Progress in Neurobiology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

Review article

Neural circuitry underlying REM sleep: A review of the literature and

current concepts
Yi-Qun Wang 1, Wen-Ying Liu 1, Lei Li, Wei-Min Qu, Zhi-Li Huang *
Department of Pharmacology, School of Basic Medical Sciences and State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes
of Brain Science, Fudan University, Shanghai, 200032, China

A R T I C L E I N F O A B S T R A C T

Keywords: As one of the fundamental sleep states, rapid eye movement (REM) sleep is believed to be associated with
Rapid eye movement sleep dreaming and is characterized by low-voltage, fast electroencephalographic activity and loss of muscle tone.
REM sleep-regulatory model However, the mechanisms of REM sleep generation have remained unclear despite decades of research. Several
REM sleep behavior disorder
models of REM sleep have been established, including a reciprocal interaction model, limit-cycle model, flip-flop
Narcolepsy
model, and a model involving γ-aminobutyric acid, glutamate, and aminergic/orexin/melanin-concentrating
hormone neurons. In the present review, we discuss these models and summarize two typical disorders
related to REM sleep, namely REM sleep behavior disorder and narcolepsy. REM sleep behavior disorder is a
sleep muscle-tone-related disorder and can be treated with clonazepam and melatonin. Narcolepsy, with core
symptoms of excessive daytime sleepiness and cataplexy, is strongly connected with orexin in early adulthood.

1. Introduction NREM sleep is typically accompanied by increased slow wave activity,

during which synchronous neuronal discharge occurs (Aserinsky and
People spend nearly one-third of their lives sleeping. Adequate sleep Kleitman, 1953). In contrast, during REM sleep, cholinergic neurons
underlies optimal physical condition. Without enough sleep, people may discharge asynchronously; Intravenous injection of an anticholines­
suffer detrimental effects on brain restitution, synaptic homeostasis, terase eserine sulphate in the decerebrate cat activates cholinergic
memory consolidation, and task learning. Hence, the unique functions neurons located in the brainstem reticular formation and reproduces
and mechanisms of sleep generation and maintenance have been postural atonia typical of desynchronized sleep by using long-term re­
investigated extensively. cordings of single units neurons (Hoshino and Pompeiano, 1976; Pom­
With the development and implementation of electroencephalog­ peiano, 1975). REM sleep, which has also been referred to as
raphy (EEG), electromyography, and electrooculography, vigilance “paradoxical sleep” by Michel Jouvet, is thought to be a cortical state
states have been divided into the following stages: wakefulness, rapid closer to that of wakefulness than to NREM sleep and an independent
eye movement (REM) sleep, and non-REM (NREM) sleep. In general, state of alertness. Evidence has supported that the process of human
wakefulness is represented by high-frequency low-voltage waves and memory consolidation is strongly dependent on REM sleep; however,
high muscle tone. NREM sleep is defined by higher voltage, slower selective disruption of REM sleep results in no performance gain, while
waves, and decreased muscle tone, while REM sleep is characterized by NREM sleep disruption does not affect improvement on the performance
low-voltage fast EEG activity, dreaming, and complete loss of muscle of a basic visual discrimination task (Karni et al., 1994). Complex
tone (Aserinsky and Kleitman, 1953; Dement and Kleitman, 1957). associative (spatial) learning has been shown to be persistently impaired

Abbreviations: CNZ, clonazepam; DLB, dementia with Lewy bodies; DMH, dorsomedial hypothalamic nucleus; DPGi, dorsal paragigantocellular nucleus; DRN,
dorsal raphe nucleus; EDS, excessive daytime sleepiness; EEG, electroencephalogram; GABA, γ-aminobutyric acid; HCRT, hypocretin; LC, locus coeruleus; LDT,
laterodorsal tegmental nucleus; LH, lateral hypothalamic area; LPGi, lateral paragigantocellular nucleus; LPT, lateral pontine tegmentum; MCH, melanin-concen­
trating hormone; NREM, non-REM; PD, Parkinson’s disease; PGO, ponto-geniculo-occipital; PnO, oral pontine reticular nucleus; PPT, pedunculopontine tegmental
nucleus; PRF, pontine/mesencephalic reticular formation; RBD, REM sleep behavior disorder; REM, rapid eye movement; SLD, sublaterodorsal tegmental nucleus;
SubC, subcoeruleus nucleus; vlPAG, ventrolateral periaqueductal gray matter; vMM, ventromedial medulla.
* Corresponding author.
E-mail address: huangzl@fudan.edu.cn (Z.-L. Huang).
1
Contributed equally to this work.

