Systemic injection of a nitric oxide synthase inhibitor suppresses sleep responses to sleep deprivation in rats

We hypothesized that nitric oxide (NO) may play a role in homeostatic sleep regulation. To test this hypothesis, we studied the sleep deprivation (SD)-induced homeostatic sleep responses after intraperitoneal administration of an NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, a cumulative dose of 100 mg/kg). Amounts and intensity of sleep were increased in response to 8 h of SD in control rats (n = 8). Sleep amounts remained above baseline for 16 h after SD followed by a negative rebound. Rapid eye movement sleep (REMS) and non-REMS (NREMS) intensities were elevated for 16 and 4 h, respectively. L-NAME treatment (n = 8) suppressed the rebound increases in NREMS amount and intensity. REMS rebound was attenuated by L-NAME in the first dark period after SD; however, a second rebound appeared in the subsequent dark period. REMS intensity did not increase after SD in L-NAME-injected rats. The finding that the NO synthase inhibitor suppressed rebound increases in NREMS suggests that NO may play a role as a signaling molecule in homeostatic regulation of NREMS.     

Sleep,activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4

AimsThe type 2 muscarinic receptor (M2R) differs from the other G-protein-coupled muscarinic receptor (type 4, or M4R) in tissue distribution and physiologic effects. We studied the impact of these receptors on sleep and arousal by using M2R and M4R knock-out (KO) mice.Main methodsM2R and M4R KO and genetically intact mice were compared in terms of normal patterns of sleep, responses to sleep loss, infectious challenge and acoustic startle, and acoustic prepulse inhibition of startle (PPI).Key findingsUnder basal conditions, M2R and M4R KO mice do not differ from the background strain or each other in the amount or diurnal pattern of sleep, locomotor activity, and body temperature. After enforced sleep loss, M2R KO mice, in contrast to the other two strains, show no rebound in slow-wave sleep (SWS) time, although their SWS is consolidated, and they show a greater rebound in time spent in REMS (rapid-eye-movement sleep) and REMS consolidation. During influenza infection, M2R KO mice, as compared with the other strains, show marked hypothermia and a less robust increase in SWS. During Candida albicans infection, M2R KO mice show a greater increase in SWS and a greater inflammatory response than do the other strains. M2R KO mice also show greater acoustic startle amplitude than does the background strain, although PPI was not different across the 3 strains over a range of stimulus intensities.SignificanceTaken together, these findings support different roles for M2R and M4R in the modulation of sleep and arousal during homeostatic challenge.     

Day- and nighttime injection of a nitric oxide synthase inhibitor elicits opposite sleep responses in rats

Previous studies suggest that nitric oxide (NO) may play a role in sleep regulation, particularly in the homeostatic process. The present studies were undertaken to compare the sleep effects of injecting a NO synthase (NOS) inhibitor when homeostatic sleep pressure is naturally highest (light onset) or when it is at its nadir (dark onset) in rats. Sleep, electroencephalogram delta-wave activity during nonrapid eye movement sleep (NREMS), also known as slow-wave activity (SWA), and brain temperature responses to three doses of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME ; 5, 50, and 100 mg/kg) injected intraperitoneally at light or dark onset were examined in rats (n = 6 to 8). The effects of 5 mg/kg L-NAME were determined in both normal and vagotomized (VX) rats. Light onset administration of 50 mg/kg L-NAME decreased NREMS amounts and suppressed SWA and increased rapid eye movement sleep (REMS) amounts. At dark onset, L-NAME injection also dose dependently suppressed SWA; however, unlike light onset injections, both NREMS and REMS amounts were increased after all three doses. Sleep responses to 5 mg/kg L-NAME were not different in control and VX rats, suggesting that the sleep effects of L-NAME are not mediated through the activation of sensory vagal mechanisms. The present findings suggest that timing of the injection is a major determinant of the sleep responses observed after systemic L-NAME injection in rats.     

