Non-REM sleep as a source of learning deficits induced by REM sleep deprivation.

Procedures that deprive animal subjects of rapid eye movement sleep have often been associated with learning impairments. Previously, the conclusion has been drawn that these learning impairments are due to the absence of some positive function of rapid eye movement sleep. The present research indicates more precisely that typical impairments associated with the deprivation procedures may be due to isolated periods of non-REM sleep, rather than due to the simple absence of rapid eye movement sleep. Mice were tested for acquistion of a complex maze task, and subjected to post-trial rapid eye movement sleep deprivation by the pedestal method. Only animals demonstrating (non-REM) sleep behaviors during deprivation gave evidence of learning deficits.     

Different types of avoidance behavior in rats produce dissociable post-training changes in sleep

Avoidance learning affects post-training sleep, and post-training sleep deprivation impairs performance. However, not all rats learn to make avoidance responses, and some rats fail to escape; a definitive behavior of learned helplessness, a model of depression. This study investigated the changes in sleep associated with different behaviors adopted following avoidance training. Rats (n = 53) were trained for 100 trials over 2 days (50 trials/day), followed by 23-24 h of post-training polysomnography, then re-tested (25 trials). At re-test, rats were categorized into: 1) Active Avoiders (AA; n = 22), 2), Non-learning (NL; n = 21), or 3) Escape Failures (EF; n = 10). AA rats increased avoidances over days, whereas the NL and EF groups did not. EF rats increased escape failures over days, whereas the NL and AA rats did not. EF rats had increased rapid eye movement (REM) sleep in the first 4 h on training day 1. They also had increased non-REM sleep in the first 4 h and last 4 h on both training days. AA rats had increased REM sleep 13-20 h post-training. The type of behavioral strategy adopted throughout training is associated with a unique pattern of changes in post-training sleep. Training-dependent changes in post-acquisition sleep may reflect distinct processes involved in the consolidation of these different memory traces.     

Cold exposure and sleep in the rat: REM sleep homeostasis and body size

STUDY OBJECTIVES: Exposure to low ambient temperature (Ta) depresses REM sleep (REMS) occurrence. In this study, both short and long-term homeostatic aspects of REMS regulation were analyzed during cold exposure and during subsequent recovery at Ta 24 degrees C. DESIGN: EEG activity, hypothalamic temperature, and motor activity were studied during a 24-h exposure to Tas ranging from 10 degrees C to -10 degrees C and for 4 days during recovery. SETTING: Laboratory of Physiological Regulation during the Wake-Sleep Cycle, Department of Human and General Physiology, Alma Mater Studiorum-University of Bologna. SUBJECTS: 24 male albino rats. INTERVENTIONS: Animals were implanted with electrodes for EEG recording and a thermistor to measure hypothalamic temperature. MEASUREMENTS AND RESULTS: REMS occurrence decreased proportionally with cold exposure, but a fast compensatory REMS rebound occurred during the first day of recovery when the previous loss went beyond a "fast rebound" threshold corresponding to 22% of the daily REMS need. A slow REMS rebound apparently allowed the animals to fully restore the previous REMS loss during the following 3 days of recovery. CONCLUSION: Comparing the present data on rats with data from earlier studies on cats and humans, it appears that small mammals have less tolerance for REMS loss than large ones. In small mammals, this low tolerance may be responsible on a short-term basis for the shorter wake-sleep cycle, and on long-term basis, for the higher percentage of REMS that is quickly recovered following REMS deprivation.     

Sleep-wake stages during the subjective night of the squirrel monkey

The study of the circadian sleep-wake cycle is beset by unique technical challenges. Continuous polygraphic recordings are necessary to characterize circadian phenomena; however, the traditional method of recording sleep at high (15 mm/sec) chart speed is impractical for continuous animal studies that may last several weeks at a stretch. A system to determine four sleep-wake stages (awake, transitional, non-REM, REM) from low chart speed (1.5 mm/sec) recordings was developed and validated by direct behavioral observation using four adult male squirrel monkeys prepared for chronic recording of EEG, EOG and EMG. The polygraphic stages "transitional," non-REM and REM were highly correlated with behavioral observations of sleep, although individual sleep stages could not be resolved by behavioral parameters alone.     

