Activation of 5-HT1A receptors in the paragigantocellularis lateralis decreases shivering during cooling in the conscious piglet

Activation of 5-HT(1A) receptors in the medullary raphé decreases sympathetic outflow to thermoregulatory mechanisms, including brown adipose tissue (BAT), thermogenesis, and peripheral vasoconstriction when these mechanisms are previously activated with leptin, prostaglandins, or cooling. These same mechanisms are also inhibited during rapid eye movement (REM) sleep. It is not known whether shivering is also modulated by medullary raphé neurons. We previously showed in the conscious piglet that activation of 5-HT(1A) receptors with 8-OH-DPAT (DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the midline raphé that contains 5-HT neurons, decreases heart rate, body temperature and muscle activity during non-rapid eye movement (NREM) sleep. We therefore hypothesized that activation of 5-HT(1A) receptors in the PGCL would also attenuate shivering and peripheral vasoconstriction during cooling. During REM sleep in a cool environment, shivering, carbon dioxide production, and body temperature decreased, and ear capillary blood flow and ear skin temperature increased. Shivering associated with rapid cooling was attenuated after dialysis of DPAT into the PGCL. In animals maintained in a continuously cool environment, dialysis of DPAT into the PGCL attenuated shivering and decreased body temperature, but there were no significant increases in ear capillary blood flow or ear skin temperature. We conclude that both naturally occurring REM sleep and exogenous activation of 5-HT(1A) receptors in the PGCL are associated with a suspension of shivering during cooling. Our data are consistent with the hypothesis that 5-HT neurons in the PGCL facilitate oscillating spinal motor circuits involved in shivering but are less involved in modulating sympathetically mediated thermoregulatory mechanisms.     

Activation of 5-HT1A receptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet

Activation of 5-HT1A receptors in the medullary raphé decreases sympathetically mediated brown adipose tissue (BAT) thermogenesis and peripheral vasoconstriction when previously activated with leptin, LPS, prostaglandins, or cooling. It is not known whether shivering is also modulated by medullary raphé 5-HT1A receptors. We previously showed in conscious piglets that activation of 5-HT1A receptors with (+/-)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the raphé that contains substantial numbers of 5-HT neurons, eliminates rapid eye movement (REM) sleep and decreases shivering in a cold environment, but does not attenuate peripheral vasoconstriction. Hoffman JM, Brown JW, Sirlin EA, Benoit AM, Gill WH, Harris MB, Darnall RA. Am J Physiol Regul Integr Comp Physiol 293: R518-R527, 2007. We hypothesized that, during cooling, activation of 5-HT1A receptors in the medullary raphé would also eliminate REM sleep and, in contrast to activation of 5-HT1A receptors in the PGCL, would attenuate both shivering and peripheral vasoconstriction. In a continuously cool environment, dialysis of 8-OH-DPAT into the medullary raphé resulted in alternating brief periods of non-REM sleep and wakefulness and eliminated REM sleep, as observed when 8-OH-DPAT is dialyzed into the PGCL. Moreover, both shivering and peripheral vasoconstriction were significantly attenuated after 8-OH-DPAT dialysis into the medullary raphé. The effects of 8-OH-DPAT were prevented after dialysis of the selective 5-HT1A receptor antagonist WAY-100635. We conclude that, during cooling, exogenous activation of 5-HT1A receptors in the medullary raphé decreases both shivering and peripheral vasoconstriction. Our data are consistent with the hypothesis that neurons expressing 5-HT1A receptors in the medullary raphé facilitate spinal motor circuits involved in shivering, as well as sympathetic stimulation of other thermoregulatory effector mechanisms.     

