Extension of the Limit Cycle Reciprocal Interaction Model of REM cycle control. An integrated sleep control model

SUMMARY  The Limit Cycle Reciprocal Interaction Model (LCRIM) describes the stable interaction of REM-promoting and REM-antagonizing neurons which generates the periodic occurrence of REM sleep. The cycling of this physiological oscillator is subject to perturbation from excitatory input, referred to as E , which derives from other parts of the nervous system. An extended model is now proposed which combines the ultraradian REM regulation modelled by the LCRIM with the homeostatic regulation of slow-wave activity modelled by the Two-Process Models of Borbély, Achermann and Beersma. In addition, this integrated model extends the E construct to relate explicitly to both the REM and slow-wave sleep control systems, and to have stochastic dynamics. Overall, the model generates qualitatively realistic SWA, REM and wake-up patterns. However, its performance awaits quantitative validation.     

Parabrachial neuron discharge in the cat is altered during the carbachol-induced REM sleep-like state (DCarb)

Pontine parabrachial neurons have been suggested to play a regulatory role in both respiratory and sleep cycle control. Encouraged by the finding that microinjections of the cholinergic agonist carbachol into the medial pontine reticular formation (mPRF) of the cat produced respiratory changes paralleling those observed during rapid eye movement (REM) sleep (Neurosci. Lett., 102 (1989) 211–216), this study tested the hypothesis that cholinergic mechanisms in the mPRF can also cause state-dependent changes in the discharge of parabrachial neurons. This paper describes extracellular recordings of parabrachial neurons during REM sleep and during the carbachol-induced REM sleep-like state (DCarb). Cells which were activated (REM-on) or inactivated (REM-off) during REM maintained these same state-dependent firing patterns during the DCarb state. These results support the hypothesis that cholinergic mechanisms in the mPRF can cause state-dependent changes in the discharge of parabrachial neurons.     

Symposium: Normal and abnormal REM sleep regulation: REM sleep in depression-an overview

Abnormalities of REM sleep, i.e. shortening of REM latency, lengthening of the duration of the first REM period and heightening of REM density, which are frequently observed in patients with a major depressive disorder (MDD), have attracted considerable interest. Initial hopes that these aberrant patterns of sleep constitute specific markers for the primary/endogenous sub-type of depression have not been fulfilled. The specificity of REM sleep disinhibition for depression in comparison with other psychopathological groups is challenged as well. Demographic variables like age and sex exert strong influences on sleep physiology and must be controlled when searching for specific markers of depressed sleep. It is still an open question whether abnormalities of sleep are state- or trait-markers of depression. Beyond baseline studies, the cholinergic REM induction test (CRIT) indicated a heightened responsitivity of the REM sleep system to cholinergic challenge in depression compared with healthy controls and other psychopathological groups, with the exception of schizophrenia. A special role for REM sleep in depression is supported by the well-known REM sleep suppressing effect of most antidepressants. The antidepressant effect of selective REM deprivation by awakenings stresses the importance of mechanisms involved in REM sleep regulation for the understanding of the pathophysiology of depressive disorders. The positive effect of total sleep deprivation on depressive mood which can be reversed by daytime naps, furthermore emphasizes relationships between sleep and depression. Experimental evidence as described above instigated several theories like the REM deprivation hypothesis, the 2-process model and the reciprocal interaction model of nonREM-REM sleep regulation to explain the deviant sleep pattern of depression. The different models will be discussed with reference to empirical data gathered in the field.     

Neurochemical perspectives on the control of breathing during sleep

A specific depression of minute ventilation occurs during sleep in normal subjects. This sleep-related ventilatory depression is partially related to mechanical events and upper airway atonia but some data also indicate that it is likely to be centrally mediated. This paper reviews the anatomical and neurochemical connections between sleep/wake- and respiratory-related areas in an attempt to identify the potential implication of sleep-related neurochemicals (serotonin, catecholamines, GABA, acetylcholine) in the sleep-related hypoventilation. The review of available data suggests that the sleep-related ventilatory depression depends upon the enhanced GABAergic activity together with a loss of suprapontine influence depending on the cessation of activity of the reticular formation. During REM sleep, an additional inhibitory activity emerges from the pontine cholinergic neurons, which contributes to the breathing irregularities and the associated depression of minute ventilation and ventilatory response to chemical stimuli. This model may contribute to a better understanding of the neurochemical environment of respiratory neurons during sleep, which remains a question of importance regarding the numerous pathological states that are linked to specific perturbations of breathing control during sleep.     

