REM Sleep Episodes Research Articles

Clozapine alters sleep-wake behavior in rats.

Clozapine is an atypical antipsychotic agent showing therapeutic efficacy superior to that of classical neuroleptics. Clozapine has strong sedative effects, but detailed studies on the drug influencing sleep in rodents are lacking. We studied the effects of clozapine on sleep and body temperature in rats. Clozapine (0, 2.5, and 7.5 mg/kg) was given i.p. to male Wistar rats at the beginning of the rest period. After administration of 7.5 mg/kg clozapine, animals were significantly more awake during the first 2 h postinjection. In parallel, the slow-wave activity (SWA) was suppressed. In the following 2 h non-REM sleep was markedly increased, whereas the SWA returned to baseline. At both doses clozapine decreased overall wakefulness and increased non-REM sleep on the first treatment day, which was associated with prolonged non-REM sleep episodes. These effects were transiently present even after subchronic treatment (7 days). After acute treatment, 7.5 mg/kg clozapine significantly reduced REM sleep and pre-REM sleep due to an increase in REM sleep latency and a reduction in the number of REM sleep episodes. Furthermore, clozapine produced a transient decrease in brain temperature that was followed by a moderate, but long-lasting elevation. To conclude, clozapine affected sleep-wake behavior in a way comparable to its effects in humans, suggesting that the rat is a suitable model for further studies on the underlying mechanisms.

Seasonal aspects of sleep in the Djungarian hamster

BackgroundChanges in photoperiod and ambient temperature trigger seasonal adaptations in the physiology and behaviour of many species, including the Djungarian hamster. Exposure of the hamsters to a short photoperiod and low ambient temperature leads to a reduction of the polyphasic distribution of sleep and waking over the light and dark period. In contrast, a long photoperiod enhances the daily sleep-wake amplitude leading to a decline of slow-wave activity in NREM sleep within the light period. It is unknown whether these changes can be attributed specifically to photoperiod and/or ambient temperature, or whether endogenous components are contributing factors. The influence of endogenous factors was investigated by recording sleep in Djungarian hamsters invariably maintained at a low ambient temperature and fully adapted to a short photoperiod. The second recording was performed when they had returned to summer physiology, despite the maintenance of the 'winter' conditions.ResultsClear winter-summer differences were seen in sleep distribution, while total sleep time was unchanged. A significantly higher light-dark cycle modulation in NREM sleep, REM sleep and waking was observed in hamsters in the summer physiological state compared to those in the winter state. Moreover, only in summer, REM sleep episodes were longer and waking bouts were shorter during the light period compared to the dark period. EEG power in the slow-wave range (0.75–4.0 Hz) in both NREM sleep and REM sleep was higher in animals in the summer physiological state than in those in the 'winter' state. In winter SWA in NREM sleep was evenly distributed over the 24 h, while in summer it decreased during the light period and increased during the dark period.ConclusionEndogenous changes in the organism underlie the differences in sleep-wake redistribution we have observed previously in hamsters recorded in a short and long photoperiod.

Sleep-wake effects of yohimbine and atropine in rats with a clomipramine-based model of depression.

The present study examined the sleep-wake cycle effects of microinjections of yohimbine, an adrenergic antagonist, and atropine, a cholinergic antagonist, into the cerebral ventricle of clomipramine-induced depressed rats. Yohimbine microinjection caused a significant reduction in the total duration and the number of REM sleep episodes compared to control saline injections. Atropine microinjection caused a significant reduction in the total duration and the number of REM sleep episodes without changing the REM sleep latency compared to control saline microinjection. These results show for the first time that the REM sleep disturbances observed in clomipramine-treatment induced depressed rats can be attenuated by increasing and decreasing the brain noradrenergic and cholinergic activities, respectively.

