REM sleep function: Mythology vs. reality.

Since the discovery of REM (Rapid Eye Movement) sleep in 1953, misconceptions have arisen as to the evidence for its adaptive function and its relation to dreams. Eye movements recorded during REM sleep have not been consistently reported to mirror the eye movements predicted by dream reports. But evidence on eye movement and somatic motor expression from patients with REM sleep behavior disorder (RBD) is consistent with dream enacting behavior. The assumption that dreaming occurs only in REM sleep is incorrect, with numerous reports of nonREM dreaming. However, there may be qualitative differences between REM and nonREM dreams. Early studies that suggested a vital role for REM sleep in psychological well-being are refuted by studies of pharmacologically induced partial or complete REM sleep suppression. Studies of sleep across species show that the primitive monotreme mammals, platypus and echidna, have far more REM sleep than any other homeotherm group, whereas birds have far less REM sleep than any other homeotherm group. Human REM sleep amounts are not unusual, are correlated with nonREM sleep durations but are not correlated with intelligence. Across groups of homeotherms, REM sleep time is highly and inversely correlated (r=-0.975, P=0.02) with average core body temperature, suggesting that REM sleep cycles with nonREM sleep to regulate brain temperature during sleep. Cetacean mammals (dolphins and whales) do not have REM sleep despite their very large brain sizes and impressive cognitive abilities. Reports of "REM sleep-like states" in arachnids, cephalopods and in zebrafish larvae are lacking critical evidence that the observed behaviors are occurring during sleep and that the behaviors are homologous to mammalian REM sleep.

Sleep with Open Eyes in Two Species of Deer, the Indian Sambar (Rusa unicolor) and Sika Deer (Cervus nippon).

The relationship between postures, sleep stages and eye state was established in two species of deer, the Indian sambar (Rusa unicolor) and sika deer (Cervus nippon), based on video recording. In both species, the state of rest or behavioral sleep was recorded in the sternal position, holding the head above the ground, and in the lateral position, with the head resting on the croup or on the ground. Rest accounted for at least 80% of the time in these positions. Based on behavior criteria a substantial portion of rest represented slow-wave sleep. Episodes of rapid eye movements (REM sleep) were recorded in the lateral position. They did not exceed 2 min. When the deer were in the sternal posture, they kept their eyes open most of the time: in average 96% of the time in sambars and 82% in sika deer. Episodes of the open eye in this posture lasted up to 8.4 min in sambars and up to 3.3 min in sika deer. In the lateral position, such episodes were 4 and 1.5 times shorter. Sleeping with open eyes in ungulates may be an important mechanism of maintaining vigilance.

Characteristics of Sleep-Wakefulness Cycle and Circadian Activity in the Lesser Mouse-Deer (Tragulus kanchil).

The pattern of sleep and circadian activity of the lesser mouse-deer (Tragulus kanchil) that is the smallest (body mass between 1.5 and 2.2 kg) representative of the basal group (Tragulidae) of even-toed ungulates which evolved 40-50 Ma were studied. In naturalistic conditions, a total of 30 days of full-day video of the animal behavior and 15 days of 24-h polysomnographic data were collected in 6 animals. The mouse-deer were active less than 20% of 24 h and were quiescent during 60-80% of the remaining time. Slow wave sleep (SWS) accounted for on average 49.7 ± 3.7% of 24 h and paradoxical (rapid eye movement, REM) sleep accounted for 1.7 ± 0.3% of 24 h. During the majority of SWS (87.0 ± 4.4%) the eyes were open. The most of SWS and REM sleep occurred during the daytime hours (9 a.m. to 4 p.m.) and in the first half of the night (8 p.m. to 2 a.m.); the animals were most active during twilight hours (4-6 a.m. and 6-7 p.m.). We suggest that the main features of sleep in the mouse-deer are largely determined by ecological factors, including environmental temperature and predation, as well as the size and physiology of the mouse-deer.

Evaluation of the ability of northern fur seals to perceive and visually discriminate images under the conditions of sleep loss.

This is the first study estimating the ability of sea mammals to perceive and analyze information under the conditions of an almost complete sleep deprivation.