Thermoregulation, metabolism, and stages of sleep in cold-exposed men

Four naked men, selected for their ability to sleep in the cold, were exposed to an ambient temperature (Ta) of 21 degrees C for five consecutive nights. Electrophysiological stages of sleep, O2 consumption (VO2), and skin (Tsk), rectal (Tre), and tympanic (Tty) temperatures were recorded. Compared with five nights at a thermoneutral Ta of 29 degrees C, cold induced increased wakefulness and decreased stage 2 sleep, without significantly affecting other stages. Tre and Tty declined during each condition. The decrease in Tre was greater at 21 degrees C than at 29 degrees C, whereas Tty did not differ significantly between conditions. Increases in Tty following REM sleep onset at 21 degrees C were negatively correlated with absolute Tty. VO2 and forehead Tsk also increased during REM sleep at both TaS, whereas Tsk of the limb extremities declined at 21 degrees C. Unsuppressed REM sleep in association with peripheral vasoconstriction and increased Tty and VO2 in cold-exposed humans, do not signify an inhibition of thermoregulation during this sleep stage as has been observed in other mammals.     

A probabilistic model for the ultradian timing of REM sleep in mice

A salient feature of mammalian sleep is the alternation between rapid eye movement (REM) and non-REM (NREM) sleep. However, how these two sleep stages influence each other and thereby regulate the timing of REM sleep episodes is still largely unresolved. Here, we developed a statistical model that specifies the relationship between REM and subsequent NREM sleep to quantify how REM sleep affects the following NREM sleep duration and its electrophysiological features in mice. We show that a lognormal mixture model well describes how the preceding REM sleep duration influences the amount of NREM sleep till the next REM sleep episode. The model supports the existence of two different types of sleep cycles: Short cycles form closely interspaced sequences of REM sleep episodes, whereas during long cycles, REM sleep is first followed by an interval of NREM sleep during which transitions to REM sleep are extremely unlikely. This refractory period is characterized by low power in the theta and sigma range of the electroencephalogram (EEG), low spindle rate and frequent microarousals, and its duration proportionally increases with the preceding REM sleep duration. Using our model, we estimated the propensity for REM sleep at the transition from NREM to REM sleep and found that entering REM sleep with higher propensity resulted in longer REM sleep episodes with reduced EEG power. Compared with the light phase, the buildup of REM sleep propensity was slower during the dark phase. Our data-driven modeling approach uncovered basic principles underlying the timing and duration of REM sleep episodes in mice and provides a flexible framework to describe the ultradian regulation of REM sleep in health and disease.     

Selective REM sleep deprivation during daytime I. Time course of interventions and recovery sleep

Although repeated selective rapid eye movement (REM) sleep deprivation by awakenings during nighttime has shown that the number of sleep interruptions required to prevent REM sleep increases within and across consecutive nights, the underlying regulatory processes remained unspecified. To assess the role of circadian and homeostatic factors in REM sleep regulation, REM sleep was selectively deprived in healthy young adult males during a daytime sleep episode (7-15 h) after a night without sleep. Circadian REM sleep propensity is known to be high in the early morning. The number of interventions required to prevent REM sleep increased from the first to the third 2-h interval by a factor of two and then leveled off. Only a minor REM sleep rebound (11.6%) occurred in the following undisturbed recovery night. It is concluded that the limited rise of interventions during selective daytime REM sleep deprivation may be due to the declining circadian REM sleep propensity, which may partly offset the homeostatic drive and the sleep-dependent disinhibition of REM sleep.     

Control of motoneuron function and muscle tone during REM sleep, REM sleep behavior disorder and cataplexy/narcolepsy

REM sleep triggers a potent suppression of postural muscle tone - i.e., REM atonia. However, motor control during REM sleep is paradoxical because overall brain activity is maximal, but motor output is minimal. The skeletal motor system remains quiescent during REM sleep because somatic motoneurons are powerfully inactivated. Determining the mechanisms triggering loss of motoneuron function during REM sleep is important because breakdown in REM sleep motor control underlies sleep disorders such as REM sleep behavior disorder (RBD) and cataplexy/narcolepsy. For example, RBD is characterized by dramatic REM motor activation resulting in dream enactment and subsequent patient injury. In contrast, cataplexy a pathognomonic symptom of narcolepsy - is caused by the involuntary onset of REM-like atonia during wakefulness. This review highlights recent work from my laboratory that examines how motoneuron function is lost during normal REM sleep and it also identifies potential biochemical mechanisms underlying abnormal motor control in both RBD and cataplexy. First, I show that both GABAB and GABAA/glycine mediated inhibition of motoneurons is required for generating REM atonia. Next, I show that impaired GABA and glycine neurotransmission triggers the cardinal features of RBD in a transgenic mouse model. Last, I show that loss of an excitatory noradrenergic drive onto motoneurons is, at least in part, responsible for the loss of postural muscle tone during cataplexy in narcoleptic mice. Together, this research indicates that multiple transmitters systems are responsible for regulating postural muscle tone during REM sleep, RBD and cataplexy.     