Effects of electroacupuncture at ‘Anmian (Extra)’ acupoints on sleep activities in rats: The implication of the caudal nucleus tractus solitarius

Electroacupuncture (EAc) possesses a broad therapeutic effect, including improvement of sleep disturbances. The mechanism of sleep improvement with EAc, however, is still unclear. The present study investigated the effects of EAc stimulation of Anmian (extra) acupoints on sleep organization and the implication of an active structure, the caudal nucleus tractus solitarius (NTS). Rats were implanted with electroencephalogram (EEG) recording electrodes, and 32-gauge acupuncture needles were bilaterally inserted into Anmian (extra) acupoints in the rats, followed by electrical stimulation for 20 min. Twenty-three-hour continuous EEGs were then recorded. Results showed that rapid eye movement sleep (REMS) was enhanced during the dark period when a single EAc stimulation was given 25 min prior to the onset of the dark period. REMS and slow-wave sleep (SWS) increased during the dark period after administration of EAc stimuli on 2 consecutive days. Electrical stimulation of non-acupoints produced no change in the sleep pattern. Pharmacological blockade of muscarinic cholinergic receptors by systemic administration of scopolamine dose-dependently attenuated EAc-induced changes in REMS and SWS. Furthermore, electrical lesions in the bilateral caudal NTS produced significant blockade of EAc-induced sleep enhancement. However, in rats without EAc, scopolamine increased SWS during the dark period, but caudal NTS lesions did not alter sleep. In addition, neither EAc nor scopolamine with EAc manipulation produced any change in the slow-wave activity (SWA) during SWS; however, the SWA during SWS was significantly reduced after caudal NTS lesion with EAc. These results suggest that the caudal NTS may be involved in the regulation of EAc-induced sleep alterations.     

慢波睡眠的激素与细胞因子调节

慢波睡眠（ＳＷＳ）是最重要的睡眠成分。近年来的研究揭示：腹外侧视前区－结节乳头核（ＶＬＰＯ－ＴＭＮ）可能是睡眠－觉醒的中枢发生部位。基底前脑吻端前列腺素Ｄ２（ＰＧＤ２）敏感性睡眠促进区（ＰＧＤ２－ＳＰＺ）参与睡眠的皖控。ＰＧＤ２延长ＳＷＳ;前列腺素Ｅ２（ＰＧＥ２）延长觉醒,抑制ＳＷＳ和快动眼睡眠（ＲＥＭＳ）。ＳＷＳ与下丘脑－垂体－肾上腺皮质轴的活动呈负相关,与生长激素的分泌呈正相关。褪黑素（ｍｅｌ     

Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits

Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalographic (EEG) slow waves during the initial 9-h postinjection period, then, during hours 10-23 postinjection, reduced EEG slow-wave activity. Current data support the notion that the brain cytokine network is involved in the regulation of sleep.     

Microinjection of the melanin-concentrating hormone into the lateral basal forebrain increases REM sleep and reduces wakefulness in the rat

AimsTo examine the effects of bilateral microinjection of melanin-concentrating hormone (MCH) 50 and 100 ng into the horizontal limb of the diagonal band of Broca (HDB) on sleep variables during the light phase of the light–dark cycle of the rat.Main methodsMale Wistar rats were implanted for chronic sleep recordings. In addition, a guide cannula was implanted above the right and left HDB. Following the microinjection of MCH or control solution the electroencephalogram and the electromyogram were recorded for 6 h. Data was collected and classified as either wakefulness (W), light sleep, slow wave sleep (SWS) or REM sleep (REMS). Latencies for SWS and REMS, as well as the number of REM periods and the mean duration of REM episodes were also determined.Key findingsMCH 50 and 100 ng significantly decreased W during the first 2-h of recording. Moreover, MCH 100 ng significantly reduced REMS latency and increased REMS time during the first 2-h block of the recording, due to an increase in the number of REM periods.SignificanceOur findings tend to suggest that the basal forebrain participates in the effects of MCH on W and REMS through the deactivation of cholinergic, glutamatergic and γ-aminobutyric acid (GABA)-ergic cells.     

Time-of-day modulation of homeostatic and allostatic sleep responses to chronic sleep restriction in rats

To study sleep responses to chronic sleep restriction (CSR) and time-of-day influences on these responses, we developed a rat model of CSR that takes into account the polyphasic sleep patterns in rats. Adult male rats underwent cycles of 3 h of sleep deprivation (SD) and 1 h of sleep opportunity (SO) continuously for 4 days, beginning at the onset of the 12-h light phase ("3/1" protocol). Electroencephalogram (EEG) and electromyogram (EMG) recordings were made before, during, and after CSR. During CSR, total sleep time was reduced by ～60% from baseline levels. Both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) during SO periods increased initially relative to baseline and remained elevated for the rest of the CSR period. In contrast, NREMS EEG delta power (a measure of sleep intensity) increased initially, but then declined gradually, in parallel with increases in high-frequency power in the NREMS EEG. The amplitude of daily rhythms in NREMS and REMS amounts was maintained during SO periods, whereas that of NREMS delta power was reduced. Compensatory responses during the 2-day post-CSR recovery period were either modest or negative and gated by time of day. NREMS, REMS, and EEG delta power lost during CSR were not recovered by the end of the second recovery day. Thus the "3/1" CSR protocol triggered both homeostatic responses (increased sleep amounts and intensity during SOs) and allostatic responses (gradual decline in sleep intensity during SOs and muted or negative post-CSR sleep recovery), and both responses were modulated by time of day.     