https://doi.org/10.1016/j.pneurobio.2021.102106
Received 11 November 2020; Received in revised form 25 April 2021; Accepted 9 June 2021
Available online 16 June 2021
0301-0082/© 2021 Elsevier Ltd. All rights reserved.

Please cite this article as: Yi-Qun Wang, Progress in Neurobiology, https://doi.org/10.1016/j.pneurobio.2021.102106
Y.-Q. Wang et al. Progress in Neurobiology xxx (xxxx) xxx

by restricting REM sleep for a short critical period each day (Bjorness 2.2. Neural foundation underlying REM sleep regulation
et al., 2005). However, REM sleep perturbation itself is stressful and
resulting in a general cognitive impairment. The REM sleep is generally thought to be generated from interactions
hypothalamic-pituitary-adrenal axis takes responsibility for the core between cholinergic laterodorsal/pedunculopontine tegmental nucleus
hormonal response caused by homeostatic changes. And several pro­ (LDT/PPT) and the glutamatergic pontine/mesencephalic reticular for­
cedures were used to reduce stress in these experiments as follows: (a) mation (PRF) (Elazar and Berchanski, 2001; Thakkar et al., 1996). Ex­
multiple platforms were used to reduce immobility stress; (b) the water periments using a variety of techniques—such as ablations, lesions,
level was adjusted below the platform avoiding the animals’ tails touch pharmacology, immunohistochemistry, and electrophysiological re­
the water; (c) the animals were allowed to drink fresh water at all times; cordings (Jones, 1991; Jouvet, 1962; Sakai and Koyama, 1996; Van­
and (d) the period of restriction lasted only for four hours (Bjorness ni-Mercier et al., 1989) —have indicated that neurons in the brain stem
et al., 2005). Theta activities during REM sleep show a relationship with and dorsolateral pons, especially the sublaterodorsal tegmental nucleus
emotional memory consolidation (Boyce et al., 2016). Interestingly, (SLD; equivalent to the subcoeruleus nucleus [SubC]) (Sakai et al.,
when researchers investigated REM sleep in the platypus, they found 2001), are responsible for controlling REM sleep (Boissard et al., 2002;
that EEG in this state exhibits a moderate or high voltage, which has Jones, 1991; Jouvet, 1962; Vanni-Mercier et al., 1989). Neurons in the
been characterized as NREM sleep in adult placental and marsupial medulla, such as GABAergic neurons in the ventral and dorsomedial
mammals (Siegel et al., 1999). Therefore, an increasing number of medulla (Verret et al., 2006; Weber et al., 2015), especially the lateral
studies have supported that low-voltage EEG is indicative of mammalian paragigantocellular nucleus(LPGi), are believed to act as
REM sleep (Siegel et al., 1999). In addition, data have suggested that the REM-sleep-active neurons (Sapin et al., 2009), participating in REM
percentage of REM sleep is much higher in children and younger sleep muscle atonia (Magoun and Rhines, 1946; Schenkel and Siegel,
mammals such as rats, which spend the majority of their early lives in 1989), sleep transitions, and REM sleep maintenance (Liu and Dan,
REM sleep (Blumberg et al., 2005; Roffwarg et al., 1966). REM sleep 2019). In addition, inhibition of A2A receptor neurons in the olfactory
varies considerably across different species (Peever and Fuller, 2017). bulb increases REM sleep (Wang et al., 2017, 2012). However, greater
Importantly, all recent discoveries related to REM sleep would not have attention has been focused on the role of glutamatergic neurons in REM
been possible without the landmark discovery of REM sleep in 1953. sleep generation, as the selective elimination of glutamatergic neuro­
For many years, most studies investigating sleep regulation have transmission reduces REM sleep (Krenzer et al., 2011). Cell-type-specific
focused on NREM sleep. In contrast, little attention has been devoted to microendoscopic calcium imaging demonstrates that glutamatergic
elucidating REM sleep. Hence, the mechanisms underlying the regula­ neurons are maximally active during REM sleep (Cox et al., 2016), and
tion of REM sleep have remained unclear. In this review, we focus on juxtacellular recording and labeling in naturally sleeping–waking also
current knowledge regarding mechanisms controlling REM sleep and show that some glutamatergic neurons are REM sleep maximally active
two typical REM-sleep-related disorders, namely REM sleep behavior (Boucetta et al., 2014). Taken together, REM sleep regulation is modu­