Cold exposure impairs dark-pulse capacity to induce REM sleep in the albino rat

In the albino rat, a REM sleep (REMS) onset can be induced with a high probability and a short latency when the light is suddenly turned off (dark pulse, DP) during non-REM sleep (NREMS). The aim of this study was to investigate to what extent DP delivery could overcome the integrative thermoregulatory mechanisms that depress REMS occurrence during exposure to low ambient temperature (Ta). To this aim, the efficiency of a non-rhythmical repetitive DP (3 min each) delivery during the first 6-h light period of a 12 h:12 h light-dark cycle in inducing REMS was studied in the rat, through the analysis of electroencephalogram, electrocardiogram, hypothalamic temperature and motor activity at different Tas. The results showed that DP delivery triggers a transition from NREMS to REMS comparable to that which occurs spontaneously. However, the efficiency of DP delivery in inducing REMS was reduced during cold exposure to an extent comparable with that observed in spontaneous REMS occurrence. Such impairment was associated with low Delta activity and high sympathetic tone when DPs were delivered. Repetitive DP administration increased REMS amount during the delivery period and a subsequent negative REMS rebound was observed. In conclusion, DP delivery did not overcome the integrative thermoregulatory mechanisms that depress REMS in the cold. These results underline the crucial physiological meaning of the mutual exclusion of thermoregulatory activation and REMS occurrence, and support the hypothesis that the suspension of the central control of body temperature is a prerequisite for REMS occurrence.     

Sleep deprivation suppresses the increase of rapid eye movement density across sleep cycles

We investigated the association between rapid eye movement (REM) density (REMd) and electroencephalogram (EEG) activity during non‐rapid eye movement (NREM) and REM sleep, within the re‐assessment, in a large sample of normal subjects, of the reduction of oculomotor activity in REM sleep after total sleep deprivation (SD). Coherently with the hypothesis of a role of homeostatic sleep pressure in influencing REMd, a negative correlation between changes in REMd and slow‐wave activity (SWA) was expected. A further aim of the study was to evaluate if the decreased REMd after SD affects ultradian changes across sleep periods. Fifty normal subjects (29 male and 21 female; mean age = 24.3 ± 2.2 years) were studied for four consecutive days and nights. Sleep recordings were scheduled in the first (adaptation), second (baseline) and fourth night (recovery). After awakening from baseline sleep, a protocol of 40 h SD started at 10:00 hours. Polysomnographic measures, REMd and quantitative EEG activity during NREM and REM sleep of baseline and recovery nights were compared. We found a clear reduction of REMd in the recovery after SD, due to the lack of REMd changes across cycles. Oculomotor changes positively correlated with a decreased power in a specific range of fast sigma activity (14.75–15.25 Hz) in NREM, but not with SWA. REMd changes were also related to EEG power in the 12.75–13.00 Hz range in REM sleep. The present results confirm the oculomotor depression after SD, clarifying that it is explained by the lack of changes in REMd across sleep cycles. The depression of REMd can not simply be related to homeostatic mechanisms, as REMd changes were associated with EEG power changes in a specific range of spindle frequency activity, but not with SWA.     

Quantification of electromyographic activity during REM sleep in multiple muscles in REM sleep behavior disorder

STUDY OBJECTIVES: The aim of our study was to determine which muscle or combination of muscles (either axial or limb muscles, lower or upper limb muscles, or proximal or distal limb muscles) provides the highest rates of rapid eye movement (REM) sleep phasic electromyographic (EMG) activity seen in patients with REM sleep behavior disorder (RBD). SETTING: Two university hospital sleep disorders centers. PARTICIPANTS: Seventeen patients with idiopathic RBD (n = 8) and RBD secondary to Parkinson disease (n = 9). INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Patients underwent polysomnography, including EMG recording of 13 different muscles. Phasic EMG activity in REM sleep was quantified for each muscle separately. A mean of 1459.6 +/- 613.8 three-second REM sleep mini-epochs were scored per patient. Mean percentages of phasic EMG activity were mentalis (42 +/- 19), flexor digitorum superficialis (29 +/- 13), extensor digitorum brevis (23 +/- 12), abductor pollicis brevis (22 +/- 11), sternocleidomastoid (22 +/- 12), deltoid (19 +/- 11), biceps brachii (19 +/- 11), gastrocnemius (18 +/- 9), tibialis anterior (right, 17 +/- 12; left, 16 +/- 10), rectus femoris (left, 11 +/- 6; right, 9 +/- 6), and thoraco-lumbar paraspinal muscles (6 +/- 5). The mentalis muscle provided significantly higher rates of excessive phasic EMG activity than all other muscles but only detected 55% of all the mini-epochs with phasic EMG activity. Simultaneous recording of the mentalis, flexor digitorum superficialis, and extensor digitorum brevis muscles detected 82% of all mini-epochs containing phasic EMG activity. This combination provided higher rates of EMG activity than any other 3-muscle combination. Excessive phasic EMG activity was more frequent in distal than in proximal muscles, both in upper and lower limbs. CONCLUSION: Simultaneous recording of the mentalis, flexor digitorum superficialis, and extensor digitorum brevis muscles provided the highest rates of REM sleep phasic EMG activity in subjects with RBD.     