Interleukin-13 and transforming growth factor-beta1 inhibit spontaneous sleep in rabbits

Proinflammatory cytokines, including interleukin-1beta and tumor necrosis factor-alpha are involved in physiological sleep regulation. Interleukin (IL)-13 and transforming growth factor (TGF)-beta1 are anti-inflammatory cytokines that inhibit proinflammatory cytokines by several mechanisms. Therefore, we hypothesized that IL-13 and TGF-beta1 could attenuate sleep in rabbits. Three doses of IL-13 (8, 40, and 200 ng) and TGF-beta1 (40, 100, and 200 ng) were injected intracerebroventricularly 3 h after the beginning of the light period. In addition, one dose of IL-13 (200 ng) and one dose of TGF-beta1 (200 ng) were injected at dark onset. The two higher doses of IL-13 and the highest dose of TGF-beta1 significantly inhibited spontanenous non-rapid eye movement sleep (NREMS) when they were given in the light period. IL-13 also inhibited NREMS after dark onset administration; however, the inhibitory effect was less potent than that observed after light period administration. The 40-ng dose of IL-13 inhibited REMS duration during the dark period. TGF-beta1 administered at dark onset had no effect on sleep. These data provide additional evidence for the hypothesis that a brain cytokine network is involved in regulation of physiological sleep.     

Spontaneous sleep and homeostatic sleep regulation in ghrelin knockout mice

Ghrelin is well known for its feeding and growth hormone-releasing actions. It may also be involved in sleep regulation; intracerebroventricular administration and hypothalamic microinjections of ghrelin stimulate wakefulness in rats. Hypothalamic ghrelin, together with neuropeptide Y and orexin form a food intake-regulatory circuit. We hypothesized that this circuit also promotes arousal. To further investigate the role of ghrelin in the regulation of sleep-wakefulness, we characterized spontaneous and homeostatic sleep regulation in ghrelin knockout (KO) and wild-type (WT) mice. Both groups of mice exhibited similar diurnal rhythms with more sleep and less wakefulness during the light period. In ghrelin KO mice, spontaneous wakefulness and rapid-eye-movement sleep (REMS) were slightly elevated, and non-rapid-eye-movement sleep (NREMS) was reduced. KO mice had more fragmented NREMS than WT mice, as indicated by the shorter and greater number of NREMS episodes. Six hours of sleep deprivation induced rebound increases in NREMS and REMS and biphasic changes in electroencephalographic slow-wave activity (EEG SWA) in both genotypes. Ghrelin KO mice recovered from NREMS and REMS loss faster, and the delayed reduction in EEG SWA, occurring after sleep loss-enhanced increases in EEG SWA, was shorter-lasting compared with WT mice. These findings suggest that the basic sleep-wake regulatory mechanisms in ghrelin KO mice are not impaired and they are able to mount adequate rebound sleep in response to a homeostatic challenge. It is possible that redundancy in the arousal systems of the brain or activation of compensatory mechanisms during development allow for normal sleep-wake regulation in ghrelin KO mice.     

Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis

The effects of the central (CB1) cannabinoid receptor antagonist SR 141716A on the sleep-waking cycle were investigated in freely-moving rats using time scoring and power spectral analysis of the electroencephalogram (EEG). Over a 4-hour recording period, SR 141716A (0.1, 0.3, 1, 3 and 10 mg/kg I.P.) dose-dependently increased the time spent in wakefulness at the expense of slow-wave sleep (SWS) and rapid eye movement sleep (REMS), delayed the occurrence of REMS but did not change the mean duration of REMS episodes. Moreover, the compound induced no change in motor behavior. At the efficient dose of 3 mg/kg I.P., SR 141716A reduced the spectral power of the EEG signals typical of SWS but did not affect those of wakefulness. Taken together, these results demonstrate that the EEG effects of SR 141716A reflect arousal-enhancing properties. In addition, the present study suggests that an endogenous cannabinoid-like system is involved in the control of the sleep-waking cycle.     

Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes

In mammals, sleep is regulated by circadian and homeostatic mechanisms. The circadian component, residing in the suprachiasmatic nucleus (SCN), regulates the timing of sleep, whereas homeostatic factors determine the amount of sleep. It is believed that these two processes regulating sleep are independent because sleep amount is unchanged after SCN lesions. However, because such lesions necessarily damage neuronal connectivity, it is preferable to investigate this question in a genetic model that overcomes the confounding influence of circadian rhythmicity. Mice with disruption of both mouse Period genes (mPer)1 and mPer2 have a robust diurnal sleep-wake rhythm in an entrained light-dark cycle but lose rhythmicity in a free-run condition. Here, we examine the role of the mPer genes on the rhythmic and homeostatic regulation of sleep. In entrained conditions, when averaged over the 24-h period, there were no significant differences in waking, slow-wave sleep (SWS), or rapid eye movement (REM) sleep between mPer1, mPer2, mPer3, mPer1-mPer2 double-mutant, and wild-type mice. The mice were then kept awake for 6 h (light period 6-12), and the mPer mutants exhibited increased sleep drive, indicating an intact sleep homeostatic response in the absence of the mPer genes. In free-run conditions (constant darkness), the mPer1-mPer2 double mutants became arrhythmic, but they continued to maintain their sleep levels even after 36 days in free-running conditions. Although mPer1 and mPer2 represent key elements of the molecular clock in the SCN, they are not required for homeostatic regulation of the daily amounts of waking, SWS, or REM sleep.     

Sepsis-induced alterations in sleep of rats

Sepsis is a systemic immune response to infection that may result in multiple organ failure and death. Polymicrobial infections remain a serious clinical problem, and in the hospital, sepsis is the number-one noncardiac killer. Although the central nervous system may be one of the first systems affected, relatively little effort has been made to determine the impact of sepsis on the brain. In this study, we used the cecal ligation and puncture (CLP) model to determine the extent to which sepsis alters sleep, the EEG, and brain temperature (Tbr) of rats. Sepsis increases the amount of time rats spend in non-rapid eye movement sleep (NREMS) during the dark period, but not during the light period. Rapid eye movements sleep (REMS) of septic rats is suppressed for about 24 h following CLP surgery, after which REMS increases during dark periods for at least three nights. The EEG is dramatically altered shortly after sepsis induction, as evidenced by reductions in slow-frequency components. Furthermore, sleep is fragmented, indicating that the quality of sleep is diminished. Effects on sleep, the EEG, and Tbr persist for at least 84 h after sepsis induction, the duration of our recording period. Immunohistochemical assays focused on brain stem mechanisms responsible for alterations in REMS, as little information is available concerning infection-induced suppression of this sleep stage. Our immunohistochemical data suggest that REMS suppression after sepsis onset may be mediated, in part, by the brain stem GABAergic system. This study demonstrates for the first time that sleep and EEG patterns are altered during CLP-induced sepsis. These data suggest that the EEG may serve as a biomarker for sepsis onset. These data also contribute to our knowledge of potential mechanisms, whereby infections alter sleep and other central nervous system functions.     

Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation

To determine the relationships among plasma ghrelin and leptin concentrations and hypothalamic ghrelin contents, and sleep, cortical brain temperature (Tcrt), and feeding, we determined these parameters in rats in three experimental conditions: in free-feeding rats with normal diurnal rhythms, in rats with feeding restricted to the 12-h light period (RF), and in rats subjected to 5-h of sleep deprivation (SD) at the beginning of the light cycle. Plasma ghrelin and leptin displayed diurnal rhythms with the ghrelin peak preceding and the leptin peak following the major daily feeding peak in hour 1 after dark onset. RF reversed the diurnal rhythm of these hormones and the rhythm of rapid-eye-movement sleep (REMS) and significantly altered the rhythm of Tcrt. In contrast, the duration and intensity of non-REMS (NREMS) were hardly responsive to RF. SD failed to change leptin concentrations, but it promptly stimulated plasma ghrelin and induced eating. SD elicited biphasic variations in the hypothalamic ghrelin contents. SD increased plasma corticosterone, but corticosterone did not seem to influence either leptin or ghrelin. The results suggest a strong relationship between feeding and the diurnal rhythm of leptin and that feeding also fundamentally modulates the diurnal rhythm of ghrelin. The variations in hypothalamic ghrelin contents might be associated with sleep-wake activity in rats, but, unlike the previous observations in humans, obvious links could not be detected between sleep and the diurnal rhythms of plasma concentrations of either ghrelin or leptin in the rat.     