disorder (RBD) and narcolepsy. lated by several neural circuits, including noradrenergic, serotonergic,
cholinergic, glycinergic, GABAergic, and glutamatergic neurons (Bois­
2. REM sleep-circuitry assessment sard et al., 2003; Brown et al., 2008; Clement et al., 2011; Ford et al.,
1995; Lu et al., 2006; Maloney et al., 1999, 2000). Furthermore, these
2.1. General characteristics of REM sleep findings have promoted the development of several animal models for
elucidating the mechanisms underlying REM sleep regulation, which we
REM sleep (also called paradoxical sleep) is a sleep state paradoxi­ discuss below.
cally associated with highly synchronized discharges of theta rhythms
(4–8 Hz) activity and muscle atonia. Furthermore, REM sleep only ap­ 2.3. Summary of models reported in studies of REM sleep circuits
pears in mammals (Siegel et al., 1998), especially at a young age
(Roffwarg et al., 1966). The characteristics of REM sleep are as follows: 2.3.1. Reciprocal interaction model
(a) hippocampal theta oscillations, which are signs of REM sleep in ro­ McCarley and Hobson proposed a reciprocal interaction model to
dents and can be divided into two types of activity, namely type I explain conversion between REM-on and REM-off states (Hobson et al.,
(4–7 Hz) and type II (7–12 Hz) (Shin et al., 2005); (b) 1975; McCarley and Hobson, 1975). REM-on refers to a group of neurons
ponto-geniculo-occipital (PGO) waves, which are field potentials whose firing rates increase when REM sleep is initiated and maintained,
generated from the cholinergic brain stem, the pons, lateral geniculate while REM-off refers to neurons with an opposite pattern of activity. In
nucleus, and occipital cortex since intraperitoneal injection of anticho­ this model, cholinergic neurons in the LDT and PPT are REM-on neurons
linergic agent atropine sulfate to cats blocked the occurrence of bursts of (Hobson et al., 1975; McGinty and Harper, 1976), whereas noradren­
PGO waves (Henriksen et al., 1972), while lesions of these regions ergic and serotoninergic neurons are proposed to be REM-off neurons (el
abolished PGO waves which was induced by intravenous injection of an Mansari et al., 1989; Kayama et al., 1992; Steriade et al., 1990).
anticholinesterase eserine sulphate (Magherini et al., 1971), indicate The activity pattern of this model hypothesizes that REM-on neurons
onset of REM sleep (Jacobs et al., 1972); (c) cortical activation, which are inhibited by activated REM-off neurons during wakefulness and
arises from excitatory inputs of the activated thalamic basal forebrain, NREM sleep. When the firing of REM-off neurons decreases, REM-on
including the horizontal limb of the diagonal band, substantia innomi­ neurons are disinhibited and local REM sleep is initiated. As a result,
nata, and magnocellular preoptic region (Lee et al., 2005, 2004; Taka­ downstream effectors of REM-on neurons are stimulated, generating
hashi et al., 2009); (d) muscle atonia, which results from active REM sleep. In addition, activity of REM-on neurons is enhanced via
inhibition such as from increased levels of γ-amino butyric acid (GABA) mutual positive feedback to stabilize the REM sleep state. Furthermore,
and glycine (Chase et al., 1989; Xi et al., 2001) and de-facilitation of REM-on neurons send excitatory projections to REM-off neurons to
excitatory inputs from the brain stem (Fenik et al., 2005); (e) REM in gradually arouse the REM-off state. In this model, the activity of pre­
both tonic (postural muscle atonia) and phasic (cranial muscle twitching sumed REM sleep related neurons (i.e., cholinergic and aminergic neu­
of the jaw, whisker, and tongue muscles) states, which are regulated by rons) keeps pace with alternations between sleep states (Hobson et al.,
separate brainstem neural circuits (Anaclet et al., 2010; Marquez-Ruiz 1975; Lydic et al., 1983; Thakkar et al., 1998); The LDT and PPT send
and Escudero, 2008); and (f) changes in heart and breathing rates, as cholinergic projections to reticular formation areas (e.g., the oral
well as body temperature (Monti et al., 2002; Negoescu and Csiki, pontine reticular nucleus [PnO] and caudal pontine reticular nucleus
1989). regions) (Mitani et al., 1988) and activate aminergic neurons (Li et al.,
1998). The cholinergic agonist, carbachol, activates reticular neurons