Effect of sleep stage on breathing in children with central hypoventilation.

The early literature suggests that hypoventilation in infants with congenital central hypoventilation syndrome (CHS) is less severe during rapid eye movement (REM) than during non-REM (NREM) sleep. However, this supposition has not been rigorously tested, and subjects older than infancy have not been studied. Given the differences in anatomy, physiology, and REM sleep distribution between infants and older children, and the reduced number of limb movements during REM sleep, we hypothesized that older subjects with CHS would have more severe hypoventilation during REM than NREM sleep. Nine subjects with CHS, aged (mean +/- SD) 13 +/- 7 yr, were studied. Spontaneous ventilation was evaluated by briefly disconnecting the ventilator under controlled circumstances. Arousal was common, occurring in 46% of REM vs. 38% of NREM trials [not significant (NS)]. Central apnea occurred during 31% of REM and 54% of NREM trials (NS). Although minute ventilation declined precipitously during both REM and NREM trials, hypoventilation was less severe during REM (drop in minute ventilation of 65 +/- 23%) than NREM (drop of 87 +/- 16%, P = 0.036). Despite large changes in gas exchange during trials, there was no significant change in heart rate during either REM or NREM sleep. We conclude that older patients with CHS frequently have arousal and central apnea, in addition to hypoventilation, when breathing spontaneously during sleep. The hypoventilation in CHS is more severe during NREM than REM sleep. We speculate that this may be due to increased excitatory inputs to the respiratory system during REM sleep.     

Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema

In five patients with hypoxic chronic bronchitis and emphysema we measured ear O2 saturation (SaO2), chest movement, oronasal airflow, arterial and mixed venous gas tensions, and cardiac output during nine hypoxemic episodes (HE; SaO2 falls greater than 10%) in rapid-eye-movement (REM) sleep and during preceding periods of stable oxygenation in non-REM sleep. All nine HE occurred with recurrent short episodes of reduced chest movement, none with sleep apnea. The arterial PO2 (PaO2) fell by 6.0 +/- 1.9 (SD) Torr during the HE (P less than 0.01), but mean arterial PCO2 (PaCO2) rose by only 1.4 +/- 2.4 Torr (P greater than 0.4). The arteriovenous O2 content difference fell by 0.64 +/- 0.43 ml/100 ml of blood during the HE (P less than 0.05), but there was no significant change in cardiac output. Changes observed in PaO2 and PaCO2 during HE were similar to those in four normal subjects during 90 s of voluntary hypoventilation, when PaO2 fell by 12.3 +/- 5.6 Torr (P less than 0.05), but mean PaCO2 rose by only 2.8 +/- 2.1 Torr (P greater than 0.4). We suggest that the transient hypoxemia which occurs during REM sleep in patients with chronic bronchitis and emphysema could be explained by hypoventilation during REM sleep but that the importance of changes in distribution of ventilation-perfusion ratios cannot be assessed by presently available techniques.     

Effects of selective sleep deprivation on ventilation during recovery sleep in normal humans.