Short-term homeostasis of REM sleep assessed in an intermittent REM sleep deprivation protocol in the rat

An intermittent rapid eye movement (REM) sleep deprivation protocol was applied to determine whether an increase in REM sleep propensity occurs throughout an interval without REM sleep comparable with the spontaneous sleep cycle of the rat. Seven chronically implanted rats under a 12 : 12 light-dark schedule were subjected to an intermittent REM sleep deprivation protocol that started at hour 6 after lights-on and lasted for 3 h. It consisted of six instances of a 10-min REM sleep permission window alternating with a 20-min REM sleep deprivation window. REM sleep increased throughout the protocol, so that total REM sleep in the two REM sleep permission windows of the third hour became comparable with that expected in the corresponding baseline hour. Attempted REM sleep transitions were already increased in the second deprivation window. Attempted transitions to REM sleep were more frequent in the second than in the first half of any 20-min deprivation window. From one deprivation window to the next, transitions to REM sleep changed in correspondence to the amount of REM sleep in the permission window in-between. Our results suggest that: (i) REM sleep pressure increases throughout a time segment similar in duration to a spontaneous interval without REM sleep; (ii) it diminishes during REM sleep occurrence; and (iii) that drop is proportional to the intervening amount of REM sleep. These results are consistent with a homeostatic REM sleep regulatory mechanism that operates in the time scale of spontaneous sleep cycle.     

Intrahippocampal administration of anandamide increases REM sleep

A nascent literature has postulated endocannabinoids (eCBs) as strong sleep-inducing lipids, particularly rapid-eye-movement sleep (REMs), nevertheless the exact mechanisms behind this effect remain to be determined. Anandamide and 2-arachidonyl glycerol, two of the most important eCBS, are synthesized in the hippocampus. This structure also expresses a high concentration of cannabinoid receptor 1 (CB1). Recent extensive literature supports eCBs as important regulators of hippocampal activity. It has also been shown that these molecules vary their expression on the hippocampus depending on the light–dark cycle. In this context we decided to analyze the effect of intrahippocampal administration of the eCB anandamide (ANA) on the sleep–waking cycle at two points of the light–dark cycle. Our data indicate that the administration of ANA directly into the hippocampus increases REMs in a dose dependent manner during the dark but not during the light phase of the cycle. The increase of REMs was blocked by the CB1 antagonist AM251. This effect was specific for the hippocampus since ANA administrations in the surrounding cortex did not elicit any change in REMs. These results support the idea of a direct relationship between hippocampal activity and sleep mechanisms by means of eCBs. The data presented here show, for the first time that eCBs administered into the hippocampus trigger REMs and support previous studies where chemical stimulation of limbic areas triggered sleep.     

Selective increase in brain dopamine metabolism during REM sleep rebound in the rat

Rats implanted with electrodes for EEG and EMG recording were placed on small or large platforms for either 24 or 96 hr and the effects on the subsequent REM sleep rebound were observed. Only the 96 hr protocol produced a selective REM sleep rebound in rats placed on small platforms. Brain MOPEG-SO₄, a final metabolite of norepinephrine, was determined fluorometrically and dopamine metabolites HVA and DOPAC, as well as the serotonin metabolite 5-HIAA, were measured by using an HPLC method with electrochemical detection. The results show that selective increases in brain HVA and DOPAC were obtained only during the REM sleep rebound in rats from small platforms. Non-specific increases were observed in MOPEG-SO₄ and 5-HIAA during the recovery period in rats from both small and large platforms which could be related to the effects of immobilization stress.     