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through ionotropic nicotinic and muscarinic receptors (Greene et al., during the waking state (Nitz and Siegel, 1997a, b).
1989; Stevens et al., 1993). Cholinergic neurons in the LDT/PPT receive
signals from serotonergic neurons in the dorsal raphe nucleus (DRN) and 2.3.3. Flip-flop model
median raphe nuclei as well as noradrenergic neurons in the locus Ablation of cholinergic and monoaminergic nuclei in the brain stem
coeruleus (LC) (Pickel et al., 1974; Semba and Fibiger, 1992). Norepi­ has only a limited influence on REM sleep (Jones et al., 1977; Lu et al.,
nephrine and 8-hydroxy-2-dipropylaminotetralin (5-HT1A agonist) can 2006; Mouret and Coindet, 1980), which contradicts earlier models.
inhibit brain stem cholinergic neurons (Thakkar et al., 1998; Williams Therefore, it is doubtful that interactions between these two cell groups
and Reiner, 1993). Enhancement of cholinergic tone or attenuation of are necessary for REM sleep (Lu et al., 2006). This model suggests that
aminergic tone promotes REM sleep (i.e., decreases REM sleep latency REM sleep arises from reciprocal inhibition between REM-off (i.e.,
and increases the amount of REM sleep (Kubin, 2001; Lauriello et al., vlPAG and LPT) and REM-on (i.e., SLD, precoeruleus, and LDT/PPT)
1993; Reid et al., 1994)) or inhibits REM sleep (Rauniar et al., 1998) regions.
reversely. In human and animal models, most monoaminergic and This flip-flop switch shows that REM-off neurons are dominated by
noradrenergic antidepressants can effectively suppress REM sleep. the extended ventrolateral preoptic nucleus, LC, DRN, LDT/PPT, and
This model has several limitations. Many studies have presented SLD. Meanwhile, GABAergic neurons in the vlPAG and LPT also inhibit
evidence that is inconsistent with this model. For example, LDT/PPT/LC REM-on neurons in the SLD and precoeruleus (Hayashi et al., 2015;
lesions do not significantly change the amount of REM sleep (Blanco-­ Weber et al., 2015). Furthermore, it is noteworthy that glutamatergic
Centurion et al., 2004), and the duration of REM sleep is significantly neurons in the vlPAG and LPT also negatively regulate REM sleep
decreased in muscarinic (M)3-/- but not in M2/M4-/- mice (Goutagny (Kashiwagi et al., 2020; Zhong et al., 2019). In support of this model,
et al., 2005). In addition, the number of activated cholinergic neurons is microinjection of bicuculine or kainic acid into the SLD leads to the
not increased during the REM sleep rebound period after selective REM enhancement of REM sleep (Onoe and Sakai, 1995). Tract-tracing
sleep deprivation (Verret et al., 2005). In addition, this model neglects studies have found that GABAergic and glutamatergic neurons in the
the influence of circadian rhythms and excludes the role of descending SLD project to the vlPAG and LPT, while the projections from the vlPAG
pathways from the forebrain. and LPT to the SLD are GABAergic (Boissard et al., 2003; Hayashi et al.,
2015; Kashiwagi et al., 2020; Lu et al., 2006). In addition, LPT
2.3.2. Limit-cycle model GABAergic neurons also project to the lateral hypothalamic area (LH)
The limit-cycle model is a reciprocal interaction model and has been and the DRN, which regulates REM sleep and muscle tone (Chen et al.,
proposed by McCarley and colleagues (Brown et al., 2012; Massaquoi 2019). Furthermore, orexinergic neurons are suppressed during REM
and McCarley, 1992; McCarley and Massaquoi, 1986). The brain stem sleep (Takahashi et al., 2008), and a deficiency in this process may be a
contains a large number of GABAergic neurons. Anatomical studies have cause of narcolepsy (Thannickal et al., 2000). Collectively, the major
confirmed that these neurons interact with REM-sleep-related regions function of this switch is to stabilize the REM-on or REM-off state
(Boissard et al., 2003; Brown et al., 2008; Ford et al., 1995; Maloney (Hanriot et al., 2007).
et al., 2000; Sapin et al., 2009). Furthermore, this model takes into
consideration the circadian influence of the REM oscillator and the role 2.3.4. A model involving GABAergic, glutamatergic, and aminergic/orexin/
of local GABAergic neurons. melanin-concentrating hormone (MCH) neurons