Intrinsic dreams are not produced without REM sleep mechanisms: evidence through elicitation of sleep onset REM periods

The hypothesis that there is a strict relationship between dreams and a specific rapid eye movement (REM) sleep mechanism is controversial. Many researchers have recently denied this relationship, yet none of their studies have simultaneously controlled both sleep length and depth prior to non-REM (NREM) and REM sleep awakenings, due to the natural rigid order of the NREM--REM sleep cycle. The failure to control sleep length and depth prior to arousal has confounded interpretations of the REM-dreams relationship. We have hypothesised that different physiological mechanisms underlie dreaming during REM and NREM sleep, based on recent findings concerning the specificity of REM sleep for cognitive function. Using the Sleep Interruption Technique, we elicited sleep onset REM periods (SOREMP) from 13 normal subjects to collect SOREMP and sleep onset NREM (NREMP) dreams without the confounds described above. Regression analyses showed that SOREMP dream occurrences were significantly related to the amount of REM sleep, while NREMP dream occurrences were related to arousals from NREM sleep. Dream properties evaluated using the Dream Property Scale showed qualitative differences between SOREMP and NREMP dream reports. These results support our hypothesis and we have concluded that although 'dreaming' may occur during both REM and NREM periods as previous researchers have suggested, the dreams obtained from these distinct periods differ significantly in their quantitative and qualitative aspects and are likely to be produced by different mechanisms.     

Pontine cholinergic mechanisms and their impact on respiratory regulation

Activation of pontomedullary cholinergic neurons may directly and indirectly cause depression of respiratory motoneuronal activity, activation of respiratory premotor neurons and acceleration of the respiratory rate during REM sleep, as well as activation of breathing during active wakefulness. These effects may be mediated by distinct subpopulations of cholinergic neurons. The relative inactivity of cholinergic neurons during slow-wave sleep also may contribute to the depressant effects of this state on breathing. Cholinergic muscarinic and nicotinic receptors are expressed in central respiratory neurons and motoneurons, thus allowing cholinergic neurons to act on the respiratory system directly. Additional effects of cholinergic activation are mediated indirectly by noradrenergic, serotonergic and other neurons of the reticular formation. Excitatory and suppressant respiratory effects with features of natural states of REM sleep or active wakefulness can be elicited in urethane-anesthetized rats by pontine microinjections of the cholinergic agonist, carbachol. Carbachol models help elucidate the neural basis of respiratory disorders associated with central cholinergic activation.     

REM-NREM cycle in the cat may be sleep-dependent

The periodicity of the rapid eye movement-nonrapid eye movement (REM-NREM) cycle in real time versus compressed sleep was determined by autocorrelation, computed on the sequence of sleep stages in recordings from spontaneously sleeping cats. The resulting autocorrelation function was correlated to damped cosine waves, and the highest squared correlation coefficient (r2) was taken as indicating the most likely periodicity in the data entered for each animal. The periodicity of REM sleep was stronger (significantly higher r2) in the compressed sleep data than in the real-time data, indicating sleep dependency of the REM-NREM cycle. The REM-NREM cycle lengths determined by the autocorrelation technique were not significantly different for the real-time and compressed sleep data. The REM sleep episode interval, defined as the average interval between the start of successive REM sleep episodes, was significantly shorter for real-time sustained sleep than the cycle lengths as determined by the autocorrelation technique. A model is proposed which explains this phenomenon as due to fragmentation of REM sleep within the time periods with high probability for REM sleep. When such fragmentation occurs, the average REM sleep episode interval will not reflect an ultradian REM sleep periodicity.     

Sleep cycle organization in narcoleptic and normal dogs.

