Rapid eye movement (REM) sleep is a fundamental state of consciousness of the mammalian brain. Initially, sleep was assumed to be a passive process; however, electrophysiological recording of neural activity in the sleeping brain revealed its dual nature [1,2]. Contrary to non-REM sleep, REM sleep is marked by wake-like brain activity of low-voltage fast waves occurring in combination with temporary muscle paralysis and vivid dreaming. REM sleep is additionally characterized by phasic phenomena, including muscle twitching and REMs. Moreover, cardiorespiratory control and autonomic tone typically exhibit significant variability in REM sleep.
All these changes accompanying REM sleep are well tolerated by normal individuals; however, these changes can give rise to pathological states and/or exacerbate existing disease in vulnerable clinical populations, for example, sleep apnea . It is important to note that these physiological and pathophysiological characteristics are ultimately the product of interactions between REM sleep control circuitry and other parts of the nervous system. Hence, understanding the complex neural circuit that generates REM sleep will help clarify the mechanisms underlying REM sleep-associated pathologies. The following review aims to summarize the recent advances in our understanding of REM sleep control mechanisms and the relationships between these circuits and three major disease states.
THE RAPID EYE MOVEMENT SLEEP CORE COMPRISES A GABAERGIC/GLUTAMATERGIC CIRCUIT
Lesion, pharmacology and electrical stimulation studies localized the main neural network required for generating REM sleep within the brainstem. More recent studies have identified that this network receives influences from hypothalamic and forebrain structures [4,5]. The center of this REM sleep-generating circuit lies ventral to the locus coeruleus and medial to the trigeminal motor nucleus – the subcoeruleus (SubC) nucleus [6–8]. The neurons of this nucleus are REM active, meaning that they are most active during REM sleep [6,7,9–11]. The majority of these cells synthesize glutamate . Their drug-induced stimulation triggers motor atonia [6–13], whereas bilateral lesions result in loss of REM sleep paralysis (atonia) and/or reduced REM sleep amounts [6–7]. SubC cells induce REM atonia by recruiting inhibitory circuits localized in the ventromedial medulla and spinal cord, which in turn trigger atonia by directly inhibiting skeletal motoneurons [7,13–16].
At the level of the motoneuron, muscle paralysis in REM sleep is caused by both gamma-aminobutyric acid (GABA) and glycine inhibition [17–19]. Receptor pharmacology studies show that simultaneously antagonizing GABAA/GABAB/glycine receptors on motoneurons are necessary to prevent REM sleep atonia [18,19]. These data indicate that both GABA and glycine-mediated inhibition of motoneurons underlie REM sleep atonia. However, there is critical involvement of acetylcholine (Ach) for suppressing respiratory motoneurons (i.e., hypoglossal) and genioglossus motor activity during REM sleep (see below, Obstructive Sleep Apnea: Mechanisms and Treatment).
In addition to the activation of the SubC neurons, another group of GABA-containing neurons, the dorsal paragigantocellular reticular nucleus (DPGi), may contribute to the generation of REM sleep by inhibiting wake-promoting areas . These neurons are active during REM sleep and are hypothesized to inhibit the locus coeruleus, dorsal raphe and part of the ventrolateral periaqueductal gray (vlPAG) . Pharmacological and electrical activation of the DPGi promotes REM sleep [22–24].
The vlPAG region contains GABAergic neurons that are divided into two subpopulations: REM-active and REM-inhibiting neurons. REM-active neurons of this region project to wake-promoting neurons of the locus coeruleus and dorsal raphe and are hypothesized to inhibit them during REM sleep [20,21,25], whereas REM-inhibiting neurons of the vlPAG project to the SubC region and may silence the core of the REM sleep-generating circuit [7,26,27]. Lesions and pharmacologic inhibition of these vlPAG neurons lead to a significant increase in REM sleep duration [27,28]. The concerted interaction between the SubC, vlPAG and DPGi is responsible for the generation of REM sleep and its characteristics.
Finally, hypothalamic and forebrain structures contribute to REM sleep control as well. Optogenetic activation of melanin-concentrating hormone (MCH) neurons shortens sleep onset and increases the duration of REM sleep [29▪▪,30▪▪]. These neurons promote REM sleep by inactivating wake-promoting histaminergic neurons of the tuberomammillary nucleus and noradrenergic cells of the locus coeruleus, through a release of GABA [29▪▪,30▪▪]. Similarly, neurons of the extended ventrolateral preoptic area are REM active  and send GABAergic projection to several brainstem regions, including the REM sleep-inhibiting region of the vlPAG, thereby releasing the SubC region from its inactivated state .