The general framework of this model is as follows. LDT/PPT Many studies have demonstrated that cholinergic and aminergic
cholinergic neurons, which act as REM-on neurons, exhibit excitatory neurons act as modulators in REM sleep control. Coexpression of Fos and
interactions with glutamatergic neurons in the PRF to promote REM vesicular glutamate transporter 2 in the SLD during recovery from REM
sleep. They also excite GABAergic interneurons that send inhibitory sleep deprivation suggests that glutamatergic neurons have a consider­
projections to DRN serotonergic and LC noradrenergic REM-off neurons able impact on the REM-on state (Lu et al., 2006; Valencia Garcia et al.,
as well as to neurons responsible for inhibiting PRF glutamatergic 2017). Studies have shown that the SLD sends direct projections to
neurons in the REM sleep state. As REM sleep progresses, REM-on GABAergic and glycinergic neurons in the spinal cord (Clement et al.,
neurons gradually activate REM-off neurons to reverse the sleep state. 2011), as well as to the nucleus raphe magnus, ventral gigantocellular
In contrast, REM-off neurons inhibit REM-on neurons during wakeful­ reticular nucleus, alpha gigantocellular reticular nucleus, and LPGi
ness and NREM sleep. There is also mutual negative feedback among (Boissard et al., 2002) to control atonia (Verret et al., 2006). This glu­
REM-off neurons to facilitate the onset of REM sleep (Dunmyre et al., tamatergic signaling also affects the posterior hypothalamus, basal
2014). forebrain, and intralaminar thalamic nuclei (Luppi et al., 2013), which
Based on the previous reciprocal interaction model, additional evi­ may cooperate with activated LDT/PPT cholinergic neurons and retic­
dence has been presented. Retrograde tracing experiments have indi­ ular formation glutamatergic neurons to result in cortical activation
cated that GABAergic neurons in the PnO, lateral pontine tegmentum (Boissard et al., 2002; Valencia Garcia et al., 2017).
(LPT), and ventrolateral periaqueductal gray matter (vlPAG) project to This model emphasizes the importance of the LH especially MCH
the SubC in rats (Boissard et al., 2003; Lu et al., 2006). In cats and rats, neurons in REM sleep onset and maintenance. MCH neurons occupy
bicuculline (GABAA receptor antagonist) acting on the SubC or PnO has approximately one-third of activated GABAergic LH neurons during the
an inhibitory effect on the REM sleep state (Sanford et al., 2003; Xi et al., REM recovery period (Hanriot et al., 2007; Sapin et al., 2010). Activated
1999), whereas muscimol (GABAA receptor agonist) enhances REM MCH neurons send inhibitory inputs to vlPAG GABAergic neurons,
sleep by inhibiting the vlPAG and LPT (Sapin et al., 2009; Schenck et al., monoaminergic REM-off neurons, histaminergic neurons, and hypo­
1993). However, a line of evidence suggests that REM sleep is not cretinergic neurons, which contribute to the generation of REM sleep
affected by inactivating GABAergic and glycinergic neurotransmission (Arrigoni et al., 2019; Luppi et al., 2013). REM-sleep-active MCH neu­
in the caudal LDT-SLD and vlPAG-LPT regions (Krenzer et al., 2011). rons in the hypothalamus are also involved in active forgetting in the
GABAergic neurons surrounding the LC are activated when rats recover hippocampus (Izawa et al., 2019).
from REM sleep deprivation (Maloney et al., 1999), and the cholinergic The role of SLD neurons in the regulation of REM sleep is compli­
agonist, carbachol, excites SubC GABAergic neurons (Brown et al., cated. Valencia et al. found that SLD neurons are involved in muscle
2008). Retrograde tracing experiments have confirmed that the DRN atonia rather than REM sleep generation; SLD neurons do not innervate
receives GABAergic inputs from the rostral PnO and vlPAG/LPT, and the the intralaminar thalamus but only send descending projections to
LC receives GABAergic input from REM-on neurons (Sapin et al., 2009; GABAergic/glycinergic neurons in the ventral medulla, which plays a
Verret et al., 2006). Microdialysis has shown that GABA levels are crucial role in muscle atonia (Valencia Garcia et al., 2017). Chemo­
increased in the LC and DRN during REM sleep compared with those genetic activation of SLD glutamatergic neurons results in an immediate