The normal sleep-wake patterns of four narcoleptic and four normal dogs were recorded electrographically for 48 hours in a laboratory setting. The amount of the various stages of vigilance (wake, light slow wave sleep, deep slow wave sleep and REM sleep) were similar for both sets of dogs except that narcoleptic dogs has significantly less REM sleep and had an additional state scored as cataplexy. Mean episode durations and the number of episodes per 48 hr were not significantly different except that narcoleptic dogs had fewer REM episodes and a trend toward more waking episodes. There was a significant difference in the state progression between normal and narcoleptic dogs before and after REM episodes. Narcoleptic dogs had an increase in LSWS and a decrease in DSWS during the last 5 min before REM sleep onset in comparison to the reverse pattern in controls. In the stages following REM there was a marked elevation of wakefulness in narcoleptic dogs. These data support the notion that narcolepsy is a sleep disorder characterized by a disruption of the normal sleep-wake cycle. These results parallel similar findings in humans and provide strong evidence that this disease entity is similar in man and dog.     

Application of histamine or serotonin to the hypoglossal nucleus increases genioglossus muscle activity across the wake–sleep cycle

The decrease in genioglossus (GG) muscle activity during sleep, especially rapid eye movement (REM) or paradoxical sleep, can lead to airway occlusion and obstructive sleep apnoea (OSA). The hypoglossal nucleus innervating the GG muscle is under the control of serotonergic, noradrenergic and histaminergic neurons that cease firing during paradoxical sleep. The objectives of this study were to determine the effect on GG muscle activity during different wake–sleep states of the microdialysis application of serotonin, histamine (HA) or noradrenaline (NE) to the hypoglossal nucleus in freely moving cats. Six adult cats were implanted with electroencephalogram, electro-oculogram and neck electromyogram electrodes to record wake–sleep states and with GG muscle and diaphragm electrodes to record respiratory muscle activity. Microdialysis probes were inserted into the hypoglossal nucleus for monoamine application. Changes in GG muscle activity were assessed by power spectrum analysis. In the baseline conditions, tonic GG muscle activity decreased progressively and significantly from wakefulness to slow-wave sleep and even further during slow-wave sleep with ponto-geniculo-occipital waves and paradoxical sleep. Application of serotonin or HA significantly increased GG muscle activity during the wake–sleep states when compared with controls. By contrast, NE had no excitatory effect. Our results indicate that both serotonin and HA have a potent excitatory action on GG muscle activity, suggesting multiple aminergic control of upper airway muscle activity during the wake–sleep cycle. These data might help in the development of pharmacological approaches for the treatment of OSA.     

Renin as a biological marker of the NREM-REM sleep cycle: effect of REM sleep suppression

SUMMARY  We have previously described that, in normal man, the nocturnal oscillations of plasma renin activity (PRA) exactly reflect the rapid eye movement (REM)–non(N)REM sleep cycles, with increasing PRA levels during NREM sleep and decreasing levels during REM sleep. This study was carried out to determine whether REM sleep suppression affects nocturnal renin profiles and to define which sleep stage is essential for renin release.
In a first experimental series, REM sleep was suppressed by using clomipramine, a tricyclic antidepressant. Seven healthy young men were studied once during a night when a placebo was given and once during a night following a single dose of 50 mg clomipramine. Blood was collected every 10 min from 23.00 hours to 07.00 hours. PRA was measured by radio-immunoassay and the nocturnal profiles were analysed using the pulse detection program ULTRA. Clomipramine suppressed REM sleep in all subjects but one, but did not affect the number of SWS episodes nor their duration. Similar PRA profiles were observed in both experimental conditions. Neither the mean levels, nor the number and the amplitude of the oscillations were modified and the normal relationship between slow wave sleep and increasing PRA levels was preserved.
In a second experimental series, REM sleep was prevented by rapidly awakening the subjects as soon as they fell into REM sleep. The four subjects studied attempted several times to go into REM sleep, but only when PRA levels were decreasing. The interruption of REM sleep by short waking periods did not disturb PRA for which the oscillations remained unaffected. Again, the relationship between SWS and increasing PRA levels was preserved.
These results provide evidence that mechanisms increasing slow-wave activity are principally involved in increasing PRA levels and that replacing REM sleep by waking periods and light sleep does not modify nocturnal PRA oscillations.     