To assess the effects of selective sleep loss on ventilation during recovery sleep, we deprived 10 healthy young adult humans of rapid-eye-movement (REM) sleep for 48 h and compared ventilation measured during the recovery night with that measured during the baseline night. At a later date we repeated the study using awakenings during non-rapid-eye-movement (NREM) sleep at the same frequency as in REM sleep deprivation. Neither intervention produced significant changes in average minute ventilation during presleep wakefulness, NREM sleep, or the first REM sleep period. By contrast, both interventions resulted in an increased frequency of breaths, in which ventilation was reduced below the range for tonic REM sleep, and in an increased number of longer episodes, in which ventilation was reduced during the first REM sleep period on the recovery night. The changes after REM sleep deprivation were largely due to an increase in the duration of the REM sleep period with an increase in the total phasic activity and, to a lesser extent, to changes in the relationship between ventilatory components and phasic eye movements. The changes in ventilation after partial NREM sleep deprivation were associated with more pronounced changes in the relationship between specific ventilatory components and eye movement density, whereas no change was observed in the composition of the first REM sleep period. These findings demonstrate that sleep deprivation leads to changes in ventilation during subsequent REM sleep.     

Ventilation during early and late rapid-eye-movement sleep in normal humans.

Because successive rapid-eye-movement (REM) sleep periods in the night are longer in duration and have more phasic events, ventilation during late REM sleep might be more affected than in earlier episodes. Despite the increase in eye movement density (EMD) in late REM sleep, average minute ventilation was, however, not reduced compared with that in early REM sleep. Decreases in rib cage motion (mean inspiratory flow of the rib cage) in association with increasing EMD were offset by increments in respiratory frequency. Apart from expiratory time, there were no significant changes in the slopes of the relationships between EMD and specific ventilatory components, from early to late REM sleep periods. However, there was an increase in the number of episodes when ventilation was reduced during late REM sleep. Changes in ventilatory pattern during late REM sleep are due to changes in the underlying nature of REM sleep. The ventilatory response during eye movements is, however, subject specific. Some subjects exhibit large decrements in mean inspiratory flow of the rib cage and increments in respiratory frequency during bursts of eye movement, whereas other individuals demonstrate only small changes in these ventilatory parameters.     

快速眼动睡眠产生的神经机制:蓝斑核神经元停止发放是一个必要的条件

两种类型的神经元参与了快速眼动（rapid eye movement,REM）睡眠的调节：快速眼动一发放（REM-ON）神经元和快速眼动-沉寂神经元（REM-OFF）。快速眼动-沉寂神经元属去甲肾上腺素能神经元,正如名字表示的那样——在快速眼动睡眠期间停止发放。已有研究表明,这些神经元放电活动的停止是导致快速眼动睡眠的前提条件,γ-氨基丁酸（γ-aminobutyric acid,GABA）可使它们停止发放。如果这嗤神经元不停止发放,脑中的去甲肾上腺素水平将升高,不出现快速眼动睡眠。剥夺快速眼动睡眠所引起的去甲肾上腺素增加,至少是快速眼动睡眠丧失引起Na^＋-K^＋ATP酶活性增加的原因,而这可能是导致快速眼动睡眠剥夺所引发的各种效应的主要因素。     

Basal forebrain acetylcholine release during REM sleep is significantly greater than during waking

Cholinergic neurons of the basal forebrain supply the neocortex with ACh and play a major role in regulating behavioral arousal and cortical electroencephalographic activation. Cortical ACh release is greatest during waking and rapid eye movement (REM) sleep and reduced during non-REM (NREM) sleep. Loss of basal forebrain cholinergic neurons contributes to sleep disruption and to the cognitive deficits of many neurological disorders. ACh release within the basal forebrain previously has not been quantified during sleep. This study used in vivo microdialysis to test the hypothesis that basal forebrain ACh release varies as a function of sleep and waking. Cats were trained to sleep in a head-stable position, and dialysis samples were collected during polygraphically defined states of waking, NREM sleep, and REM sleep. Results from 22 experiments in four animals demonstrated that means +/- SE ACh release (pmol/10 min) was greatest during REM sleep (0.77 +/- 0.07), intermediate during waking (0.58 +/- 0.03), and lowest during NREM sleep (0.34 +/- 0.01). The finding that, during REM sleep, basal forebrain ACh release is significantly elevated over waking levels suggests a differential role for basal forebrain ACh during REM sleep and waking.     