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increase in wakefulness and subsequent increase in REM sleep (Erickson muscles (sleep paralysis), as well as emotional (depression), sleep-wake
et al., 2019). However, glutamatergic neurons in the SLD that are pos­ (disturbed sleep), and metabolic (obesity) disturbances (Scammell,
itive for Atoh1 also negatively regulate REM sleep (Hayashi et al., 2015). 2015). To aid diagnosis, symptoms are organized into the classic tetrad
A similar finding was made by Horner et al. (Grace and Horner, as follows (Yoss and Daly, 1957): (1) EDS: sudden or persistent falling
2015; Valencia Garcia et al., 2017). They found that activation of PPT asleep during the day, irrespective of the amount or quality of sleep the
cholinergic inputs to the SubC enhances REM sleep, while SubC night before; (2) cataplexy: sudden loss of muscle tone, which is usually
cholinergic receptor antagonism does not yield an opposite effect. triggered by positive emotion rather than negative emotional stimuli
Furthermore, local blockage of cholinergic receptors in the SubC does and may lead to disinhibition of REM sleep atonia circuitry by activating
not disrupt the onset of REM sleep. These findings support a minor role neurons in the amygdala and median prefrontal cortex (Anic-Labat
of pontine cholinergic input in modulating the transition from NREM to et al., 1999); (3) hypnogogic hallucinations: starting sleep with unreal,
REM sleep, but not in generation of REM sleep. This research group has vivid auditory or visual perceptions; and (4) sleep paralysis/temporary
further proposed that the roles of nuclei in REM sleep control cannot be inability: temporarily unable to move while awakening or falling asleep.
determined by gain-of-function experiments; instead, loss-of-function According to the International Classification of Sleep Disorders (Medi­
experiments are required (Grace and Horner, 2015; Grace et al., 2014). cine, 2014), narcolepsy can be differentiated into two types. Type 1
refers to narcolepsy with cataplexy, and type 2 refers to narcolepsy
3. Diseases involved in dysfunction of REM sleep circuits without cataplexy (Sateia, 2014).
Hypocretin (HCRT/orexin), a neuropeptide produced by neurons in
Sleep disruption is strongly linked with impairment of human the posterior hypothalamus, is believed to be associated with the path­
cognitive, emotional, and executive performance. The studies on the ogenesis of narcolepsy. It has been reported that complex immune-
mechanism of REM sleep will provide a basis for the treatment of REM mediated processes induced by genetic and environmental factors are
sleep related diseases. In this section, we review two typical REM sleep the primary cause of loss of HCRT neurons and their projections to wake-
disorders, RBD and narcolepsy. promoting regions, which may result in the onset of narcolepsy with
cataplexy (Liblau et al., 2015; Nishino et al., 2000). Similar to paralysis
3.1. REM sleep parasomnia of REM sleep (Burgess and Scammell, 2012), cataplexy associated with
narcolepsy is thought to be driven by an imbalance between cholinergic
Parasomnia is used to describe a series of dissociated sleep disorders and monoaminergic systems in the pons resulting from monoaminergic
characterized by undesirable and unpleasant behaviors or experiential hypoactivity and cholinergic hypersensitivity (Boehme et al., 1984;
phenomena that always occur around or during sleep, such as som­ Mefford et al., 1983).
nambulism (sleepwalking) and sleep terrors (nightmares) (Ylikoski
et al., 2014). Parasomnias may occur during NREM sleep, sleep-wake 4. Discussion
transitions, and REM sleep. According to the International Classifica­
tion of Sleep Disorders (Medicine, 2014), three main disorders are 4.1. Networks underlying REM sleep
recognized as REM sleep parasomnias: nightmare disorder, recurrent