Induction of rapid eye movement sleep by neurotrophin-3 and its co-localization with choline acetyltransferase in mesopontine neurons

Because neurotrophin-3 (NT-3), a neurotrophic factor closely related to nerve growth factor, is capable of modulating neuronal activity [Yamuy et al., Neuroscience 95 (2000a) 1089-1100], we sought to examine if the microinjection of NT-3 into the nucleus reticularis pontis oralis (NPO) of chronically prepared cats also induced changes in behavior. In contrast to vehicle administration, NT-3 injection induced, with a mean latency of 4.7 min, long-duration episodes (mean, 21.6 min) of a state that was polygraphically indistinguishable from naturally occurring REM sleep. If NT-3 plays a physiologic role in the generation of REM sleep, then an endogenous source for this neurotrophin that is capable of controlling the activity of NPO neurons should exist. We therefore determined whether cholinergic neurons in the latero-dorsal and pedunculo-pontine tegmental (LDT and PPT) nuclei, which are involved in the initiation of REM sleep and project to the NPO, contained NT-3. Most, if not all, of the LDT-PPT cholinergic neurons exhibited NT-3 immunoreactivity. A portion (10%) of the NT-3+ neurons in the LDT-PPT were not cholinergic. The present data indicate that NT-3 rapidly modulates the activity of NPO neurons involved in REM sleep and that cholinergic neurons in the LDT and PPT contain NT-3. Taken together, these results support the hypothesis that NT-3 may be involved in the control of naturally occurring REM sleep.     

Sleep spindle frequency changes during the menstrual cycle

SUMMARY  Five healthy adult women aged 20 to 28 had 12–15 polysomnographic recordings, as well as daily basal body temperature and multiple LH, FSH, estrogen and progesterone measurements taken during a single menstrual cycle. Sleep stages were scored both visually and with a spindle and delta-wave, real-time, automatic analysing system. A cubic growth-curve model showed that the frequency of sleep spindles changed markedly over the menstrual cycle: spindle frequency was lowest about 18 days before onset of menses and highest 3 days before onset of menses. Slow waves did not change. The percentages of Stage 1 and REM sleep showed small changes during the menstrual cycle, and other parameters of visually scored sleep showed no tendency to change. Spindle frequency may reflect the effects of sex hormones on the reticular thalamic nucleus and may be a quantitative marker of premenstrual sleep disturbances.     

Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline

Cholinergic basal forebrain structures are implicated in cortical arousal and regulation of the sleep–wake cycle. Cholinergic neurones are innervated by noradrenergic terminals, noradrenaline excites them via alpha‐1 receptors and microinjection of noradrenaline into the basal forebrain enhances wakefulness. However, it is not known to what extent the cholinergic versus non‐cholinergic basal forebrain projection neurones contribute to the arousing effects of noradrenaline. To elucidate the roles of cholinergic basal forebrain structures we administered methoxamine, an alpha‐1‐adrenergic agonist into the basal forebrain, in intact animals and again after selective destruction of the basal forebrain cholinergic cells by 192 IgG‐saporin. In eight male Han–Wistar rats implanted with electroencephalogram/electromyogram electrodes, a microdialysis probe targeted into the basal forebrain was perfused with artificial cerebrospinal fluid for 6 h on a baseline day, and with cerebrospinal fluid in the first and with methoxamine in the second 3‐h period of the subsequent day. The sleep–wake activity was recorded for 24 h on both days. Saporin was then injected into the basal forebrain and 2 weeks later the same experimental schedule (with cerebrospinal fluid and methoxamine) was repeated. In the intact animals, methoxamine exhibited a robust arousing effect and non‐rapid eye movement (NREM) and REM sleep was suppressed. Lesioning of the basal forebrain cholinergic neurones abolished almost completely the NREM sleep‐suppressing effect of methoxamine, whereas the REM sleep‐suppressing effect remained intact. Thus, the basal forebrain cholinergic neurones mediate, at least in part, cortical arousal and non‐REM sleep‐suppression, but they are not involved in the REM sleep‐suppressing effects of noradrenaline.     

Microinjections of nicotine in the medial pontine reticular formation elicits REM sleep

Microinfusion of non-specific cholinergic muscarinic-nicotinic agonists, such as carbachol, into the medial pontine reticular formation readily elicits REM sleep. It has generally been assumed that muscarinic receptors mediate the action of cholinergic agonists in triggering rapid eye movement (REM) sleep. Very little is known, however, about the role of nicotinic mechanisms in REM sleep generation. In this study, we administered nicotine and Ringer's solution into the medial pontine reticular formation of freely moving cats. Compared to control Ringer's injections, nicotine increased REM sleep and decreased wake and slow wave sleep (SWS) I percentage. Nicotine also shortened the time to REM sleep onset. These findings suggest a role of nicotinic mechanisms in REM sleep generation.     

