Genetics of sleep and sleep disorders

Sleep remains one of the least understood phenomena in biology--even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association studies (GWAS) have uncovered ～14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep.     

Extended nights, sleep loss, and recovery sleep in adolescents

In summary, this study of sleep in adolescents on an atypical schedule of 18-hour nights showed marked but not unanticipated differences in sleep as function of prior sleep deprivation. Unanticipated was the evidence of "recovery" sleep in adolescents who not only were not sleep deprived, but who had been on a sleep "optimizing" schedule and had been awake for only 10 hours. Extended sleep beginning about 4 hours in advance of entrained sleep onset phase was not associated with a return of SWS, a finding coinciding with predictions from studies in adults. Finally, this study provides an indication that the homeostatic sleep/wake process becomes less robust or sleep responsive during adolescent development, a phenomenon that may influence the delay of sleep common in adolescents.     

Overview of sleep and sleep medicine in Asian countries

While there are a number of sleep medicine and sleep research publications in Asia, and their quality is increasing each year, the actual situation of sleep disorders in the general population still remains an issue of major concern. Scientists and medical doctors believe that, for the first time in history, the general lack of sleep could lead to a diminution of life expectancy. It is also known that, as people are working more and more and are more tired, they are more likely to become victims of accidents. Most of the time these incidents have little gravity, but sometimes they can cost thousands of innocent lives or contribute to disasters such as the Chernobyl nuclear plant explosion or the Bhopal gas tragedy. Based on the Asian Sleep Research Society Summit and Symposium Round Table held during the fall of 2009 on Okinawa, this review aims to give an accurate view of the actual situation of sleep research and medicine in Asia. The particular example of the obstructive sleep apnea syndrome will illustrate the importance of sleep medicine in this part of the world. Finally, the actual situation will be discussed to elaborate some possible strategies to improve the sleep situation for Asian populations.

     

Effect of cold stimulation during slow-wave sleep on sleep cycle

To clarify the effect of cold stimulation during slow-wave sleep (SWS) on the sleep cycle, we conducted a sleep experiment. Five healthy males slept on a bedding system we developed to make the inside of bedding cooler. When the subject was sleeping deeply in the second and fourth SWS, the system cooled their bedding. When the subject's sleep condition shifted toward arousal, the cold air was stopped. As a result, all subjects’ sleep stage shifted to light sleep and reached arousal. After stopping stimulation, they immediately returned to the SWS at the first stimulation. But at the second stimulation, the sleep state did not return to the SWS.     

Effect of sleep and circadian cycle on sleep period energy expenditure

Energy expenditure is lower during sleep than relaxed wakefulness. However, there is disagreement as to the particular metabolic changes that produce the difference. The present study assessed the contribution of sleep, circadian cycle, and the specific dynamic action effect of the evening meal to the sleep period fall in metabolic rate. Five subjects were tested for a total of nine nights under three conditions in a repeated-measures design. Subjects were confined to bed throughout their usual sleep period but were instructed to go to sleep 0, 3, or 6 h after their usual time for lights out. O2 consumption was measured in all conditions for the 0.5 h before and after each of the times for lights out and then throughout the sleep period after lights out. The results demonstrated that changes in energy expenditure during the sleep period are a function of both sleep and circadian cycle. In this study, the contribution of the two components was approximately equal. However, the effect of sleep was rapid asymptoting within 15 min of sleep onset, whereas that of circadian cycle was constant over the assessment period.     