isolated sleep paralysis, and RBD. To explain all the transitions among wake, REM sleep, and NREM
Nightmares are defined as disturbing mental experiences that seem sleep states, Dan et al. proposed an arousal-action model (Liu and Dan,
vivid and might lead to a wide range of negative emotions (e.g., fear, 2019), which includes wakefulness-, REM sleep-, and NREM
anxiety, and anger) and somatic manifestations (e.g., tachycardia, sleep-promoting neurons. Additionally, the REM-sleep-promoting neu­
sweating, and tachypnea). Recurrent isolated sleep paralysis is recog­ rons in the arousal-action model include several neuronal types, such as
nized as a persistence of REM sleep into wakefulness when the sleeper the following: cholinergic, GABAergic, galanin-expressing, and gluta­
awakes with muscle atonia. RBD is characterized by an absence of matergic neurons and related brain regions; the dorsomedial hypotha­
muscle atonia during REM sleep (REM sleep paralysis), thereby inducing lamic nucleus (DMH), DPGi, LDT, LPGi, preoptic area, PPT, raphe
an acting out dreams (Medicine, 2014). These sleep behaviors usually pallidus area, and SLD (Liu and Dan, 2019). Based on the above infor­
enact fight-or-flight reactions and appear in violent dreams (Tinuper mation, here we summarize networks underlying REM sleep regulation.
et al., 2007). For REM sleep generation and maintenance, neurons in the preoptic
Compared with the other two REM sleep parasomnias, RBD has area, LH, and DMH are activated. In addition, DMH galanin-expressing
attracted much more attention. It has been shown that RBD is highly neurons send inhibitory signals to the raphe pallidus area and SLD
associated with synucleinopathy-related neurodegenerative disorders, neurons project to the vlPAG and LPT to release their suppression on
especially Parkinson’s disease (PD), dementia with Lewy bodies (DLB), REM-on neurons. Furthermore, SLD neurons also project to GABAergic
multiple system atrophy, and pure autonomic failure (Boeve et al., and glycinergic neurons in the spinal cord, and neurons in the
2001). RBD can precede the onset of neurodegenerative clinical mani­ LPGi/DPGi (the majority of which are GABAergic neurons) also project
festation by years to decades (Boeve, 2010; Boeve et al., 2013, 2003b). A to the spinal cord. The networks underlying REM sleep are summarized
16-year update study reported that 80.8 % of patients initially diagnosed in Fig. 1.
with RBD developed a parkinsonism/dementia (Schenck et al., 2013). It
has been shown that more than one-third of patients with PD share a 4.2. Degeneration of REM sleep networks in RBD
secondary or symptomatic RBD, and most of them experience other
parasomnias and/or isolated sleep symptoms (Ylikoski et al., 2014). The pathogenesis of RBD is believed to be associated with a degen­
erative breakdown of the brain stem network that controls REM sleep
3.2. Narcolepsy (Peever et al., 2014). Lesions of the pontine tegmentum and ventro­
medial medulla in cats, rats, and mice produce RBD-like behaviors
Narcolepsy is a rare neurological disorder that involves the central (Hendricks et al., 1982; Holmes and Jones, 1994). Neuroimaging studies
nervous system. It affects approximately 0.026–0.050 % of the popula­ in RBD patients have revealed structural damage in the midbrain
tion (Ohayon et al., 2002), and the first symptoms often (>50 %) tegmentum and rostral pons (Scherfler et al., 2011). Post-mortem
develop during adolescence or young adulthood (Dauvilliers et al., studies of patients with RBD and subsequent PD or DLB have also
2001). Narcolepsy has core symptoms of excessive daytime sleepiness revealed neuronal cell loss and Lewy pathology in the brainstem nuclei
(EDS) and cataplexy, and presents with disordered regulation of REM that regulate REM sleep paralysis, such as the LC, PPT, gigantocellular
sleep with sudden episodes of partial or complete paralysis of voluntary reticular nucleus, and amygdala (Iranzo et al., 2013).