Toward an integrative theory of sleep and dreaming

Non-rapid-eye-movement sleep (NREMS) is triggered by the accumulation of adenosine, as a result of the perceptual overload of the brain cortex. NREMS starts in the most burdened regions of the cortex first and then eventually, after the released adenosine has reached the ventrolateral pre-optic nucleus area of the hypothalamus, triggers the "general NREMS pattern". This is accompanied by the usual familiar changes in the thalamocortical system. When NREMS reaches the slow-wave sleep (SWS) phase, with its predominant delta activity, brain metabolism drops significantly with the brain temperature, and this is recognized by the alarm system in the pre-optic anterior hypothalamus and/or the other thermostat circuit in the brainstem as a life-threatening situation. This alarm system triggers a reaction similar to abortive or partial awakening called rapid-eye-movement sleep (REMS), which is aimed at restoring the optimal body-core temperature. As soon as this restoration is accomplished by the activation of the brainstem-to-cortex ascending pathways, NREMS may continue, as may the interchange of the two sleep phases during the entire sleep period. During both NREMS and REMS, the same essential pattern occurs in the cortex: the loops "used" during the previous waking period, now deprived of external input, replay their waking activity at a lower frequency, one which enables them to restore the membrane's potential (possibly by means of LTD). During REMS, however, the cholinergic flood originating in the LTD/PPT nuclei of the pons tegmentum, increases in the basal forebrain and, provoking theta activity in the medial septum is extended to the hippocampus, causing the circuits that are active at that particular moment in the cortex, to store the information they carry as memory. This is the explanation of both the memory improvement known to be related to REMS and of dreams. Both phenomena are clearly side effects of REMS.     

Control of activity of the diaphragm in rapid-eye-movement sleep

Respiration in rapid-eye-movement sleep (REMS) is known to be highly variable. The purpose of this study was to investigate the source of this variability and to determine which ordering principles remained operative in REM sleep. In unrestrained, naturally sleeping cats we recorded the electroencephalogram, electrooculogram, neck electromyogram, and diaphragmatic electromyogram (EMG) and computed its moving average (MAdi). As a reference, we first examined MAdi during "tonic" REMS, since breathing is fairly regular in this state. "Control" ranges for peak amplitude (PEMG), inspiratory time (TI), duration of postinspiratory inspiratory activity, expiratory time, and the calculated inspiratory slope (PEMG/TI) were determined by overlaying individual breath traces of the time course of MAdi during tonic REMS to form a composite tracing. Next, the time course of the EMG during individual breaths in slow-wave sleep (SWS) and a complete period of consecutive breaths in REMS (both tonic and phasic) were compared with this tonic REMS composite. The number of eye movements per breath was tabulated as an index of phasic activity. The inspiratory slopes during SWS and tonic REMS were similar. However, during phasic REMS, many breaths displayed either increases (excitation) or decreases (inhibition) in slope compared with the "typical" breaths seen in tonic REMS. The occurrence of these altered slopes increased with the frequency of phasic events. TI was inversely related to the slope of the EMG, which tended to minimize changes in PEMG.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytokine- and microbially induced sleep responses of interleukin-10 deficient mice

Interleukin (IL)-1 and tumor necrosis factor (TNF) promote slow-wave sleep (SWS), whereas IL-10 inhibits the synthesis of IL-1 and TNF and promotes waking. We evaluated the impact of endogenous IL-10 on sleep-wake behavior by studying mice that lack a functional IL-10 gene. Under baseline conditions, C57BL/6-IL-10 knockout (KO) mice spent more time in SWS during the dark phase of the light-dark cycle than did genetically intact C57BL/6 mice. The two strains of mice showed generally comparable responses to treatment with IL-1, IL-10, or influenza virus, but differed in their responses to lipopolysaccharide (LPS). In IL-10 KO mice, LPS induced an initial transient increase and a subsequent prolonged decrease in SWS, as well as profound hypothermia. These responses were not observed in LPS-treated C57BL/6 mice. These data demonstrate that in the absence of endogenous IL-10, spontaneous SWS is increased and the impact of LPS on vigilance states is altered. Collectively, these observations support a role for IL-10 in sleep regulation and provide further evidence for the involvement of cytokines in the regulation 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.     

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.