Circadian gene variants influence sleep and the sleep electroencephalogram in humans

The sleep electroencephalogram (EEG) is highly heritable in humans and yet little is known about the genetic basis of inter-individual differences in sleep architecture. The aim of this study was to identify associations between candidate circadian gene variants and the polysomnogram, recorded under highly controlled laboratory conditions during a baseline, overnight, 8 h sleep opportunity. A candidate gene approach was employed to analyze single-nucleotide polymorphisms from five circadian-related genes in a two-phase analysis of 84 healthy young adults (28 F; 23.21 ± 2.97 years) of European ancestry. A common variant in Period2 (PER2) was associated with 20 min less slow-wave sleep (SWS) in carriers of the minor allele than in noncarriers, representing a 22% reduction in SWS duration. Moreover, spectral analysis in a subset of participants (n = 37) showed the same PER2 polymorphism was associated with reduced EEG power density in the low delta range (0.25–1.0 Hz) during non-REM sleep and lower slow-wave activity (0.75–4.5 Hz) in the early part of the sleep episode. These results indicate the involvement of PER2 in the homeostatic process of sleep. Additionally, a rare variant in Melatonin Receptor 1B was associated with longer REM sleep latency, with minor allele carriers exhibiting an average of 65 min (87%) longer latency from sleep onset to REM sleep, compared to noncarriers. These findings suggest that circadian-related genes can modulate sleep architecture and the sleep EEG, including specific parameters previously implicated in the homeostatic regulation of sleep.     

Masseter EMG activity during sleep and sleep bruxism

The masseter muscle is involved in the complex and coordinated oromotor behaviors such as mastication during wakefulness. The masseter electromyographic (EMG) activity decreases but does not disappear completely during sleep: the EMG activity is generally of low level and inhomogeneous for the duration, amplitude and intervals. The decreased excitability of the masseter motoneurons can be determined by neural substrates for NREM and REM sleep. The masseter EMG activity is increased in association with the level of arousal fluctuations within either sleep state. In addition, there are some motor events such as REM twitches, swallowing and rhythmic masticatory muscle activity (RMMA), whose generation might involve the additional activation of specific neural circuits. Sleep bruxism (SB) is characterized by exaggerated occurrence of RMMA. In SB, the rhythmic activation of the masseter muscle can reflect the rhythmic motor inputs to motoneurons through, at least in part, common neural circuits for generating masticatory rhythm under the facilitatory influences of transient arousals. However, it remains elusive as to which neural circuits determine the genesis of sleep bruxism. Based on the available knowledge on the masseter EMG activity during sleep, this review presents that the variety of the masseter EMG phenotypes during sleep can result from the combinations of the quantitative, spatial and temporal neural factors eventually sending net facilitatory inputs to trigeminal motoneurons under sleep regulatory systems.     

Effect of sleep and sleep deprivation on ventilatory response to bronchoconstriction

To characterize ventilatory responses to bronchoconstriction during sleep and to assess the effect of prior sleep deprivation on ventilatory and arousal responses to bronchoconstriction, bronchoconstriction was induced in eight asthmatic subjects while they were awake, during normal sleep, and during sleep after a 36-h period of sleep deprivation. Each subject was bronchoconstricted with increasing concentrations of aerosolized methacholine while ventilatory patterns and lower airway resistance (Rla) were continually monitored. The asthmatic patients maintained their minute ventilation as Rla increased under all conditions, demonstrating a stable tidal volume with a mild increase in respiratory frequency. Inspiratory drive, as measured by occlusion pressure (P0.1), increased progressively and significantly as Rla increased under all conditions (slopes of P0.1 vs. Rla = 0.249, 0.112, and 0.154 for awake, normal sleep, and sleep after sleep deprivation, respectively, P less than 0.0006). Chemostimuli did not appear to contribute significantly to the observed increases in P0.1. Prior sleep deprivation had no effect on ventilatory and P0.1 responses to bronchoconstriction but did significantly raise the arousal threshold to induced bronchoconstriction. We conclude that ventilatory responses to bronchoconstriction, unlike extrinsic loading, are not imparied by the presence of sleep, nor are they chemically mediated. However, prior sleep deprivation does increase the subsequent arousal threshold.     

An attempt to influence by drugs recovery sleep after sleep deprivation.

