs, significant correlations were found in the CCTQ sleep-wake parameters, including bedtime, get-up time, sleep latency, sleep period, time in bed, and mid-sleep point on both the scheduled (ρ = 0.31 to 0.76) and free days (ρ = 0.27 to 0.52), but not in sleep latency and sleep period on free days. The results of the present study suggest that the Chinese version of the CCTQ is a reliable and valid tool for assessing chronotypes in Chinese school-aged children in Hong Kong.     

Molecular genetic studies on sleep-wake regulation, with special emphasis on the prostaglandin D(2) system.

To elucidate the exact role of the PGD(2) system in sleep-wake regulation in vivo, the sleep behavior of knockout mice, generated in the author's and other laboratories, was examined for lipocalin-type PGD synthase (L-PGDS), PGD receptor, adenosine A(2A) receptor, and histamine H(1) receptor; transgenic mice overexpressing the human L-PGDS gene, generated in the author's laboratory, were also examined. The circadian profiles of sleep patterns of wild-type and the genetically manipulated mice were essentially identical, indicating the possibility that the deficiency of one system may be effectively compensated by some other systems during development. Available evidence indicated that the PGD(2) system is involved in the homeostatic regulation of non-rapid eye movement sleep and that the arousal effect of orexin A is mediated by the histamine H(1) receptor system.     

Effects of dietary resveratrol on the sleep-wake cycle in the non-human primate gray mouse lemur (Microcebus murinus)

Converging evidence shows that the non-human primate gray mouse lemur (Microcebus murinus) is ideal for the study of the aging process and for testing the effects of new therapies and dietary interventions on age-associated pathologies. One such dietary supplement is resveratrol (RSV), a dietary polyphenolic compound with several positive effects on metabolic functions and longevity. However, little is known about the effect of RSV on the lemur sleep-wake cycle, which reflects mammalian brain function and health. In the present study, the authors investigated this effect by comparing sleep-wake cycles in adult lemurs based on electroencephalographic (EEG) rhythms. The effect of short-term RSV supplementation on the sleep-wake cycle of mouse lemurs was evaluated in entrained conditions (long-day photoperiods, light:dark 14:10). After 3 wks of RSV supplementation, the animals exhibited a significantly increased proportion of active-wake time, occurring mainly during the resting phase of the sleep-wake cycle (+163%). The increase in active-wake time with RSV supplementation was accompanied by a significant reduction of both paradoxical sleep (-95%) and slow-wave sleep (-38%). These changes mainly occurred during the resting phase of the sleep-wake cycle (RSV supplementation induced negligible changes in active-wake time during the active phase of the sleep-wake cycle). The present data suggest that RSV may be a potent regulator of sleep-wake rhythms and could be of major interest in the study of sleep perturbations associated with aging and neuropathology.     

Dynamical properties of the two-process model for sleep-wake cycles in infantile autism

The two-process model is a scheme for the timing of sleep that consists of homeostatic (Process S) and circadian (Process C) variables. The two-process model exhibits abnormal sleep patterns such as internal desynchronization or sleep fragmentation. Early infants with autism often experience sleep difficulties. Large day-by-day changes are found in the sleep onset and waking times in autistic children. Frequent night waking is a prominent property of their sleep. Further, the sleep duration of autistic children is often fragmented. These sleep patterns in infants with autism are not fully understood yet. In the present study, the sleep patterns in autistic children were reproduced by a modified two-process model using nonlinear analysis. A nap term was introduced into the original two-process model to reproduce the sleep patterns in early infants. The nap term and the time course of Process S are mentioned in the present study. Those parameters led to bifurcation of the sleep-wake cycle in the modified two-process model. In a certain range of these parameter sets, a small external noise was amplified, and an irregular sleep-wake cycle appeared. The short duration of sleep led to another irregular sleep onset or waking. Consequently, an irregular sleep-wake cycle appeared in early infantile autism.     

Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback

This mini-review article presents the remarkable progress that has been made in the past decade in our understanding of the neural circuitry underlying the regulation of sleep-wake states and circadian control of behaviors. Following a brief introduction to sleep architecture and physiology, the authors describe the neural circuitry and neurotransmitters that regulate sleep and cortical arousal (i.e., wakefulness). They next examine how sleep and wakefulness are regulated by mutual inhibition between sleep-and arousal-promoting circuitry and how this interaction functions analogously to an electronic "flip-flop" switch that ensures behavioral state stability. The authors then discuss the role of circadian and homeostatic processes in the consolidation of sleep, including the physiologic basis of homeostatic sleep drive (i.e., wake-dependent increase in sleep propensity) and the role of the SCN in the circadian regulation of sleep-wake cycles. Finally, they describe the hypothalamic circuitry for the integration of photic and nonphotic environmental time cues and how this integration allows organisms to sculpt patterns of rest-activity and sleep-wake cycles that are optimally adaptive.     