Sleep patterning and behaviour in cats with pontine lesions creating REM without atonia

SUMMARY  Lesions of the dorsal pontine tegmentum release muscle tone and motor behaviour, much of it similar to orienting during wakefulness, into rapid eye movement sleep (REM), a state normally characterized by paralysis. Sleep after pontine lesions may be altered, with more REM-A episodes of shorter duration compared to normal REM. We examined behaviour, ponto-geniculo-occipital (PGO) waves (which may be central markers of orienting) and sleep in lesioned cats: (i) to characterize the relationship of PGO waves to behaviour in REM-A; (ii) to determine whether post-lesion changes in the timing and duration of REM-A episodes were due to activity-related awakenings; and (iii) to determine whether alterations in sleep changed the circadian sleep/wake cycle in cats. Behavioural release in REM-A was generally related to episode length, but episode length was not necessarily shorter than normal REM in cats capable of full locomotion in REM-A. PGO wave frequency was reduced overall during REM-A, but was higher during REM-A with behaviour than during quiet REM-A without overt behaviour. Pontine lesions did not significantly alter the circadian sleep/wake cycle; REM-A had approximately the same Light/Dark distribution as normal REM. Differences in the patterning of normal REM and REM-A within sleep involve more than mere movement-induced awakenings. Brainstem lesions that eliminate the atonia of REM may damage neural circuitry involved in REM initiation and maintenance; this circuitry is separate from circadian control mechanisms.     

Upper Airway Collapsibility During REM Sleep in Children with the Obstructive Sleep Apnea Syndrome

Study Objectives:

In children, most obstructive events occur during rapid eye movement (REM) sleep. We hypothesized that children with the obstructive sleep apnea syndrome (OSAS), in contrast to age-matched control subjects, would not maintain airflow in the face of an upper airway inspiratory pressure drop during REM sleep.

Design:

During slow wave sleep (SWS) and REM sleep, we measured airflow, inspiratory time, inspiratory time/total respiratory cycle time, respiratory rate, tidal volume, and minute ventilation at a holding pressure at which flow limitation occurred and at 5 cm H₂O below the holding pressure in children with OSAS and in control subjects.

Setting:

Sleep laboratory.

Participants:

Fourteen children with OSAS and 23 normal control subjects.

Results:

In both sleep states, control subjects were able to maintain airflow, whereas subjects with OSAS preserved airflow in SWS but had a significant decrease in airflow during REM sleep (change in airflow of 18.58 ± 12.41 mL/s for control subjects vs −44.33 ± 14.09 mL/s for children with OSAS, P = 0.002). Although tidal volume decreased, patients with OSAS were able to maintain minute ventilation by increasing the respiratory rate and also had an increase in inspiratory time and inspiratory time per total respiratory cycle time

Conclusion:

Children with OSAS do not maintain airflow in the face of upper-airway inspiratory-pressure drops during REM sleep, indicating a more collapsible upper airway, compared with that of control subjects during REM sleep. However, compensatory mechanisms exist to maintain minute ventilation. Local reflexes, central control mechanisms, or both reflexes and control mechanisms need to be further explored to better understand the pathophysiology of this abnormality and the compensation mechanism.

Citation:

Huang J; Karamessinis LR; Pepe ME; Glinka SM; Samuel JM; Gallagher PR; Marcus CL. Upper airway collapsibility during REM sleep in children with the obstructive sleep apnea syndrome. SLEEP 2009;32(9):1173-1181.     

Increased apoptosis in rat brain after rapid eye movement sleep loss

Rapid eye movement (REM) sleep loss impairs several physiological, behavioral and cellular processes; however, the mechanism of action was unknown. To understand the effects of REM sleep deprivation on neuronal damage and apoptosis, studies were conducted using multiple apoptosis markers in control and experimental rat brain neurons located in areas either related to or unrelated to REM sleep regulation. Furthermore, the effects of REM sleep deprivation were also studied on neuronal cytoskeletal proteins, actin and tubulin. It was observed that after REM sleep deprivation a significantly increased number of neurons in the rat brain were positive to apoptotic markers, which however, tended to recover after the rats were allowed to undergo REM sleep; the control rats were not affected. Further, it was also observed that REM sleep deprivation decreased amounts of actin and tubulin in neurons confirming our previous reports of changes in neuronal size and shape after such deprivation. These findings suggest that one of the possible functions of REM sleep is to protect neurons from damage and apoptosis.     