Effect of Chronic Phenelzine Treatment on REM Sleep: Report of Three Patients

Antidepressants belonging to the class of monoamine oxidase inhibitors (MAOI) such as phenelzine have long been known to drastically suppress REM sleep. Sleep and the electroencephalogram (EEG) in sleep and waking were studied in three depressed patients at regular time intervals before, during and after 6 to 18 months of phenelzine treatment. While REM sleep was initially eliminated in all patients, short REM sleep episodes reappeared after three to six months of medication. Total sleep time and EEG slow-wave activity (SWA, spectral power within 0.75–4.5 Hz) in nonREM sleep (stages 1–4) were not changed. In contrast, EEG theta frequency activity (TFA, power within 4.75–8.0 Hz) during a 5-min wake interval recorded prior to the sleep episodes was initially enhanced, and tended to correlate negatively with the percentage of REM sleep (p = .06). This observation indicates that compensatory REM sleep mechanisms may occur in wakefulness during chronic MAOI treatment.

REM sleep enhancement due to rhythmical auditory stimulation in the rat

From a physiological viewpoint, REM sleep (REMS) is a period during which homeostatic physiological regulations are impaired. In the rat, REMS occurs in two forms respectively characterized by episodes separated by long intervals (single REMS episodes) and by episodes which have short intervals and occur in sequences (REMS clusters). Since the partition of REMS in the form of either single or clustered episodes may reveal how the REMS drive and body homeostatic processes interact in the control of REMS occurrence, we have used this approach to clarify the effects of the rhythmical delivery of an auditory stimulus (1000 Hz, 63 or 88 dB, 50 ms, every 20 s), which has been previously observed by different authors to enhance REMS in the absence of a previous sleep deprivation. Stimuli were delivered to pairs of animals and triggered by the occurrence of REMS in one rat (REMS-selective stimulation), whilst the other animal received the same stimulus irrespectively of the stage of the wake-sleep cycle (REMS-unselective stimulation). The results showed that the REMS-selective stimulation did not change the overall amount of REMS, since an increase in the occurrence of REMS clusters was concomitant with a decrease in the occurrence of single REMS episodes. In contrast, under the REMS-unselective stimulation, the total amount of REMS was increased during the second day of stimulation through an increase in the duration of both types of REMS episodes. Since during the REMS-unselective stimulation 87% of the stimuli fell outside REMS (i.e., during the REMS interval), the results show that the occurrence of REMS is more consistently affected when the stimuli are delivered in a period during which homeostatic physiological regulations are fully operant.

Pattern of REM sleep occurrence in continuous darkness following the exposure to low ambient temperature in the rat

The occurrence of REM sleep episodes, separated by intervals >3 min (single episodes) and ≤3 min (sequential episodes), was determined in the rat during the recovery (ambient temperature (Ta) 23°C, L period of the LD [12 h:12 h]-cycle), which followed the exposure to low Ta (0 and −10°C) during the D period of the previous LD-cycle, either in normal light (DL) or in continuous darkness (DD). Both exposures were characterized by an almost complete disappearance of REM sleep, whilst the recoveries showed an increase in the amount of REM sleep in the form of sequential episodes, which in DD was particularly prominent and concomitant with a decrease in the amount of REM sleep in the form of single episodes. The initial 2 h-rate of REM sleep occurrence was lower following the exposure to Ta −10°C, than to Ta 0°C. In DD, such an effect was due to the large reduction in the occurrence of sequential REM sleep episodes. A functional correlate of this finding is that the accumulation capacity of a second messenger (cAMP) was found to be lower at the end of the exposure to Ta −10°C, with respect to both the control (Ta 23°C) and the end of exposure to Ta 0°C, in the preoptic–anterior hypothalamus, but not in the cerebral cortex.

Control of REM sleep: an aspect of the regulation of physiological homeostasis.

Since REM sleep is characterized by a suspension of the hypothalamic integration of homeostatic regulations, it has been assumed that the duration of both REM sleep episodes and of the time interval between the end of one episode and the beginning of the following episode may be regulated according to sleep related processes and the homeostatic needs of the organism. A series of studies performed on the rat has shown that REM sleep episodes occur as two basic types: single REM sleep episodes, that are separated by intervals > 3 min and sequential episodes, that are separated by intervals < or = 3 min and appear in a cluster. Moreover, it has been observed that, in this species, a change in REM sleep occurrence is caused by a modification in the number of episodes and not in their duration. With respect to this, sleep deprivation and recovery are characterized by a decrease and an increase, respectively, in the number of sequential REM sleep episodes, but the number of single episodes tends to be kept constant. The central aspects of this kind of regulation have been examined biochemically in the preoptic-anterior hypothalamus, an area involved in the control of autonomic and sleep related processes. The results show that the accumulation of adenosine 3':5'-cyclic monophosphate (cAMP) is impaired, in this region, during sleep deprivation and appears to return to the control levels, during the recovery, with a rate inversely related to the degree of the previous deprivation. Moreover, it has been observed that the systemic administration of DL-propranolol and LiCl reduces cAMP accumulation mainly in the preoptic-anterior hypothalamus; this condition is concomitant with a reduction in REM sleep occurrence.

Alpha activity in the human REM sleep EEG: topography and effect of REM sleep deprivation

The topographical distribution of alpha activity (8.125–11.125 Hz) in the REM sleep EEG, its time course within and across REM sleep episodes, and the effects of selective REM sleep deprivation were investigated in 8 young males. Power spectra of bipolar derivations along the antero–posterior axis in the left (F3C3, C3P3, P3O1) and right (F4C4, C4P4, P4O2) hemisphere were calculated. Alpha activity increased along the antero–posterior axis in both hemispheres, and was dominant in the right hemisphere. It decreased within and across REM sleep episodes. Selective REM sleep deprivation resulted in a reduction of alpha activity in the REM sleep EEG. However, the topographical distribution and the time course were not affected. It is suggested that alpha activity in the REM sleep EEG is a marker of REM sleep homeostasis.

Effects of Parlodel on sleep-wake cycles in rats with MPTP-induced depressive syndrome

Chronic treatment with Parlodel normalized the parameters of REM sleep disturbed by multiple systemic administration of the dopaminergic neurotoxin MPTP, which is a novel model of depressive syndrome in rats. When administered prior to MPTP, Parlodel reduced the occurrence of REM sleep episodes, shortened duration of REM sleep, and prolonged REM sleep latency. It also reduced the percentage of REM sleep episodes in the total time of sleep.

Scoring of sleep and wakefulness by behavioral analysis from video recordings in rhesus monkeys: comparison with conventional EEG analysis

Extensive work on sleep-wake cycles in non-human primates has been carried out using conventional EEG scoring. In this study, simultaneous somnopolygrams and video recordings at 1 frame/s were performed on 6 adult rhesus monkeys ( Macaca mulatta) during a 24 h period. Wakefulness, NREM sleep and REM sleep were scored by analysis of animal behavior from video data, using characteristic criteria for each state of vigilance. Results were then compared with those of conventional EEG scoring. Values of the total amount for each state obtained by the two scoring methods during the light and the dark periods were significantly closely related ( P<0.001) with a high correlation coefficient for wakefulness ( r 1 =0.99956), for NREM sleep ( r 1 =0.99641) and for REM sleep ( r 1 =0.98708). Moreover, the epoch by epoch analysis between both methods showed a high concordance with percent agreement values of 95.68% for wakefulness, 93.52% for NREM sleep and 94.02% for REM sleep. The number of REM sleep episodes was similarly defined. The patterns of successive sleep-wake cycles determined from both scorings were superimposable, as were the frequent state changes for the same time segments. The video method's main limitation was that the 4 stages of NREM sleep could not be differentiated. Reliability and advantages of sleep-wake scoring by behavioral analysis are discussed. These results suggest that the video methodology is relevant as a non-invasive technique complementary to conventional EEG analysis for sleep studies in rhesus monkeys.

The influence of a heavy thermal load on REM sleep in the rat

This study was carried out in order to further test the hypothesis that the occurrence of REM sleep in the rat in the form of episodes separated by long intervals ( single REM sleep episodes) and by short intervals ( sequential REM sleep episodes) is differently influenced by changes in both sleep and ambient related processes. Rats were studied during the exposure to Ta −10°C for 24 or 48 h and during a 12 h recovery period at laboratory Ta (23°C) following either the first or the second 24 h of cold exposure. The exposure to such a low Ta induced an almost complete abolition of REM sleep which was followed, during recovery, by a marked REM sleep rebound. However, in spite of the larger REM sleep deprivation, the REM sleep rebound was weaker following the 48 h-exposure than that following the exposure for 24 h. The increase in the amount of REM sleep during the recovery period was due to an increase in the amount of that occurring in the form of sequential episodes, whilst that in the form of single episodes did not change with respect to control levels. However, the occurrence of REM sleep in the form of sequential episodes was partially impaired during the REM sleep rebound observed in the recovery period following the 48 h-exposure. These results would suggest that the homeostatic regulation of physiological variables may conflict with that of REM sleep occurrence and that the degree of such a contrast is indicated, at low Ta, by the amount of REM sleep in the form of single episodes and, during the following recovery, by the amount of REM sleep in the form of sequential episodes.

REM sleep disorders in rats with experimental depressive syndrome caused by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Rats receiving daily injections of the neurotoxin MPTP in a dose of 20 mg/kg for 12 days develop disorders of REM sleep, including increased frequency of REM-sleep episodes, decreased REM latency, and increased REM sleep duration, both absolute and relative. The first two of these REM sleep disorders are characteristic of endogenous depression. The results indicate that systemically administered MPTP causes a state similar to endogenous depression.

Motor disorders in sleep.

Sleep is normally a time of motor quiescence. Motor disorders may, however, arise during the different phases of sleep. Nocturnal myoclonus or periodic leg movements in sleep usually occur during light sleep and may be considered the motor accompaniment of the cyclic fluctuations in excitability typical of such stages. Nocturnal frontal lobe epilepsy also occurs during NREM sleep and may be misdiagnosed as parasomnia. REM behavior disorders are instead dissociated episodes of REM sleep without atonia, often associated with or even heralding Parkinson's disease or multiple system atrophy.

Shortening of the photoperiod affects sleep distribution, EEG and cortical temperature in the Djungarian hamster

To asses the influence of photoperiod on sleep regulation EEG, EMG, and cortical temperature were continuously recorded for two baseline days and after 4 h sleep deprivation in Djungarian hamsters (Phodopus sungorus) adapted to a short photoperiod (light dark 8:16). Comparison to previous data collected in a long photoperiod (light:dark 16:8) showed several major effects of photoperiod: 1. A prominent change in the 24-h distribution, duration and number of vigilance state episodes, whereas the total amount of sleep and waking was unchanged; 2. Cortical temperature was 0.7 degree C lower in the short photoperiod; 3. There was a significant negative correlation between cortical temperature and the frequency of REM sleep episodes; and 4. Absolute EEG power density showed a marked reduction in the short photoperiod. After sleep deprivation EEG slow-wave activity (mean power density 0.75-4.0 Hz) in NREM sleep showed a remarkably similar increase in both photoperiods demonstrating the robustness of the homeostatic regulation of sleep. Cortical temperature remained above baseline values after sleep deprivation in the short photoperiod whereas a negative rebound was present in the long photoperiod. Our results support the hypothesis that cortical temperature has a strong influence on REM sleep propensity and indicate the possibility of an optimum cortical temperature for recovery sleep after sleep deprivation. The lower EEG power density in the short photoperiod may contribute to energy conservation.

Sleep EEG analysis by linear prediction: frequency changes of slow-wave activity within NREM and REM sleep episodes in healthy men.

The linear prediction method was applied to obtain a power spectra estimate of sleep EEG in 10 healthy young men. In order to analyze frequency changes of the slow-wave activity (EEG power in the delta band, 0.05-2.88 Hz), the delta mean frequency was computed for each 20-second sleep epoch. A mean delta mean frequency was calculated for each sleep stage in each individual. Our observations indicate that the delta mean frequency decreases during NREM periods and increases mainly at the onset of the REM episodes. This finding, in parallel with the detailed analysis of slow-wave power variations, leads to an additional description of sleep characteristics during transitions between the NREM-REM sleep episodes.

Characteristic changes in sleep patterns during pregnancy in rats

The purpose of this study was to evaluate changes in sleep patterns during pregnancy. We uninterrupted recorded electroencephalogram (EEG), electromyogram (EMG), and brain temperature (Tbr) throughout pregnancy in rats. The duration of non-rapid eye movement (non-REM) sleep decreased after day 5 of pregnancy associated with an inverse increase in the number of non-REM sleep episodes. Thus, the amount of total non-REM sleep time remained constant throughout pregnancy. The amount of total REM sleep time decreased on day 17 of pregnancy after which the reduced state was sustained. That was mainly due to a decrease in the number of REM sleep episodes. Brain temperature (Tbr) gradually decreased as pregnancy advanced, reaching its lowest value 3 days before delivery. These observations provide a better understanding of the sleep patterns during pregnancy, and useful information for investigation of mechanisms of sleep regulation during pregnancy.

Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep.

Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.

Orienting-like reaction after ibotenic acid injections into the thalamic centre median nucleus in the cat.

The excitotoxin ibotenic acid was injected bilaterally into the intralaminar centre median nucleus of chronically implanted cats in order to study the effects of early excitation of centre median population on electrographic correlates of behavioral states and to compare them to those induced by injection into intralaminar centralis lateralis nucleus, previously shown. Immediately and during the first 24h after injection, highly aroused behavior with electrocortical activation, myoclonic jerks, enhancement of ocular movements and ponto-geniculo-occipital waves were observed. Surprisingly, in contrast to the increase of REM sleep episodes in centralis lateralis cases, REM sleep was obliterated. The injection sites were histologically confirmed. The different connectional properties of the two intralaminar population may explain the differential results. 5. In conclusion, the present behavioral observations and electrographic findings taken together with the known afferent and efferent projections suggest that the caudal group of intralaminar nuclei is involved in orienting-like behavior.

Chronic mild stress-induced anhedonia model of depression

A core symptom of human depressive disorder is anhedonia, the loss of interest or pleasure in daily activities. Anhedonia, measured as subsensitivity to reward, can be induced in rats by a regimen of repeated, mild, unpredictable stressors. Here, the hedonic state of rats was assessed using an intracranial self-stimulation (ICSS) procedure. The ICSS frequency threshold was determined before, during and after a period of exposure to the stress regimens. After 13 days of repeated mild stress, the ICSS threshold was significantly increased, suggesting a gradual decrease of sensitivity to reward. This anhedonic state lasted throughout the stress period. When stressed anhedonic animals were given electroshock treatment, the stress-induced increase in ICSS threshold was rapidly and completely reversed. Moreover, biological markers of human depression such as reduced latency to the first REM sleep episode or increased time spent in REM sleep were also found in electroencephalographic recordings of chronically stressed animals. These sleep abnormalities were observed beginning in the second week of a three-week stress regimen and progressively disappeared after termination of stress. In conclusion, these data provide further evidence supporting stress-induced anhedonia in rats as a unique animal model of human depression combining convergent elements of biological, etiological, symptomatological and therapeutic validity.

Monoaminergic and cholinergic modulation of REM-sleep timing in rats

The effects on sleep structure of systemic administration of benchmark cholinergic, serotonergic, and noradrenergic antagonists (QNB, ritanserin, metergoline, and prazosin) were characterized in rats using a new technique for identifying transitions (NRTs) from non-REM (NREM) sleep to REM sleep. In agreement with previous studies, all agents tested reduced REM-sleep expression (by 36–86%). In addition, the serotonergic and noradrenergic antagonists reduced NRT frequency (by 58–81%). The cholinergic antagonist QNB had no effect on NRT frequency. These findings suggest that blockade of serotonergic or noradrenergic receptors increases the interval between REM-sleep episodes, perhaps reducing the rate of accumulation of REM-sleep propensity. Blockade of cholinergic receptors, by contrast, decreases REM-sleep-expression by interfering with REM-sleep maintenance, not by modulating REM-sleep timing. These conclusions are contrary to the predictions of a number of published models of REM-sleep timing.