Cerebrospinal fluid hypocretin (orexin) levels are elevated by play but are not raised by exercise and its associated heart rate, blood pressure, respiration or body temperature changes.

Hypocretin (Hcrt) has been implicated in the control of motor activity and in respiration and cardiovascular changes. Loss of Hcrt in narcolepsy is linked to sleepiness and to cataplexy, a sudden loss of muscle tone which is triggered by sudden strong emotions. In the current study we have compared the effects of treadmill running, to yard play on cerebrospinal fluid (CSF) Hcrt level in normal dogs. We find that treadmill locomotion, at a wide range of speeds, does not increase Hcrt level beyond baseline, whereas yard play produces a substantial increase in Hcrt, even though both activities produce comparable increases in heart rate, respiration and body temperature. We conclude that motor and cardiovascular changes are not sufficient to elevate CSF levels of Hcrt and we hypothesize that the emotional aspects of yard play account for the observed increase in Hcrt.

Modulation of hypothalamus and amygdalar activation levels with stimulus valence.

In spite of long-standing evidence showing that the hypothalamus is instrumental in generating behaviors associated with positive and negative emotions, little is known about the role of the hypothalamus in normal human emotional processing. Recent findings have suggested that the hypothalamus plays a role beyond mere control of HPA-axis function; this is also supported by the existence of rich anatomical connections between the hypothalamus and the amygdala, a region known for its important role in emotional processing. However, evidence of emotion-induced hypothalamic activity from neuroimaging studies has been inconsistent, possibly due to methodological limitations (e.g., low spatial resolution). Taking advantage of recent improvements in fMRI technology we set out to explore a possible valence-dependent modulation of hypothalamic activity. Using second order parametric analysis of high-resolution BOLD fMRI, we assessed hypothalamic activation patterns during passive viewing of visual stimuli of varying valence, and compared the results with the activity pattern in the amygdalae, i.e. nuclei with known valence-dependent activity profiles. We show that both hypothalamic and amygdalar activation is modulated by the second-order stimulus valence term, i.e., there is increased neural activity following the processing of both positive and negative stimuli. Our results suggest that the hypothalamus may serve a role in generating emotions broader than generally assumed.

The REM sleep-memory consolidation hypothesis.

It has been hypothesized that REM (rapid eye movement) sleep has an important role in memory consolidation. The evidence for this hypothesis is reviewed and found to be weak and contradictory. Animal studies correlating changes in REM sleep parameters with learning have produced inconsistent results and are confounded by stress effects. Humans with pharmacological and brain lesion-induced suppression of REM sleep do not show memory deficits, and other human sleep-learning studies have not produced consistent results. The time spent in REM sleep is not correlated with learning ability across humans, nor is there a positive relation between REM sleep time or intensity and encephalization across species. Although sleep is clearly important for optimum acquisition and performance of learned tasks, a major role in memory consolidation is unproven.

Pontine reticular formation neurons: relationship of discharge to motor activity.

The discharge correlates of pontine reticular formation units were investigated in unrestrained cats. In agreement with previous investigations using immobilized preparations, we found that these cells had high rates of activity in rapid eye movement sleep, and responded in waking to somatic, auditory, and vestibular stimuli at short latencies, many having polysensory responses and exhibiting rapid "habituation." However, despite the sensory responses of these cells, most unit activity could not be explained by the presence of sensory stimuli. Intense firing occurred in association with specific movements. Units deprived of their adequate somatic, vestibular, and auditory stimuli showed undiminished discharge rates during motor activity. Discrete sensory stimuli evoked sustained unit firing only when they also evoked a motor response. We conclude that activity in pontine reticular formation neurons is more closely related to motor output than to sensory input.

Brainstem neurons without spontaneous unit discharge.

A new class of single neurons showing no spontaneous activity in waking, rapid eye movement sleep, and slow-wave sleep was found in the brainstem of unrestrained cats. Systematic testing showed that these cells discharge only in response to specific stimuli and remain silent for as long as 40 minutes in the absence of stimulation. Silent cells were widely distributed in the pons and midbrain and constituted a major percentage of observed neurons. The economy of discharge shown by these cells contrasts with the spontaneous activity of virtually all other neurons that have been observed in the brains of unrestrained animals and suggests the widespread existence of specialized neural systems that show only phasic activity.

Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.

Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.

[Rest and activity states in the Commerson's dolphin (Cephalorhynchus commersonii)].

The unihemispheric slow-wave sleep, the ability to sleep during swimming with one open eye and the absence of paradoxical sleep in the form of it is observed in all terrestrial mammals are unique features of sleep in cetaceans. Visual observations supplement electrophysiological studies and allow obtaining novel data about sleep of cetaceans. In the present study we examined behavior of 3 adult Commerson's dolphins Cephalorhynchus commersonii which were housed in the oceanarium Sea-World (San Diego, USA). The behavior of the dolphins can be subdivided into 5 swimming types: 1) active swimming marked by variable speed and irregular trajectory of movement (on average for 3 dolphins 35.1 +/- 2.7% of the 24-h period) was scored as active wakefulness; 2) circular swimming was divided into slow and fast swimming and occupied, on average, 44.4 +/- 3.8 and 9.7 +/- 0.8% of the 24-h period, respectively; while in circular swimming, dolphins swam from 1 to 6 circles on one respiration pause; 3) quiet chaotic swimming (3.9 +/- 1.2%) that occurred at the bottom and was not accompanied by signs of activity; 4) floating, and 5) slow swimming at the surface (4.1 +/- 0.5 and 2.8 +/- 0.4%), respectively; the latter two swimming types were accompanied by frequent respiration (hyperventilation). We suggest that sleep in Commerson's dolphins occurred predominantly during the circular and quiet swimming. From time to time the dolphins slowed down their speeds and even stopped for several seconds. Such episodes appeared to be the deepest sleep episodes. In all dolphins muscle jerks as well erections in the male were observed. Jerks and erections occurred during the circular and quiet chaotic swimming. Similar to other studied small cetaceans, Commerson's dolphins are in a state of almost uninterrupted swimming during 24 h per day and they sleep during swimming. Some muscle jerks that we observed in the dolphins in this study might have been episodes of paradoxical sleep.

Reduced number of hypocretin neurons in human narcolepsy.

Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin) precursor or Hcrt receptor genes. In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the Hcrt system. Thus, the cause of human narcolepsy remains unknown. Here we show that human narcoleptics have an 85%-95% reduction in the number of Hcrt neurons. Melanin-concentrating hormone (MCH) neurons, which are intermixed with Hcrt cells in the normal brain, are not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons. The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the Hcrt cell loss in narcolepsy.

Neurotoxic lesions at the ventral mesopontine junction change sleep time and muscle activity during sleep: an animal model of motor disorders in sleep.

There is no adequate animal model of restless legs syndrome (RLS) and periodic leg movements disorder (PLMD), disorders affecting 10% of the population. Similarly, there is no model of rapid eye movement (REM) sleep behavior disorder (RBD) that explains its symptoms and its link to Parkinsonism. We previously reported that the motor inhibitory system in the brainstem extends from the medulla to the ventral mesopontine junction (VMPJ). We now examine the effects of damage to the VMPJ in the cat. Based on the lesion sites and the changes in sleep pattern and behavior, we saw three distinct syndromes resulting from such lesions; the rostrolateral, rostromedial and caudal VMPJ syndromes. The change in sleep pattern was dependent on the lesion site, but was not significantly correlated with the number of dopaminergic neurons lost. An increase in wakefulness and a decrease in slow wave sleep (SWS) and REM sleep were seen in the rostrolateral VMPJ-lesioned animals. In contrast, the sleep pattern was not significantly changed in the rostromedial and caudal VMPJ-lesioned animals. All three groups of animals showed a significant increase in periodic and isolated leg movements in SWS and increased tonic muscle activity in REM sleep. Beyond these common symptoms, an increase in phasic motor activity in REM sleep, resembling that seen in human RBD, was found in the caudal VMPJ-lesioned animals. In contrast, the increase in motor activity in SWS in rostral VMPJ-lesioned animals is similar to that seen in human RLS/PLMD patients. The proximity of the VMPJ region to the substantia nigra suggests that the link between RLS/PLMD and Parkinsonism, as well as the progression from RBD to Parkinsonism may be mediated by the spread of damage from the regions identified here into the substantia nigra.

Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study.

A complete suppression of muscle tone in the postural muscles and a reduction of muscle tone in the respiratory related musculature occur in rapid eye movement (REM) sleep. Previous studies have emphasized the role of glycine in generating these changes. Because the activity of norepinephrine- and serotonin-containing neurons is known to decrease in REM sleep, we hypothesized that a decrease in release in one or both of these transmitters might be detected at the motoneuronal level during muscle tone suppression elicited by brainstem stimulation in the decerebrate animal. We compared release in the ventral horn with that in the hypoglossal nucleus to determine whether the mechanism of muscle tone suppression differs in these nuclei as has been hypothesized. Electrical stimulation and cholinergic agonist injection into the mesopontine reticular formation produced a suppression of tone in the postural and respiratory muscles and simultaneously caused a significant reduction of norepinephrine and serotonin release of similar magnitude in both hypoglossal nucleus and spinal cord. Norepinephrine and serotonin release in the motoneuron pools was unchanged when the stimulation was applied to brainstem areas that did not generate bilateral suppression. No change in dopamine release in the motoneuron pools was seen during mesopontine stimulation-induced atonia. We hypothesize that the reduction of monoamine release that we observe exerts a disfacilitatory effect on both ventral horn and hypoglossal motoneurons and that this disfacilitatory mechanism contributes to the muscle atonia elicited in the decerebrate animal and in the intact animal during REM sleep.

Activation of pontine and medullary motor inhibitory regions reduces discharge in neurons located in the locus coeruleus and the anatomical equivalent of the midbrain locomotor region.

Activation of the pontine inhibitory area (PIA) including the middle portion of the pontine reticular nucleus, oral part (PnO), or the gigantocellular reticular nucleus (Gi) suppresses muscle tone in decerebrate animals. The locus coeruleus (LC) and midbrain locomotor region (MLR) have been implicated in the facilitation of muscle tone. In the current study we investigated whether PIA and Gi stimulation causes changes in activity in these brainstem motor facilitatory systems. PIA stimulation evoked bilateral muscle tone suppression and inhibited 26 of 28 LC units and 33 of 36 tonically active units located in the anatomical equivalent of the MLR (caudal half of the cuneiform nucleus and the pedunculopontine tegmental nucleus). Gi stimulation evoked bilateral suppression of hindlimb muscle tone and inhibited 20 of 35 LC units and 24 of 24 neurons located in the MLR as well as facilitated 11 of 35 LC units. GABA and glycine release in the vicinity of LC was increased by 20-40% during ipsilateral PnO stimulation inducing hindlimb muscle tone suppression on the same side of the body. We conclude that activation of pontine and medullary inhibitory regions produces a coordinated reduction in the activity of the LC units and neurons located in the MLR related to muscle tone facilitation. The linkage between activation of brainstem motor inhibitory systems and inactivation of brainstem facilitatory systems may underlie the reduction in muscle tone in sleep as well as the modulation of muscle tone in the isolated brainstem.

Glutamatergic and cholinergic projections to the pontine inhibitory area identified with horseradish peroxidase retrograde transport and immunohistochemistry.

Previous studies in our laboratory have shown that microinjection of acetylcholine and non-N-methyl-D-aspartate (NMDA) glutamate agonists into the pontine inhibitory area (PIA) induce muscle atonia. The present experiment was designed to identify the PIA afferents that could be responsible for these effects, by use of retrograde transport of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP), glutamate immunohistochemistry and NADPH-diaphorase staining techniques. Experiments were performed in both decerebrate and intact cats. Dense retrograde WGA-HRP labelling was found in neurons in the periaqueductal gray (PAG) and mesencephalic reticular formation (MRF) at the red nucleus (RN) level, ventral portion of paralemniscal tegmental field (vFTP), retrorubral nucleus (RRN), contralateral side of PIA (cPIA), pontis reticularis centralis caudalis (PoC), and most rostral portion of the nucleus parvicellularis (NPV) and nucleus praepositus hypoglossi (PH) at the level of the pontomedullary junction; moderate labelling was seen in pedunculopontine nucleus, pars compacta (PPNc), laterodorsal tegmental nucleus (LDT), superior colliculus (SC), MRF and PAG at the level caudal to RN, medial and superior vestibular nuclei, and principle sensory trigeminal nucleus (5P); and light labelling was seen in dorsal raphe (DR) and locus coeruleus complex (LCC). The projection neurons were predominantly ipsilateral to the injection site, except for both vFTP and RRN, which had more projection cells on the contralateral side. Double labelled WGA-HRP/NADPH-d neurons could be found in PPNc and LDT. Double labelled WGA-HRP/glutamatergic neurons could be seen at high densities in MRF, RRN, vFTP, and cPIA, moderate densities in SC, LDT, PPNc, PoC, and NPV, and low densities in PH, 5P, DR, LCC, and PAG.(ABSTRACT TRUNCATED AT 250 WORDS)

Brainstem projections to the ventromedial medulla in cat: retrograde transport horseradish peroxidase and immunohistochemical studies.

Stimulation of the nucleus magnocellularis (NMC) of the medulla produces changes in locomotion, muscle tone, heart rate, and blood pressure. Glutamatergic input has been found to modulate muscle tone, whereas cholinergic input has been found to mediate cardiovascular changes produced by stimulation of the NMC. The current study was designed to identify the brainstem afferents to NMC by using retrograde transport of wheat germ agglutinin and horseradish peroxidase (WGA-HRP) combined with glutamate and choline acetyltransferase (ChAT) immunohistochemical and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemical techniques. Fifty nanoliters of 2.5% WGA-HRP were microinjected into the NMC in the cat. A heavy density of WGA-HRP-labeled neurons was found in the ipsilateral mesencephalic reticular formation (MRF), periaqueductal gray, Kolliker-Fuse nucleus, and pontis centralis caudalis (PoC), in the contralateral pontis centralis oralis (PoO), and bilaterally in the nucleus paragigantocellularis lateralis. A moderate density of retrogradely labeled neurons was found in the ipsilateral side of the nuclei parvocellularis, retrorubral (RRN), PoO, and vestibular complex, in the contralateral PoC and nucleus gigantocellularis, and bilaterally in the inferior vestibular nucleus. Retrograde HRP/glutamate-positive cells could be found throughout the brainstem, with a high percentage in RRN, PoO, PoC, and MRF. Double-labeled WGA-HRP/ChAT neurons were found in the pedunculopontine nucleus. Double-labeled WGA-HRP/NADPH-d-positive neurons could be seen in many nuclei of the brainstem, although the number of labeled neurons was small. The dense glutamatergic projections to the NMC support the hypothesis that rostral brainstem glutamatergic mechanisms regulate muscle activity and locomotor coordination via the NMC, whereas the pontine cholinergic projections to the NMC participate in cardiovascular regulation.

A brief history of hypocretin/orexin and narcolepsy.

The hypothalamic peptides named the orexins, or hypocretins, were discovered in 1998. In 1999 it was established that genetic narcolepsy could be caused by mutations in the genes synthesizing these peptides or their receptors. In September of 2000 it was found that most human narcolepsy is caused by loss of hypocretin cells, most likely as a result of a degenerative process. This paper reviews these events and their implications for our understanding of brain arousal and motor control systems.

GABA release in the locus coeruleus as a function of sleep/wake state.

GABA, glutamate, and glycine release in the locus coeruleus were measured as a function of sleep/wake state in the freely-behaving cat using the microdialysis technique. GABA release was found to increase during rapid-eye-movement sleep as compared to waking values. GABA release during slow-wave sleep was intermediate between that of waking states and rapid-eye-movement sleep. The concentration of glutamate and glycine in microdialysis samples was unchanged across sleep and wake states. Our findings are consistent with the hypothesis that GABAergic inhibition is responsible for the cessation of discharge in locus coeruleus neurons during REM sleep. The data suggest that a population of GABAergic neurons innervating the locus coeruleus are selectively active during rapid-eye-movement sleep.