Rats were deprived of sleep by placing them for 36 hours in a slowly moving drum. After this procedure, during recovery sleep, the latency of onset of the first rhombencephalic - paradoxical sleep period decreased and the proportion of telencephalic/rhombencephalic - slow wave sleep reversed (during the first hour of recovery sleep). Repeated administration during the deprivation period of physostigmine (0,5 mg/kg i. p. in 30 min intervals 20-30 times) inducing in waking animals in EEG pattern close to that of rhombencephalic sleep, or atropine (1 mg/kg i. p. in 60 min intervals 10-15 times) evoking an activity resembling telencephalic sleep, did not change the above measures of recovery sleep. Pharmacologically induced sleep-like patterns did not substitute for the sleep the rats were deprived off.     

Heat production during sleep

Heat production during sleep was studied by continuous indirect calorimetry with simultaneous electroencephalographic monitoring. Controlling for gross influences on heat production, comparisons of heat production during different sleep stages showed heat production in stage 4 sleep to be significantly lower than in other sleep stages. There appeared to be a gradation in heat production in non-rapid-eye-movement stages of sleep with stage 2 higher and stage 4 lower than stage 3. Heat production in stage 4 was less variable than in any other sleep stage. Both the level and variability of heat production was similar in stage 2 and rapid-eye-movement sleep. Heat production during the night was 9% lower than during resting wakefulness. The average heat production in stage 4 sleep was 14.4% lower than resting wakeful values.     

Segmental organization of sleep

Segmental organization of sleep was studied in healthy subjects and insomniac patients. Theoretical and practical aspects of sleep organization are discussed. The disintegration syndrome (decreased stability of development of sleep stage segments and change in sleep stage sequence characteristic of normal sleep) is an inherent feature of sleep disorders and a fine index of adaptive possibilities of sleep systems. It is suggested that each segment of any sleep stage has its specific functional role different from the functional significance of the stage as a whole. Depending on the time of appearance of any specific segment, it can be an important preliminary of transition to another functional state and be involved in preparation for triggering corresponding sleep-organizing systems. At the same time, it can be a reflection of the process of estimation of the achieved result. The dynamic change in sleep stages is determined by subsequent activation of different brain structures and also suggests a possibility of a change in the functional role of a certain stage depending on the initial functional state of sleep systems.     

Antioxidant defense responses to sleep loss and sleep recovery

Sleep deprivation in humans is widely believed to impair health, and sleep is thought to have powerful restorative properties. The specific physical and biochemical factors and processes mediating these outcomes, however, are poorly elucidated. Sleep deprivation in the animal model produces a condition that eventually becomes highly lethal, lacks specific localization, and is reversible with sleep, implying mediation by a biochemical abnormality. Metabolic and immunological consequences of sleep deprivation point to a high potential for antioxidant imbalance. The objective, therefore, was to study glutathione content in the liver, heart, and lung, because glutathione is considered a major free radical scavenger that reflects the degree to which a tissue has been oxidatively challenged. We also investigated major enzymatic antioxidants, including catalase and glutathione peroxidase, as well as indexes of glutathione recycling. Catalase activity and glutathione content, which normally are tightly regulated, were both decreased in liver by 23-36% by 5 and 10 days of sleep deprivation. Such levels are associated with impaired health in other animal models of oxidative stress-associated disease. The decreases were accompanied by markers of generalized cell injury and absence of responses by the other enzymatic antioxidants under study. Enzymatic activities in the heart indicated an increased rate of oxidative pentose phosphate pathway activity during sleep deprivation. Recovery sleep normalized antioxidant content in liver and enhanced enzymatic antioxidant activities in both the liver and the heart. The present results link uncompensated oxidative stress to health effects induced by sleep deprivation and provide evidence that restoration of antioxidant balance is a property of recovery sleep.     