Case study of circadian rhythm sleep disorder following haloperidol treatment: reversal by risperidone and melatonin

A patient with Gilles de la Tourette syndrome treated with haloperidol, ingested once daily after awakening from sleep, exhibited an irregular sleep-wake pattern with a free-running component of approximately 48 h. Transfer to risperidone, ingested once daily after awakening from sleep, was beneficial resulting in a sleep-wake cycle more synchronized at the appropriate phase to the external zeitgebers, and fewer nocturnal disturbances. The circadian sleep-wake schedule was fully synchronized when the patient had been subsequently treated with melatonin at 21:00h, before intended nocturnal sleep, in addition to risperidone in the morning. Restoration of the sleep-wake circadian pattern was accompanied by the patient's subjective report of significant improvement in his quality of life, social interactions, and occupational status. This observation suggests that circadian rhythm sleep disorders can be related to the typical neuroleptic haloperidol and restored by the atypical neuroleptic risperidone. Similar findings reported in patients suffering from other disorders support the hypothesis that the described disruption of the sleep-wake schedule is medication rather than illness-related. Therefore, it is very important to realize that circadian rhythm sleep disorders may be a side effect of neuroleptics.     

Adapting test timing to the sleep-wake schedule: effects on diurnal neurobehavioral performance changes in young evening and older morning chronotypes

The synchrony effect refers to the beneficial impact of temporal matching between the timing of cognitive task administration and preferred time-of-day for diurnal activity. Aging is often associated with an advance in sleep-wake timing and concomitant optimal performance levels in the morning. In contrast, young adults often perform better in the evening hours. So far, the synchrony effect has been tested at fixed clock times, neglecting the individual's sleep-wake schedule and thus introducing confounds, such as differences in accumulated sleep pressure or circadian phase, which may exacerbate synchrony effects. To probe this hypothesis, the authors tested older morning and young evening chronotypes with a psychomotor vigilance and a Stroop paradigm once at fixed morning and evening hours and once adapting testing time to their preferred sleep-wake schedule in a within-subject design. The authors observe a persistence of synchrony effects for overall median reaction times during a psychomotor vigilance task, even when testing time is adapted to the specific individual's sleep-wake schedule. However, data analysis also indicates that time-of-day modulations are weakened under those conditions for incongruent trials on Stroop performance and the slowest reaction times on the psychomotor vigilance task. The latter result suggests that the classically observed synchrony effect may be partially mediated by a series of parameters, such as differences in socio-professional timing constraints, the amount of accumulated sleep need, or circadian phase, all leading to differential arousal levels at testing.     

The Relationships between Sleep-Wake Cycle and Academic Performance in Medical Students

Survey and laboratory studies suggest that several factors, such as social and academic demands, part-time jobs and irregular school schedules, affect the sleep-wake cycle of college students. In this study, we examined the sleep-wake pattern and the role played by academic schedules and individual characteristics on the sleep-wake cycle and academic performance. The subjects were 36 medical students (male = 21 and female = 15), mean age = 20.7 years, SD = 2.2. All students attended the same school schedule, from Monday to Friday. The volunteers answered a morningness-eveningness questionnaire, the Pittsburgh Sleep Quality Index (PSQI) and kept a sleep-wake diary for two weeks. The relationships between sleep-wake cycle, PSQI, chronotypes and academic performance were analyzed by a multiple regression technique. The results showed that 38.9% of the students had a poor sleep quality according to the PSQI. When the medical students were evening type or moderate evening type the PSQI showed a tendency of poor sleep. The multiple regression analysis showed a correlation between sleep onset, sleep irregularity and sleep length with academic performance. These results suggest that chronotypes influence the quality of the sleep-wake cycle and that irregularity of the sleep-wake cycle, as well as sleep deprivation (average length was 6:52), influence the learning of college students.     

The Relationships between Sleep-Wake Cycle and Academic Performance in Medical Students

Survey and laboratory studies suggest that several factors, such as social and academic demands, part-time jobs and irregular school schedules, affect the sleep-wake cycle of college students. In this study, we examined the sleep-wake pattern and the role played by academic schedules and individual characteristics on the sleep-wake cycle and academic performance. The subjects were 36 medical students (male = 21 and female = 15), mean age = 20.7 years, SD = 2.2. All students attended the same school schedule, from Monday to Friday. The volunteers answered a morningness-eveningness questionnaire, the Pittsburgh Sleep Quality Index (PSQI) and kept a sleep-wake diary for two weeks. The relationships between sleep-wake cycle, PSQI, chronotypes and academic performance were analyzed by a multiple regression technique. The results showed that 38.9% of the students had a poor sleep quality according to the PSQI. When the medical students were evening type or moderate evening type the PSQI showed a tendency of poor sleep. The multiple regression analysis showed a correlation between sleep onset, sleep irregularity and sleep length with academic performance. These results suggest that chronotypes influence the quality of the sleep-wake cycle and that irregularity of the sleep-wake cycle, as well as sleep deprivation (average length was 6:52), influence the learning of college students.     

Melatonin in sleep disorders and jet-lag

In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency. This is particularly marked in Alzheimer's disease (AD) patients. Melatonin is effective to reduce significantly benzodiazepine use. In addition, melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag. Urinary levels of 6-sulphatoxymelatonin decrease with age and in chronic diseases like AD or coronary heart disease. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect).