Increase In Rapid Eye Movement Sleep Research Articles

The Relationship Between REM Sleep and Memory Consolidation in Old Age and Effects of Cholinergic Medication

Recent findings in young adults suggest that rapid eye movement (REM) sleep plays a role in procedural memory consolidation. The significance of REM sleep for memory consolidation in old age has not yet been investigated. Effects of REM sleep manipulation on declarative and procedural memory consolidation were investigated in 107 healthy older adults, ages 60-82 years. Rapid eye movement sleep deprivation was achieved by REM sleep awakenings and compared with non-REM sleep awakenings. Rapid eye movement sleep augmentation was realized physiologically by REM sleep rebound and pharmacologically by administering an acetylcholinesterase inhibitor in a double-blind, placebo-controlled design. Memory performance was tested by a paired associate list and a mirror tracing task at 9:30 pm and 7:30 am with sleep intervening between 11:00 pm and 7:00 am. Although REM sleep deprivation led to a significant reduction in total and phasic REM sleep, memory consolidation remained unaffected. Both REM sleep augmentation groups showed a significant increase in phasic REM sleep, whereas only pharmacological cholinergic REM sleep manipulation exerted a significant positive effect on procedural memory consolidation. Because only after cholinergic stimulation of phasic REM sleep procedural memory consolidation is improved, cholinergic activation seems to be a crucial component of REM sleep-related memory consolidation in old age.

Ketogenic Diet Improves Sleep Quality in Children with Therapy‐resistant Epilepsy

The study purpose was to evaluate sleep structure during ketogenic diet (KD) treatment in children with therapy-resistant epilepsy and to correlate possible alterations with changes in clinical effects on seizure reduction, seizure severity, quality of life (QOL), and behavior. Eighteen children were examined with ambulatory polysomnographic recordings initially and after 3 months of KD treatment. Eleven children continued with the KD and were also evaluated after 12 months. Sleep parameters were estimated. Seizure frequency was recorded in a diary and seizure severity in the National Health Seizure Severity Scale (NHS3). QOL was assessed with a visual analogue scale. Child behavior checklist and Ponsford and Kinsella's rating scale of attentional behavior were used. KD induced a significant decrease in total sleep (p = 0.05) and total night sleep (p = 0.006). Slow wave sleep was preserved, rapid eye movement (REM) sleep increased (p = 0.01), sleep stage 2 decreased (p = 0.004), and sleep stage 1 was unchanged. Eleven children continued with the KD and were also evaluated after 12 months. They showed a significant decrease in daytime sleep (p = 0.01) and a further increase in REM sleep (p = 0.06). Seizure frequency (p = 0.001, p = 0.003), seizure severity (p < 0.001, p = 0.005) and QOL (p < 0.001, p = 0.005) were significantly improved at 3 and 12 months. Attentional behavior was also improved, significantly so at 3 months (p = 0.003). There was a significant correlation between increased REM sleep and improvement in QOL (Spearman r = 0.6, p = 0.01) at 3 months. KD decreases sleep and improves sleep quality in children with therapy-resistant epilepsy. The improvement in sleep quality, with increased REM sleep, seems to contribute to the improvement in QOL.

Mirtazapine-Induced Nightmares

Sir: Mirtazapine is classed as a noradrenergic and specific serotonergic antidepressant (NaSSA). It acts by blocking α2 receptors on noradrenergic neurons and enhancing norepinephrine release.1 Increased levels of norepinephrine act on α1-adrenoceptors on serotonergic cell bodies, increasing serotonergic firing.1 Nightmares occur only in rapid eye movement (REM) sleep. Most antidepressants suppress REM sleep; hence, nightmares are not a commonly reported side effect of therapy with antidepressants. We report the first ever case, to our knowledge, of a patient who developed severe nightmares on initiation of therapy with mirtazapine, which necessitated stopping the drug. Case report. Mr. A, a 52-year-old white man, presented in 2006 with depressive symptoms including low mood, poor sleep and appetite, loss of weight, hopelessness, and fatigue. Because of his symptom profile, he was started on mirtazapine, 15 mg at night. One day later, he reported vivid nightmares of being murdered and his body being cut up. These nightmares woke him from sleep and left him feeling very scared and upset. He recalled that he had been treated with mirtazapine 2 years ago and it had to be discontinued because of similar distressing nightmares. After 4 days of therapy and experiencing nightmares every night, he requested that the medication be stopped. The nightmares disappeared 1 day after cessation of mirtazapine. He denied ever experiencing such distressing nightmares in the past, except when he was taking mirtazapine. His only other concurrent medication was hydroxymorphone. The temporal relationship between the initiation of treatment with mirtazapine and onset of nightmares and their disappearance with discontinuation of the drug, and also their occurrence during a previous episode of mirtazapine treatment, suggest a causal etiology. Most antidepressants suppress REM sleep.2 Mirtazapine has been shown to increase REM sleep even with acute administration, i.e., at 2 days.3 It has also been shown to increase total sleep time, sleep efficiency, and stage 2 and slow wave sleep. These effects persisted after 5 weeks of treatment.3 Vivid dreams and nightmares have been reported with other antidepressants that increase REM sleep, such as bupropion.4 It is possible that mirtazapine increased REM sleep in this patient, which may have induced nightmares. Clinicians should be aware of this side effect, as it can potentially affect treatment adherence.

REM sleep changes in rats induced by siRNA‐mediated orexin knockdown

Short interfering RNAs (siRNA) targeting prepro-orexin mRNA were microinjected into the rat perifornical hypothalamus. Prepro-orexin siRNA-treated rats had a significant (59%) reduction in prepro-orexin mRNA compared to scrambled siRNA-treated rats 2 days postinjection, whereas prodynorphin mRNA was unaffected. The number of orexin-A-positive neurons on the siRNA-treated side decreased significantly (23%) as compared to the contralateral control (scrambled siRNA-treated) side. Neither the colocalized dynorphin nor the neighbouring melanin-concentrating hormone neurons were affected. The number of orexin-A-positive neurons on the siRNA-treated side did not differ from the number on the control side 4 or 6 days postinjection. Behaviourally, there was a persistent (approximately 60%) increase in the amount of time spent in rapid eye movement (REM) sleep during the dark (active) period for 4 nights postinjection, in rats treated with prepro-orexin siRNA bilaterally. This increase occurred mainly because of an increased number of REM episodes and decrease in REM-to-REM interval. Cataplexy-like episodes were also observed in some of these animals. Wakefulness and NREM sleep were unaffected. The siRNA-induced increase in REM sleep during the dark cycle reverted to control values on the 5th day postinjection. In contrast, the scrambled siRNA-treated animals only had a transient increase in REM sleep for the first postinjection night. Our results indicate that siRNA can be usefully employed in behavioural studies to complement other loss-of-function approaches. Moreover, these data suggest that the orexin system plays a role in the diurnal gating of REM sleep.

Disruptions in Sleep Time and Sleep Architecture in a Mouse Model of Repeated Ethanol Withdrawal

Insomnia and other sleep difficulties are perhaps the most common and enduring symptoms reported by alcoholics undergoing detoxification, especially those alcoholics with a history of multiple detoxifications. While some studies have reported sleep disruptions in animal models after chronic ethanol exposure, the reports are inconsistent and few address sleep architecture across repeated ethanol exposures and withdrawals. The present study evaluated sleep time and architecture in a well-characterized mouse model of repeated chronic ethanol exposure and withdrawal. C57BL6/J mice were fitted with electrodes in frontal cortex, hippocampus, and nuchal muscle for collection of continuous electroencephalogram (EEG)/electromyogram (EMG) data. Baseline data were collected, after which mice received 4 cycles of 16-hour exposure to alcohol (ethanol: EtOH) vapor separated by 8-hour periods of withdrawal or similar handling in the absence of EtOH vapor. Ethanol-exposed mice attained a blood ethanol concentration of 165 mg%. Upon completion of vapor exposure, EEG/EMG data were again collected across 4 days of acute withdrawal. Data were subjected to automated analyses classifying 10-second epochs into wake, non-rapid eye movement (REM) sleep, or REM sleep states. Mice in withdrawal after chronic EtOH exposure showed profound disruptions in the total time asleep, across the acute withdrawal period. Sleep architecture, the composition of sleep, was also disrupted with a reduction in non-REM sleep concomitant with a profound increase in REM sleep. While altered sleep time and non-REM sleep loss resolved by the fourth day of withdrawal, the increase in REM sleep ("REM rebound") persisted. These results mirror those reported for the human alcoholic and demonstrate that EtOH withdrawal-induced sleep disruptions are evident in this mouse model of alcohol withdrawal-induced sensitization. This mouse model may provide mechanisms to investigate fully the high correlation between unremitting sleep problems and increased risk of relapse documented clinically.

Urotensin II Modulates Rapid Eye Movement Sleep through Activation of Brainstem Cholinergic Neurons

Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast synaptic transmission because it persisted in the presence of TTX and antagonists of ionotropic glutamate, GABA, and glycine receptors. Collectively, these results suggest that UII plays a role in the regulation of REM sleep independently of its cerebrovascular actions by directly activating cholinergic brainstem neurons.

Sleep disturbance at simulated altitude indicated by stratified respiratory disturbance index but not hypoxic ventilatory response

At high altitudes, the clinically defined respiratory disturbance index (RDI) and high hypoxic ventilatory response (HVR) have been associated with diminished sleep quality. Increased RDI has also been observed in some athletes sleeping at simulated moderate altitude. In this study, we investigated relationships between the HVR of 14 trained male endurance cyclists with variable RDI and sleep quality responses to simulated moderate altitude. Blood oxygen saturation (SpO2%), heart rate, RDI, arousal rate, awakenings, sleep efficiency, rapid eye movement (REM) sleep, non-REM sleep stages 1, 2 and slow wave sleep as percentages of total sleep time (%TST) were measured for two nights at normoxia of 600 m and one night at a simulated altitude of 2,650 m. HVR and RDI were not significantly correlated with sleep stage, arousal rate or awakening response to nocturnal simulated altitude. SpO2 was inversely correlated with total RDI (r = -0.69, P = 0.004) at simulated altitude and with the change in arousal rate from normoxia (r = -0.65, P = 0.02). REM sleep response to simulated altitude correlated with the change, relative to normoxia, in arousal (r = -0.63, P = 0.04) and heart rate (r = -0.61, P = 0.04). When stratified, those athletes at altitude with RDI >20 h(-1) (n = 4) and those with <10 h(-1) (n = 10) exhibited no difference in HVR but the former had larger falls in SpO2 (P = 0.05) and more arousals (P = 0.03). Neither RDI (without stratification) nor HVR were sufficiently sensitive to explain any deterioration in REM sleep or arousal increase. However, the stratified RDI provides a basis for determining potential sleep disturbance in athletes at simulated moderate altitude.

Pontine‐wave generator activation‐dependent memory processing of avoidance learning involves the dorsal hippocampus in the rat

The aim of this study was to test the hypothesis that the dorsal hippocampus plays a critical role in pontine-wave (P-wave) generator activation-dependent memory processing of two-way active avoidance (TWAA) learning. To achieve this objective, rats were given small bilateral lesions in the CA1, dentate gyrus (DG), or CA3 region of the dorsal hippocampus by microinjecting ibotenic acid. After recovery, lesioned and sham-lesioned rats were trained on a TWAA learning paradigm, allowed a 6-hr period of undisturbed sleep, and then were tested on the same TWAA paradigm. It was found that lesions in the CA3 region impaired retention of avoidance learning. Conversely, lesions in the CA1 and DG regions had no effect on TWAA learning retention. None of the groups showed any changes in the baseline sleep-wake cycle or in the acquisition of TWAA learning. All rats showed increased rapid eye movement (REM) sleep and increased REM sleep P-wave density during the subsequent 6-hr recording period. Impaired retention in the CA3 group occurred despite an increase in REM sleep and P-wave density, suggesting that during REM sleep, the P-wave generator interacts with the CA3 region of the dorsal hippocampus to aid in consolidation of TWAA learning. The results of the present study thus demonstrate that P-wave generator activation-dependent consolidation of memory requires an intact CA3 subfield of the dorsal hippocampus. The results also provide evidence that under mnemonic pressure, the dorsal hippocampus may not be involved directly in regulating the sleep-wake cycle.

Effects of donepezil on Alzheimer's disease: The relationship between cognitive function and rapid eye movement sleep

The aim of this study was to observe the effects of donepezil on both the cognitive function and sleep patterns in patients of Alzheimer's Type Dementia (ATD), especially to determine the relationship between the improvement of cognitive function and the amount of rapid eye movement (REM) sleep. A total of 12 patients (7 females, 5 males; age, 73.0 +/- 6.8) meeting the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) criteria of probable AD were studied. These patients presented with mild to moderate dementia, which was confirmed by a Clinical Dementia Rating score of 1 or 2. Following baseline examinations consisting of the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and polysomnography (PSG), 5 mg of donepezil was administered to the patients at breakfast every day. All patients were reassessed 6 weeks later using the same examinations. With sleep patterns, the percentage of REM sleep to total sleep time increased after the administration of donepezil. In addition, it was also found that sleep efficiency was increased and sleep latency was shortened by this administration. Although the ADAS-Jcog score did not decrease significantly, there was significant positive correlation between the decrease of the ADAS-Jcog score and the increase in the percentage of REM sleep. These results indicate the increase action of REM sleep due to activate central cholinergic systems and the possibility to improve sleep conditions due to one-time administration after breakfast of donepezil in mild to moderate ATD. It is concluded that the increase in REM sleep may reflect the improvement of cognitive function in ATD patients.

Developmental decrease in REM sleep: the shift to kainate receptor regulation

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl-D-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc.

Developmental decrease in REM sleep: the shift to kainate receptor regulation

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl- d-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc.

Sleep disorders in Alzheimer's disease and other dementias

Patients with dementias, such as Alzheimer's disease (AD), often have nocturnally disrupted sleep. Clinically, this may present as agitation during the nighttime hours, which may affect as many as a quarter of AD patients during some stage of their illness. Sleep disturbance in AD may be multifactorial and involve sleep-disordered breathing and disrupted chronobiology, both often characterized by excessive daytime napping. Polysomnographically, AD patients show decreased rapid eye movement (REM) sleep in proportion to the extent of their dementia; some evidence suggests that cholinesterase inhibitors, commonly used pharmacologic agents for cognitive loss in AD, may increase REM sleep measures. Unfortunately, such agents may also induce insomnia and vivid dreams. There have been no randomized clinical trials of sedative-hypnotic medications specifically targeted at AD patients with sleep problems. Evidence suggests that sedative-hypnotics, such as benzodiazepine site-specific agonists, may have a role in some cases, whereas atypical antipsychotics may be necessary in other cases. There are also reports of successful interventions with nonpharmacologic options (eg, exercise, illumination). The utility of melatonin as a hypnotic in this population appears equivocal.

Development of REM sleep drive and clinical implications.

Rapid eye movement (REM) sleep in the human declines from approximately 50% of total sleep time ( approximately 8 h) in the newborn to approximately 15% of total sleep time (approximately 1 h) in the adult, and this decrease takes place mainly between birth and the end of puberty. We hypothesize that without this developmental decrease in REM sleep drive, lifelong increases in REM sleep drive may ensue. In the rat, the developmental decrease in REM sleep occurs 10-30 days after birth, declining from >70% of total sleep time in the newborn to the adult level of approximately 15% of sleep time during this period. Rats at 12-21 days of age were anesthetized with ketamine and decapitated, and brain stem slices were cut for intracellular recordings. We found that excitatory responses of pedunculopontine nucleus (PPN) neurons to N-methyl-D-aspartic acid decrease, while responses to kainic acid increase, over this critical period. During this developmental period, inhibitory responses to serotonergic type 1 agonists increase but responses to serotonergic type 2 agonists do not change. The results suggest that as PPN neurons develop, they are increasingly activated by kainic acid and increasingly inhibited by serotonergic type 1 receptors. These processes may be related to the developmental decrease in REM sleep. Developmental disturbances in each of these systems could induce differential increases in REM sleep drive, accounting for the postpubertal onset of a number of different disorders manifesting increases in REM sleep drive. Examination of modulation by PPN projections to ascending and descending targets revealed the presence of common signals modulating ascending arousal-related functions and descending postural/locomotor-related functions.

Chronic mild stress affects sucrose intake and sleep in rats

Depression in humans is associated with sleep abnormalities of three types: altered rapid eye movement (REM) sleep, fragmented sleep, and reduced delta sleep. In an animal model of depression, chronic exposure to mild stressors (CMS, e.g. periods of soiled cage, reversed light/dark cycle, grouped housing, food and/or water deprivation) causes behavioral and hormonal changes which, in humans, often are associated with depression. In the CMS model, a reduced sucrose intake has been defined as one of the core symptoms of depression, anhedonia, although this finding is not consistent among various laboratories. In the present study, we investigated if the CMS procedure, in our laboratory, would cause decreased sucrose intake and, also, give sleep changes similar to what is found in depressed patients. Exposure to CMS decreased sucrose intake in our rats. The largest effect was obtained after 2 weeks of the stress protocol. CMS rats spent more time in REM sleep and showed more fragmented sleep compared to their baseline recording, while there were no changes in the control rats. Increased sleep fragmentation in CMS rats was particularly evident by increased number of arousals, and increased REM sleep and slow-wave-sleep-1 (SWS-1) episodes. The duration of sleep stage episodes was decreased. The amount of slow-wave-sleep-2 (SWS-2) was not decreased, however SWS-2 in percent of total SWS was reduced. Correlation analysis showed that animals that had less consumption of sucrose spent more time in REM sleep and had increased number of REM sleep episodes. In this study, CMS appears to be a model of depression.

A sedentary day: effects on subsequent sleep and body temperatures in trained athletes

Exercise effects on sleep in fit healthy people have been difficult to determine because their sleep is close to optimal, leaving little room for improvement. Another method for assessing exercise effects on sleep is to significantly reduce the degree of activity in highly active people. Fifteen trained athletes who exercised daily at a moderate to high intensity were employed. By requesting that subjects remain sedentary in the laboratory for an entire day, the effect of reduced exercise on subsequent sleep parameters was assessed. Sleep and temperature were recorded after a sedentary day and after a normal day of moderate to high activity (control condition) in a counterbalanced design. In the sedentary condition, slow-wave sleep (SWS) decreased by a mean of 15.5±7.0 min and slow-wave activity (SWA) differed significantly ( P<.05) between conditions in the first hour of sleep only. Rapid eye movement (REM) sleep increased by a mean of 17.9±5.7 min in the sedentary condition, while sleep onset latency (SOL) to Stages 1 and 2 increased by 10.2 and 10.7 min, respectively, and REM sleep latency decreased by 24.0±6.8 min (all P<.05). Between conditions, there was no overall effect on total sleep time (TST), sleep efficiency, wake after sleep onset or core or foot temperatures ( P>.05). With reduced exercise load, SWS pressure may have been reduced, resulting in lower levels of SWS and increased REM sleep. Thus, the data indicate that reducing exercise has significant effects on sleep that may have implications for athletes tapering for competition.

Microinjection of neostigmine into the pontine reticular formation of C57BL/6J mouse enhances rapid eye movement sleep and depresses breathing.

The cholinergic model of rapid eye movement (REM) sleep has contributed significantly to understanding sleep neurobiology and sleep-dependent respiratory depression. The model has been used extensively in cat and rat, but no previous studies have demonstrated cholinergic REM sleep enhancement in mouse. The present study used microinjection of neostigmine into pontine reticular formation of mouse to test the hypothesis that enhancing pontine cholinergic neurotransmission would cause increased REM sleep and sleep disordered breathing. Mice (n=8) were anesthetized and implanted with electrodes for measuring cortical electroencephalogram (EEG). Stainless steel cannulae were stereotaxically implanted to permit subsequent microinjections of 50 nl neostigmine (0.133 microg; 8.8 mM) or saline into the pontine reticular formation. Following recovery, an intensive within-subjects design was used to obtain measures of sleep/wake states, breathing, and locomotor activity. Inferential statistics were provided by t-tests. A probability value of < 0.05 indicated statistical significance. NA. NA. NA. Behavioral observations and manual scoring of polygraphic recordings showed that neostigmine produced a REM sleep-like state. EEG power analysis using Fast Fourier Transformation confirmed that pontine neostigmine caused EEG activation. Plethysmography demonstrated significantly disordered breathing. Compared to waking, pontine microinjection of neostigmine decreased respiratory rate (-64%) and minute ventilation (-75%). Pontine neostigmine significantly increased duration of inspiration (138%) and expiration (140%) above waking levels and decreased inspiratory flow (-69%). Additional studies showed that pontine neostigmine significantly depressed locomotor activity. This study is the first to demonstrate cholinergic REM sleep enhancement in unanesthetized, intact mouse. The results encourage future studies to characterize similarities and differences in cholinergic REM sleep enhancement in additional inbred strains and in transgenic mice. Such comparisons will help characterize sleep and breathing as intermediate phenotypes that are determined, in part, by the lower level phenotype of pontine cholinergic neurotransmission.

Developmental changes in the effects of serotonin on neurons in the region of the pedunculopontine nucleus

The percent of rapid eye movement (REM) sleep decreases dramatically between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus (PPN) is known to modulate waking and REM sleep. We recorded intracellularly from 127 neurons in the PPN in 12–21-day rat brainstem slices maintained in warmed, oxygenated artificial cerebrospinal fluid. We identified three types of PPN neurons based on intrinsic membrane properties, type I (LTS), type II (A) and type III (A+LTS), as previously described. The percent of type I neurons increased from 6% at 12 days to 17% by 21 days, while the percent of type III neurons decreased from 21% at 12–17 days, to 4% after 17 days. Thus, PPN neurons may differentiate into type I bursting neurons and type II slow-firing neurons across this critical stage in development. The 5-HT1 receptor agonist 5-carboxyamido-tryptamine (5-CT) was found to hyperpolarize 58% of 12–16-day PPN neurons, did not affect 25% and depolarized 17%. However, a higher percentage of 17–21-day PPN neurons were hyperpolarized (85%), and a lower percentage unaffected (10%) or depolarized (5%), suggesting that serotonergic responses switched from both excitatory and inhibitory before, to almost purely inhibitory after, 17 days. These findings indicate a reorganization of PPN intrinsic membrane properties and serotonergic responses occur across this stage, in keeping with the proposed presence of a REM sleep inhibitory process during development. We suggest that disturbances in this developmental process may lead to disorders marked by increased REM sleep drive.

Seizure susceptibility decreases with enhancement of rapid eye movement sleep

The study examined the effect of enhanced rapid eye movement (REM) sleep duration on the seizure threshold determined by electrical stimulation of the amygdala in rats. The duration of REM sleep was specifically increased by the microinjection of a cholinergic agonist, carbachol, into the pontine reticular formation. This was accompanied by a significant increase in the threshold current required to elicit an afterdischarge in the amygdala. The results suggest that an increase in REM sleep decreases the likelihood of cortical seizure activity, an effect that is manifest even in other stages of the sleep–wakefulness cycle and not only in the REM state, per se.

Restraint increases prolactin and REM sleep in C57BL/6J mice but not in BALB/cJ mice.