Effects of restricted sleep with different exercise loads upon subsequent sleep

Seven male cats were adapted to different schedules of restricted sleep. The cat was permitted to go to sleep either 2, 4 or 8 hours per day with the balance to 24-h periode spent in wakefulness enforced by means of a treadmill. Two experiments were run and the same cats served in both runs. The experiments and schedules were separated by at least two weeks during which time cats were maintained under ordinary laboratory conditions. Our experiment used treadmill speed of 2.6 m/min which was easily tolerated and effective in eliminating sleep. Another experiment used treadmill speed of 4.6 m/min which produced more physical exercise. As available sleep time become progressively shorter, REM sleep increased while SWS decreased. If restriction in sleep time was associated with more physical exercise then the composition of the subsequent sleep was different : SWS increased while REM sleep decreased. The functional significance of these opposite effects are presumably different. The immediate SWS response to the prior muscular exercise is suggestive of its recovery function.     

Age-related changes in the association of sleep satisfaction with sleep quality and sleep–wake pattern

Sleep and Biological Rhythms - Age-specific relationship of sleep–wake pattern with night sleep satisfaction was examined to address a question of why sleep satisfaction does not accurately...     

A comparison of sleep patterns in natural and mandrax- and tuinal-induced sleep

A within-subject comparison of the effects on the overnight sleep EEG of 1 tablet of Mandrax (containing methaqualone base 250 mg. and diphenhydramine hydrochloride 25 mg.) and 200 mg. Tuinal (equal parts of quinalbarbitone sodium and amylobarbitone sodium) in 14 normal subjects is reported.Mandrax-induced sleep was not significantly different from natural sleep in the duration of light, moderate, deep and REM phases. Tuinal produced a significant reduction in REM sleep (P < 0.01) compared with natural sleep and with Mandrax-induced sleep.     

Selective REM sleep deprivation during daytime. II. Muscle atonia in non-REM sleep

One of the hallmarks of rapid eye movement (REM) sleep is muscle atonia. Here we report extended epochs of muscle atonia in non-REM sleep (MAN). Their extent and time course was studied in a protocol that included a baseline night, a daytime sleep episode with or without selective REM sleep deprivation, and a recovery night. The distribution of the latency to the first occurrence of MAN was bimodal with a first mode shortly after sleep onset and a second mode 40 min later. Within a non-REM sleep episode, MAN showed a U-shaped distribution with the highest values before and after REM sleep. Whereas MAN was at a constant level over consecutive 2-h intervals of nighttime sleep, MAN showed high initial values when sleep began in the morning. Selective daytime REM sleep deprivation caused an initial enhancement of MAN during recovery sleep. It is concluded that episodes of MAN may represent an REM sleep equivalent and that it may be a marker of homeostatic and circadian REM sleep regulating processes. MAN episodes may contribute to the compensation of an REM sleep deficit.     

Gender and sleep in nightworkers: a quantitative analysis of sleep in days off

Differences in sleep patterns between workdays and days off contribute to shiftwork effects on workers' health and well-being. But regardless of shift schedules, female workers face more difficulties in fulfilling their sleep need because of housework. This study analyzes gender differences concerning sleep in days off by comparing sleep patterns in male and female nightworkers, analyzing sleep as related to the presence of children and testing the association of sleep features between workdays and days off. Male (n = 16) and female (n = 30) workers at a plastic plant, working from 10 p.m. to 6 a.m., on weekdays, filled sleep logs for seven consecutive weeks. Male and female samples did not differ in length of night sleep or in total length of sleep. For both samples, sleep length/day in days off increased, but the difference was lager among females. Also important were the relations between sleep in workdays and days off, specially among women. Among female workers, the results indicated that workers with children tended to sleep less in Saturday mornings, suggesting a negative effect of motherhood on sleep not restricted to workdays. The general results indicate that sleep need on the one hand, and social factors on the other determine the actual amount of sleep.     

Genetics of sleep

Main achievements in general and molecular genetics of sleep, especially NREM sleep, are regarded. Among them, discovery of such heredity disorders, as FFI, FASPS and DSPS, the finding of genetic hallmarks of sleep EEG, etc.     

Isoprene and sleep

Isoprene is one of the main constituents of endogenous origin in exhaled human breath. The concentration of isoprene seems to vary with states of sleep and wakefulness, increasing during sleep and decreasing sharply just after awakening. Thus, isoprene may be involved in in sleep upholding.