CHOLINERGIC INVOLVEMENT IN RAPID EYE MOVEMENT SLEEP GENERATION
Since the earlier postulated reciprocal interaction hypothesis – in which cholinergic REM-active neurons interact with monoaminergic wake-active neurons to generate REM sleep  – neurons containing Ach have been viewed at the center of REM sleep control. However, the extent of the contributions made by Ach is still debated .
One model posits that the critical event responsible for initiating REM sleep is the cholinergic activation of the SubC neurons. Indeed, several studies demonstrate the excitatory actions of Ach on SubC neurons. Most recently, it was shown that Ach activates spinally projecting SubC neurons [33▪▪], suggesting a role for cholinergic inputs in the SubC-mediated generation of REM sleep motor atonia. This cholinergic activation is mediated by both postsynaptic excitation and presynaptic enhancement of glutamate release. Importantly, these results demonstrate that Ach acts to both directly activate the core of the REM sleep circuitry and modulate the glutamatergic drives that underlie REM sleep control .
Previous studies investigating cholinergic involvement in REM sleep generation focused on the effects of exogenous Ach on the SubC region and were not designed to determine how endogenous cholinergic neurotransmission impacts REM sleep generation. If cholinergic neurotransmission does contribute to REM sleep generation, one would expect blockade of SubC Ach receptors to suppress REM sleep. However, findings from a recent study show that REM sleep is not reduced when SubC cholinergic receptors are blocked . Although the results indicate that cholinergic inputs into SubC neurons are not required to initiate transitions into REM sleep, the study does show that cholinergic input functions to reinforce transitions once initiated. This is evident by increases in non-REM-to-REM sleep transition duration and failure rate during cholinergic receptor blockade. Moreover, the results indicate that cholinergic neuron activation is gated by SubC activity, supporting a mutually excitatory interaction between cholinergic and glutamatergic circuits responsible for REM sleep. This kind of positive feedback increases the reliability of neural systems to switch between states of consciousness in a rapidly inducible manner .
CATAPLEXY: INTRUSION OF RAPID EYE MOVEMENT SLEEP INTO WAKEFULNESS
Approximately, 3 million people worldwide suffer from the sleep disorder narcolepsy . Cataplexy is a defining symptom of this disorder and is the involuntary loss of skeletal muscle tone (i.e., motor atonia) during wakefulness. This loss of muscle tone can range from mild impairment (e.g., drooping of the face) to total body paralysis lasting seconds to minutes [38▪]. Autoimmune-induced loss of hypocretin/orexin neurons or mutations in the genes encoding orexin appears to cause human narcolepsy [39–45]. However, the precise neural mechanisms that trigger cataplexy are unclear.
It has been hypothesized that cataplexy results from the intrusion of REM sleep paralysis into wakefulness [37,46,47]. Neuroimaging studies of patients with narcolepsy and electrophysiological recordings from isolated neurons in narcoleptic dogs show that the brainstem circuitry involved in REM sleep might have similar activity during both REM sleep and cataplexy [48,49]. Some patients with narcolepsy report hypnagogic hallucinations during cataplexic attacks and some enter into REM sleep .
A cataplectic attack is generally triggered by strong positive emotions, such as excited laughter or surprise . Orexin neurons are active in the response to strong emotions; therefore, loss of orexin neurons in narcoleptic patients hypothetically destabilizes the motor control system within the brainstem such that positive emotions trigger motor paralysis [52,53].
The amygdala plays a major role in processing emotion, and might be involved in the mechanism triggering cataplexy . In narcoleptic dogs, neurons of the amygdala increase firing during cataplectic attacks . A recent study indicates that bilateral lesions of the amygdala significantly reduce the frequency of cataplectic attacks in mice lacking orexin [55▪▪]. GABAergic neurons in the amygdala send descending inhibitory projection to the locus coeruleus, the lateral pontine tegmentum and the vlPAG – regions that function to promote waking muscle tone [55▪▪].
RAPID EYE MOVEMENT SLEEP BEHAVIOR DISORDER: BREAKDOWN OF RAPID EYE MOVEMENT SLEEP CIRCUITRY
In REM sleep behavior disorder (RBD), the normal paralysis of REM sleep is lost , leaving afflicted individuals able to enact their dreams, often injuring themselves or their bed partner in the process . It has been hypothesized that damage of the brainstem circuits responsible for REM sleep atonia underlies the expression of RBD [58▪]. Physical or genetic lesions of the REM sleep core (i.e, SubC or ventromedial medulla) in animal models lead to RBD [59,60]. Recent brain imaging studies and postmortem tissue analysis of patients affected by RBD indicate that lesions encompassing the REM sleep circuit are associated with the disorder [61–63].