The duration of REM sleep epic, odes in normal sleep

SUMMARY  The distributions of the durations of the first 3 REM sleep episodes have been analysed using a total of 134 overnight sleep recordings from 10 subjects. From investigation of the length of uninterrupted episodes of stage REM, it is shown that arousals to stage 0/1 could play an important part in the process of REM exit, and that by the middle of the sleep period, these arousals probably occur according to a Poisson process. During the first and second REM episodes a more complex process appears to be at work, which could reflect increased pressure for slow wave sleep. These findings suggest that the duration of a REM episode is determined by a process that has a large stochastic element, which is not necessarily tied to REM entry.     

Brief skin temperature changes towards thermoneutrality trigger REM sleep in rats

When rats were in slow-wave sleep (SWS) at an environmental temperature (23°C) below their thermoneutral zone (27–31°C), brief skin warming by either radiant heating, or forced air convection resulted in REM sleep on 79–80% of the trials. During control nonwarmed SWS bouts, the animals went into REM sleep on only 22–24% of the trials. When the environmental temperature was above thermoneutrality, 34°C, lowering skin temperature by convective cooling resulted in REM sleep entry 68% of the time, compared to 21% for noncooled, control trials. Skin warming and cooling at 29°C decreased the percent occurrence of REM sleep to 22% and 9% respectively, for at this thermoneutral temperature 46% of the control SWS bouts ended in REM sleep. Thus, peripheral temperature changes towards thermoneutrality trigger REM sleep in mildly thermally stressed rats.     

A selective serotonin reuptake inhibitor reduces REM sleep in the homing pigeon

Avian and mammalian 'rapid eye movement' sleep (REM sleep) resemble each other in several aspects. However, the question of whether REM sleep has a shared evolutionary ancestry in birds and mammals has yet to be thoroughly explored. The brain regions and neurotransmitter systems involved in the generation of mammalian REM sleep are phylogenetically ancient, and are also found in extant birds and reptiles. Several pharmacological experiments in birds indicate that similar neural substrates are involved in the regulation of avian and mammalian sleep. However, because the drugs used in these studies generally resulted in non-specific sleep loss, the neurochemical regulation of avian REM sleep in particular remains uncertain. The selective serotonin reuptake inhibitor (SSRI) zimelidine is known to reduce REM sleep in mammals. If avian REM sleep is similarly regulated by serotonin, it would be expected that an acute dose of a SSRI should also reduce avian REM sleep. To investigate a putative role of serotonin in the regulation of avian REM sleep, changes in sleep electroencephalogram (EEG) and behavior were recorded in five pigeons (Columba livia) after the administration of an acute dose of zimelidine. Our results demonstrate that the effects of zimelidine on avian REM sleep are comparable to those observed in mammals, indicating that serotonin may serve a similar function in the control of avian and mammalian REM sleep.     

The effect of the timing, quality and quantity of sleep upon the depression (masking) of body temperature on an irregular sleep/wake schedule

SUMMARY  Eight subjects were studied on an irregular sleep/wake schedule which was designed so that prior wake time and the time of day when 4-h sleep periods were taken were both balanced. Rectal temperature and the sleep EEG were measured throughout the 8-d protocol. A purification method was used to estimate the depression of rectal temperature (masking) caused by the first and second halves of each 4-h sleep period. On average this was 0.187 ± 0.015°C during the first 2h and 0.262 ± 0.017°C during the second 2h. Masking increases beyond the first 2 h of sleep, but any effects due to the phase of the rectal temperature when sleep is taken are very weak. However, masking did increase (that is, the temperature was depressed more) when the amount of prior wake time was greater than 4 h. When the effects of sleep content variables were considered also, masking was still greater in the second half of sleep and tended to increase with the amount of slow-wave sleep, but it decreased with increasing amounts of time awake during a sleep period (sleep latency or sleep discontinuity). Some implications of these results for the mechanism of sleep-induced masking are considered.     

Symposium: Normal and abnormal REM sleep regulation: The importance of REM sleep for brain maturation

A number of studies, some done by us, are reviewed concerning the function of foetal/neonatal REM sleep. The hypothesis is put forward that REM sleep in early life serves as an indicator for: (1) the degree of brain maturation, and (2) the promotion of further brain development. This hypothesis, although not exclusive, differs from: the original theory of Roffwarg et al. (1966) that REM sleep serves as "wakefulness" during the period in which wakefulness is limited; and also from the theory of Crick and Mitchson (1983-the "unlearning" hypothesis of REM sleep). As the functions of sleep in general, and REM sleep in particular, are still unclear, we hope this review will suggest new possibilities for future research.     