Short-term homeostasis of REM sleep assessed in an intermittent REM sleep deprivation protocol in the rat

An intermittent rapid eye movement (REM) sleep deprivation protocol was applied to determine whether an increase in REM sleep propensity occurs throughout an interval without REM sleep comparable with the spontaneous sleep cycle of the rat. Seven chronically implanted rats under a 12 : 12 light-dark schedule were subjected to an intermittent REM sleep deprivation protocol that started at hour 6 after lights-on and lasted for 3 h. It consisted of six instances of a 10-min REM sleep permission window alternating with a 20-min REM sleep deprivation window. REM sleep increased throughout the protocol, so that total REM sleep in the two REM sleep permission windows of the third hour became comparable with that expected in the corresponding baseline hour. Attempted REM sleep transitions were already increased in the second deprivation window. Attempted transitions to REM sleep were more frequent in the second than in the first half of any 20-min deprivation window. From one deprivation window to the next, transitions to REM sleep changed in correspondence to the amount of REM sleep in the permission window in-between. Our results suggest that: (i) REM sleep pressure increases throughout a time segment similar in duration to a spontaneous interval without REM sleep; (ii) it diminishes during REM sleep occurrence; and (iii) that drop is proportional to the intervening amount of REM sleep. These results are consistent with a homeostatic REM sleep regulatory mechanism that operates in the time scale of spontaneous sleep cycle.     

Short-term REM sleep deprivation increases acetylcholinesterase activity in the medulla of rats

Involvement of cholinergic ponto-medullary brainstem mechanism regulating rapid eye movement (REM) sleep is known. Recently it was found that though short term REM deprivation influenced brainstem neuronal excitability, the activity of the brainstem acetylcholinesterase was not affected until after 96 h deprivation. Therefore, it was hypothesized that short-term REM deprivation might influence acetylcholinesterase in a restricted brainstem region. Results of this study show that the enzyme activity increased only in the medulla after 24 and 48 h REM deprivation. The flower pot technique was used for depriving the experimental rats of REM sleep. Suitable control experiments were conducted to rule out the possibility of non-specific effects. Thus, the medullary cholinergic mechanism probably is more important for REM.     

The effects of 1 week of REM sleep deprivation on parvalbumin and calbindin immunoreactive neurons in central visual pathways of kittens

Many maturational processes in the brain are at high levels prenatally as well as neonatally before eye-opening, when extrinsic sensory stimulation is limited. During these periods of rapid brain development, a large percentage of time is spent in rapid eye movement (REM) sleep, a state characterized by high levels of endogenously produced brain activity. The abundance of REM sleep in early life and its ensuing decline to lower levels in adulthood strongly suggest that REM sleep constitutes an integral part of the activity-dependent processes that enable normal physiological and structural brain development. We examined the effect of REM sleep deprivation during the critical period for visual development on the development of two calcium-binding proteins that are associated with developmental synaptic plasticity and are found in the lateral geniculate nucleus (LGN) and visual cortex. In this study, REM sleep deprivation was carried out utilizing a computer-controlled, cage-shaking apparatus that successfully suppressed REM sleep. Body weight data suggested that this method of REM sleep deprivation produced less stress than the classical multiple-platform-over-water method. In REM sleep-deprived animals with normal binocular vision, the number of parvalbumin-immunoreactive (PV) neurons in LGN was found to be lower compared with control animals but was not affected in visual cortex. The pattern of calbindin-immunoreactivity (CaB) was unchanged at either site after REM sleep deprivation. Parvalbumin-immunoreactivity develops later than calbindin-immunoreactivity in the LGN, and the REM sleep deprivation that we applied from postnatal day 42-49 delayed this essential step in the development of the kitten's visual system. These data suggest that in early postnatal brain development, REM sleep facilitates the usual time course of the expression of PV-immunoreactivity in LGN neurons.