Light-Dark Difference in Arterial Pressure Variability During REM Sleep in the Rat

We have observed mean arterial pressure (MAP) variability during rapid eye movement (REM) sleep and brain temperature (Tb) in the rat during both light and dark periods over 24 h. MAP was measured using a telemetric device with a computer data capture and analysis system. As markers of MAP variability, the maximum and coefficient of variation (CV%) of MAP during REM sleep were determined. The following results were obtained: (a) there was a light-dark difference in MAP during non-REM (NREM) sleep and Tb during both NREM and REM sleep; (b) the increase of MAP in going from NREM to REM sleep in the light period was greater than that in the dark period, whereas the increase of Tb in the light period was not different from that in the dark period; (c) the maximum and CV% for MAP during REM sleep in the light period were greater than those in the dark period; (d) there was a negative correlation between the average Tb and MAP CV% during REM sleep. We suggest that phasic fluctuation of MAP during REM sleep may be influenced, in part, by a factor independent of sleep mechanisms.     

Light-Dark Difference in Arterial Pressure Variability During REM Sleep in the Rat

We have observed mean arterial pressure (MAP) variability during rapid eye movement (REM) sleep and brain temperature (Tb) in the rat during both light and dark periods over 24 h. MAP was measured using a telemetric device with a computer data capture and analysis system. As markers of MAP variability, the maximum and coefficient of variation (CV%) of MAP during REM sleep were determined. The following results were obtained: (a) there was a light-dark difference in MAP during non-REM (NREM) sleep and Tb during both NREM and REM sleep; (b) the increase of MAP in going from NREM to REM sleep in the light period was greater than that in the dark period, whereas the increase of Tb in the light period was not different from that in the dark period; (c) the maximum and CV% for MAP during REM sleep in the light period were greater than those in the dark period; (d) there was a negative correlation between the average Tb and MAP CV% during REM sleep. We suggest that phasic fluctuation of MAP during REM sleep may be influenced, in part, by a factor independent of sleep mechanisms.     

An ether stressor increases REM sleep in rats: possible role of prolactin

Sleep alterations after a 1-min exposure to ether vapor were studied in rats to determine if this stressor increases rapid eye-movement (REM) sleep as does an immobilization stressor. Ether exposure before light onset or dark onset was followed by significant increases in REM sleep starting approximately 3-4 h later and lasting for several hours. Non-REM (NREM) sleep and electroencephalographic slow-wave activity during NREM sleep were not altered. Exposure to ether vapor elicited prolactin (Prl) secretion. REM sleep was not promoted after ether exposure in hypophysectomized rats. If the hypophysectomy was partial and the rats secreted Prl after ether exposure, then increases in REM sleep were observed. Intracerebroventricular administration of an antiserum to Prl decreased spontaneous REM sleep and inhibited ether exposure-induced REM sleep. The results indicate that a brief exposure to ether vapor is followed by increases in REM sleep if the Prl response associated with stress is unimpaired. This suggests that Prl, which is a previously documented REM sleep-promoting hormone, may contribute to the stimulation of REM sleep after ether exposure.     

Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep

Human dreaming occurs during rapid eye movement (REM) sleep. To investigate the structure of neural activity during REM sleep, we simultaneously recorded the activity of multiple neurons in the rat hippocampus during both sleep and awake behavior. We show that temporally sequenced ensemble firing rate patterns reflecting tens of seconds to minutes of behavioral experience are reproduced during REM episodes at an equivalent timescale. Furthermore, within such REM episodes behavior-dependent modulation of the subcortically driven theta rhythm is also reproduced. These results demonstrate that long temporal sequences of patterned multineuronal activity suggestive of episodic memory traces are reactivated during REM sleep. Such reactivation may be important for memory processing and provides a basis for the electrophysiological examination of the content of dream states.     

Effects of bromocriptine and alpha-flupenthixol on sleep in REM sleep deprived rats.