Platelet activating factor and its metabolite promote sleep in rabbits

Platelet activating factor (PAF) is a key inflammatory mediator. PAF and its receptor are found in brain and PAF affects or is affected by the production of sleep promoting cytokines such as interleukin-1. PAF also interacts with several other sleep-regulatory substances such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, nitric oxide, prostaglandins, and prolactin. We thus hypothesized that PAF would increase sleep. In these experiments, each rabbit received an injection of 25 microl of 2% DMSO to obtain control values, and on a separate day received PAF or lyso-PAF, a metabolite of PAF. Ten, 100 and 500 nmol for each substance was injected intracerebroventricularly. Both PAF and lyso-PAF enhanced non-rapid eye movement (NREM) sleep but not REM sleep. Lyso-PAF, but not PAF, induced hyperthermia. Results are consistent with the hypothesis that the brain cytokine network is involved in physiological sleep regulation.     

Effect of rapid eye movement sleep deprivation on rat brain Na-K ATPase activity

Since rapid eye movement (REM) sleep deprivation has been reported to affect the neuronal excitability in the brain, it was hypothesized that a change in the neuronal membrane-bound Na-K ATPase activity might be at least one of the factors inducing such a change. Therefore, in this study rats were deprived of REM sleep by using the platform technique and enzyme activity was estimated in the whole brain, in different regions of the brain and in microsomal preparations. Deprivation was carried out for varying periods and suitable control experiments were conducted to rule out the possibility of nonspecific effects. The observation supported our hypothesis and showed primarily that the deprivation increased the enzyme activity in the rat brain. It showed also that the pons and the medulla were the first sites to be affected by deprivation. The probable mechanism producing such a change is discussed.     

A 20-h recovery sleep after prolonged sleep restriction: some effects of competing in a world record-setting cinemarathon

SUMMARY  The recovery sleep of a 21-year-old normal woman was assessed after she had endured 11 1/2 days of sleep restriction in a world record-setting film-viewing marathon. An exceptional sleep debt was observed as indicated by an instanteous sleep onset, a high sleep efficiency, and a total sleep duration of over 20 hours. Other striking features of this recovery sleep were very short latencies to stages 3 and 4 sleep, return of Stage 4 sleep after 14.5 h, REM and SWS sleep rebound, and a linear increase in REM sleep efficiency across 14 consecutive REM-NREM episodes. Seven of nine home dreams reported after this recording contained competition themes, but none relating to the marathon films. Comparisons of the present results with those from subjects in previous record-setting events suggest possible explanations for the extremely long recovery sleep. Results also suggest that analyses of multiple consecutive sleep cycles may provide novel ways of assessing hypotheses about regulation of the REM-NREM cycle.     

头帕肿瘤综合征蛋白与肿瘤坏死因子受体介导的坏死样凋亡

头帕肿瘤综合征蛋白(cylindromatosis,CYLD)是一种去泛素化酶,其C-末端USP结构域具有催化功能,可移除受体相互作用蛋白激酶1(receptor interacting protein kinase 1,RIPK1)的K63连接泛素链,调节RIPK1的泛素化水平,从而参与调节肿瘤坏死因子受体1(tumor necrosis factor receptor 1, TNFR1)介导的RIPK依赖的细胞坏死样凋亡等病理生理过程。阐明CYLD对RIPK1去泛素化调节的详细机制,寻找针对CYLD的特异性抑制剂,可为与坏死样凋亡相关的损伤与疾病提供治疗的新策略。     

The estimation of sleep quality in different stages and cycles of sleep

Dream content in NREM and REM sleep correlates with the subjective experience of having slept immediately before awakening. The estimation of depth of sleep depends on the quality of the NREM sleep stages. The presence of dreaming in a given sleep stage is more important for the subjective experience of having slept than the duration of the sleep episode before the awakening. Neurotic insomniac patients more often deny mental activity when awoken from NREM and REM sleep, than do healthy subjects. These data suggest that spontaneous awakenings in different sleep stages, especially in the first sleep cycle, correlate with the insomniac's tendency to underestimate sleep duration and quality.