Sleep is generally considered to be a recovery from prior wakefulness. The architecture of sleep not only depends on the duration of wakefulness but also on its quality in terms of specific experiences. In the present experiment, we studied the effects of restraint stress on sleep architecture and sleep electroencephalography (EEG) in different strains of mice (C57BL/6J and BALB/cJ). One objective was to determine if the rapid eye movement (REM) sleep-promoting effects of restraint stress previously reported for rats would also occur in mice. In addition, we examined whether the effects of restraint stress on sleep are different from effects of social defeat stress, which was found to have a non-REM (NREM) sleep-promoting effect. We further measured corticosterone and prolactin levels as possible mediators of restraint stress-induced changes in sleep. Adult male C57BL/6J and BALB/cJ mice were subjected to 1 h of restraint stress in the middle of the light phase. To control for possible effects of sleep loss per se, the animals were also kept awake for 1 h by gentle handling. Restraint stress resulted in a mild increase in NREM sleep compared with baseline, but, overall, this effect was not significantly different from sleep deprivation by gentle handling. In contrast, restraint stress caused a significant increase in REM sleep compared with handling in the C57BL/6J mice but not in BALB/cJ mice. Corticosterone levels were significantly and similarly elevated after restraint in both strains, but prolactin was increased only in the C57BL/6J mice. In conclusion, this study shows that the restraint stress-induced increase in REM sleep in mice is strongly strain dependent. The concomitant increases in prolactin and REM sleep in the C57BL/6J mice, but not in BALB/cJ mice, suggest prolactin may be involved in the mechanism underlying restraint stress-induced REM sleep. Furthermore, this study confirms that different stressors differentially affect NREM and REM sleep. Whereas restraint stress promotes REM sleep in C57BL/6J mice, we previously found that in the same strain, social defeat stress promotes NREM sleep. As such, studying the consequences of specific stressful stimuli may be an important tool to unravel both the mechanism and function of different sleep stages.

Selected Contribution: Regulation of sleep-wake states in response to intermittent hypoxic stimuli applied only in sleep.

Recurrent sleep-related hypoxia occurs in common disorders such as obstructive sleep apnea (OSA). The marked changes in sleep after treatment suggest that stimuli associated with OSA (e.g., intermittent hypoxia) may significantly modulate sleep regulation. However, no studies have investigated the independent effects of intermittent sleep-related hypoxia on sleep regulation and recovery sleep after removal of intermittent hypoxia. Ten rats were implanted with telemetry units to record the electroencephalogram (EEG), neck electromyogram, and body temperature. After >7 days recovery, a computer algorithm detected sleep-wake states and triggered hypoxic stimuli (10% O2) or room air stimuli only during sleep for a 3-h period. Sleep-wake states were also recorded for a 3-h recovery period after the stimuli. Each rat received an average of 69.0 +/- 6.9 hypoxic stimuli during sleep. The non-rapid eye movement (non-REM) and rapid-eye-movement (REM) sleep episodes averaged 50.1 +/- 3.2 and 58.9 +/- 6.6 s, respectively, with the hypoxic stimuli, with 32.3 +/- 3.2 and 58.6 +/- 4.8 s of these periods being spent in hypoxia. Compared with results for room air controls, hypoxic stimuli led to increased wakefulness (P < 0.005), nonsignificant changes in non-REM sleep, and reduced REM sleep (P < 0.001). With hypoxic stimuli, wakefulness episodes were longer and more frequent, non-REM periods were shorter and more frequent, and REM episodes were shorter and less frequent (P < 0.015). Hypoxic stimuli also increased faster frequencies in the EEG (P < 0.005). These effects of hypoxic stimuli were reversed on return to room air. There was a rebound increase in REM sleep, increased slower non-REM EEG frequencies, and decreased wakefulness (P < 0.001). The results show that sleep-specific hypoxia leads to significant modulation of sleep-wake regulation both during and after application of the intermittent hypoxic stimuli. This study is the first to determine the independent effects of sleep-related hypoxia on sleep regulation that approximates OSA before and after treatment.