Administration of bromocriptine mesylate (5 mg/kg, i.p.), a dopamine receptor stimulant, to rats which were deprived of REM sleep for 24 hours resulted in a significant increase in wakefulness as well as significant reduction of REM sleep during the first 5 hours of EEG recording. These effects were completely abolished by pretreatment with α-flupenthixol (0.2 mg/kg, i.p.), a dopamine receptor blocker. The loss of REM sleep has not been regained during the next 25 hours of EEG recording suggesting that the stimulation of dopamine receptors reduced REM sleep without causing subsequent REM rebound. These data raise questions on the negative dopamine control of REM sleep and on the potential use of dopamine stimulants in clinical situations characterized by excessive REM or by REM sleep dysfunction (narcolepsy).     

Spectral analysis of the heart rate variability in sleep

Spectral analysis of heart rate variability (HRV) during overnight polygraphic recording was performed in 11 healthy subjects. The total spectrum power, power of the VLF, LF and HF spectral bands and the mean R-R were evaluated. Compared to Stage 2 and Stage 4 non-REM sleep, the total spectrum power was significantly higher in REM sleep and its value gradually increased in the course of each REM cycle. The value of the VLF component (reflects slow regulatory mechanisms, e.g. the renin-angiotensin system, thermoregulation) was significantly higher in REM sleep than in Stage 2 and Stage 4 of non-REM sleep. The LF spectral component (linked to the sympathetic modulation) was significantly higher in REM sleep than in Stage 2 and Stage 4 non-REM sleep. On the contrary, a power of the HF spectral band (related to parasympathetic activity) was significantly higher in Stage 2 and Stage 4 non-REM than in REM sleep. The LF/HF ratio, which reflects the sympathovagal balance, had its maximal value during REM sleep and a minimal value in synchronous sleep. The LF/HF ratio significantly increased during 5-min segments of Stage 2 non-REM sleep immediately preceding REM sleep compared to 5-min segments of Stage 2 non-REM sleep preceding the slow-wave sleep. This expresses the sympathovagal shift to sympathetic predominance occurring before the onset of REM sleep. A significant lengthening of the R-R interval during subsequent cycles of Stage 2 non-REM sleep was documented, which is probably related to the shift of sympathovagal balance to a prevailing parasympathetic influence in the course of sleep. This finding corresponds to a trend of a gradual decrease of the LF/HF ratio in subsequent cycles of Stage 2 non-REM sleep.     

Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men

Several investigators have observed that irregular breathing occurs during rapid-eye-movement (REM) sleep in healthy subjects, with ventilatory suppression being prominent during active eye movements [phasic REM (PREM) sleep] as opposed to tonic REM (TREM) sleep, when ocular activity is absent and ventilation more regular. Inasmuch as considerable data suggest that rapid eye movements are a manifestation of sleep-induced neural events that may importantly influence respiratory neurons, we hypothesized that upper airway dilator muscle activation may also be suppressed during periods of active eye movements in REM sleep. We studied six normal men during single nocturnal sleep studies. Standard sleep-staging parameters, ventilation, and genioglossus and alae nasi electromyograms (EMG) were continuously recorded during the study. There were no significant differences in minute ventilation, tidal volume, or any index of genioglossus or alae nasi EMG amplitude between non-REM (NREM) and REM sleep, when REM was analyzed as a single sleep stage. Each breath during REM sleep was scored as "phasic" or "tonic," depending on its proximity to REM deflections on the electrooculogram. Comparison of all three sleep states (NREM, PREM, and TREM) revealed that peak inspiratory genioglossus and alae nasi EMG activities were significantly decreased during PREM sleep compared with TREM sleep [genioglossus (arbitrary units): NREM 49 +/- 12 (mean +/- SE), TREM 49 +/- 5, PREM 20 +/- 5 (P less than 0.05, PREM different from TREM and NREM); alae nasi: NREM 16 +/- 4, TREM 38 +/- 7, PREM 10 +/- 4 (P less than 0.05, PREM different from TREM)]. We also observed, as have others, that ventilation, tidal volume, and mean inspiratory airflow were significantly decreased and respiratory frequency was increased during PREM sleep compared with both TREM and NREM sleep. We conclude that hypoventilation occurs in concert with reduced upper airway dilator muscle activation during PREM sleep by mechanisms that remain to be established.