During normal REM sleep, muscle twitches interrupt muscle paralysis. Identifying mechanisms controlling this phasic motor activity may also clarify how exaggeration of such events contributes to RBD. Intracellular recording studies show that intermittent release of glutamate excites motoneurons and causes REM sleep muscle twitches , through activation of non-N-methyl-D-aspartate (NMDA) receptors . In addition to being responsible for the lack of muscle tone, GABA and glycine release help restrain phasic REM sleep activity. Pharmacological and genetic blockade of the GABA and glycine inhibitory mechanism increases motor twitches during REM sleep [59,60]. This suggests that the exaggerated motor activity seen in RBD patients can result from the overexcitation of the circuit generating twitches or the breakdown of components of the REM sleep muscle atonia circuit.
Movements in RBD are often highly coordinated and resemble stereotypical movements seen in wakefulness. This suggests that the motor cortex may also be involved in driving movements in RBD. Pyramidal tract neurons, which mediate voluntary limb movement, are highly active during both wakefulness and REM sleep . However, destruction of descending corticospinal fibers does not prevent expression of REM sleep muscle twitches , and twitching is still present in pontine animals (animals subjected to transection of the brain above the pons) and decorticate humans . Finally, a recent study in neonatal rats shows that REM sleep muscle twitches drive the activity and development of the motor cortex, rather than being the result of cortical activation .
Patients with RBD also exhibit changes in normal cholinergic system activity. Neuroimaging studies suggest that patients with RBD have significant degeneration of brain cholinergic systems . Given that a cholinergic mechanism contributes to promote REM sleep atonia [71▪▪], degeneration of brainstem cholinergic systems could underlie motor symptoms in patients with RBD.
OBSTRUCTIVE SLEEP APNEA: MECHANISMS AND TREATMENT
Obstructive sleep apnea (OSA) is a disorder characterized by repeated episodes of airway narrowing and closure during sleep. OSA can be severe in REM sleep  because of additional recruitment of inhibitory inputs to the cranial motor pools, thus further precipitating upper airway closure in this state. The inhibitory mechanisms responsible for the suppression of upper airway motor (i.e., hypoglossal) activity have recently been identified [73,74]. Local pharmacological manipulation of hypoglossal neurotransmission revealed that motor inactivation during REM sleep is caused by activation of muscarinic Ach receptors and G-protein coupled inwardly rectifying potassium channels [71▪▪].
In a separate study, intracellular recording of hypoglossal motor neurons showed that their inactivation in REM sleep is also caused by chloride-dependent postsynaptic inhibition . The latter was recorded from nonrespiratory/tonically active hypoglossal motoneurons, whereas the REM sleep-specific cholinergic inhibition, reported in the former study, affected the respiratory component of genioglossus muscle activity.
In respiratory muscles, some respiratory activity can persist in REM sleep despite loss of background muscle tone, suggesting that respiratory and tonic motor units may be differentially modulated by REM sleep inhibitory/excitatory processes [76,77]. REM sleep-specific cholinergic motor inhibition preferentially inhibits respiratory motoneurons and respiratory inputs. Further identification of the mechanisms responsible for pharyngeal motor control and upper airway collapse is needed to develop rational pharmacological treatment of OSA. Recent studies have identified that peripheral  and central [79,80] modulation of potassium channels may be an effective strategy to reverse upper airway collapsibility in sleep.
Complex interactions between the core of the REM sleep generation circuit and other brainstem, hypothalamic and forebrain structures lead to the expression of REM sleep. Both direct cholinergic activation [33▪▪,34] and GABAergic inhibition release [27,28], trigger activation of SubC glutamatergic neurons, and hence generate the transition into REM sleep. Descending SubC projections activate GABA and glycine release onto motoneurons [35,36], producing the total body paralysis characteristic of this state. Overexpression of REM sleep characteristics or imbalanced activation of REM sleep circuitry are the roots of several sleep disorders. Untimely activation of the REM sleep core-generating system leads to crippling body paralysis during cataplexic attacks in narcoleptic patients [38▪]. Overexpression of motor activity and/or failure to shut down muscles during REM sleep are the cardinal expressions of RBD [58▪]. Finally, cholinergic-mediated loss of muscle tone in upper airway muscles may help to explain the airway obstruction in OSA [71▪▪]. Further investigation of the interplay between the various parts of the REM sleep-generating circuit will assist in targeting new approaches to treat these sleep-related disorders.
Conflicts of interest
There are no conflicts of interest.
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