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Fig. 1. Summary of REM sleep networks. SLD glutamatergic neurons are critical in the regulation of REM sleep. For REM sleep maintenance and muscle atonia,
cholinergic neurons in the LDT/PPT are important, as are GABAergic neurons in the LPGi, DPGi, vlPAG, LPT, and spinal cord. The dashed lines in the figure show the
connectivities between the different groups of neurons. REM-active neurons are excited and directly or indirectly inhibit REM-suppressive neurons to generate and
maintain REM sleep.

During physiological REM sleep, paralysis is elicited by inhibiting including sleep deprivation, insomnia, sleep-disordered breathing, and
somatic motor neurons that receive hyperpolarizing signals from the use of improper drugs (Bassetti and Bargiotas, 2018). CNZ and
GABAergic/glycinergic neurons in the ventromedial medulla (vMM) melatonin have been regarded as the most effective RBD pharmaco­
(Arrigoni et al., 2016; Brooks and Peever, 2012; Schenkel and Siegel, logical interventions (Bassetti and Bargiotas, 2018). CNZ, a long-lasting
1989). Luppi et al. has proposed a neurotransmission imbalance hy­ benzodiazepine, is indicated as the first-line therapy (Aurora et al.,
pothesis of RBD in which REM-on glutamatergic neurons in the SLD 2010) and has been proven to be efficient in controlling violent dreams
induce muscle atonia (Torontali et al., 2019) by projecting to premotor and sleep disturbances of RBD patients (Schenck et al., 1993). However,
GABAergic/glycinergic neurons in the vMM, such as the ventral gigan­ side effects, such as daytime somnolence, confusion, falls, and exacer­
tocellular reticular nuclei and nucleus raphe magnus. However, the bation of sleep apnea, should be monitored (Anderson and Shneerson,
neurodegenerative damage in RBD disturbs this glutamatergic and 2009). Another effective medication is melatonin, which is suggested for
GABAergic/glycinergic network (Luppi et al., 2011). Transgenic mice patients for whom CNZ is contraindicated, such as those with dementia,
with deficient glycine and GABAA receptor function exhibit RBD-like gait disorders, or obstructive sleep apnea syndrome (Aurora et al.,
behaviors that can be rescued by treatment with clonazepam (CNZ). 2010). Melatonin is safer and more tolerable than clonazepam and has a
Melatonin is also involved in impaired inhibitory neurotransmission in more limited potential for drug-drug interactions (McGrane et al.,
RBD pathogenesis (Brooks and Peever, 2011). However, there are more 2015). In addition, melatonin is helpful for RBD patients with other
complex modulatory mechanisms beyond a direct neurological disorders such as PD, DLB, multiple system atrophy, nar­
glutamate-GABA/glycine pathway in the SLD and vMM. According to colepsy, and Alzheimer’s disease (Boeve et al., 2003a). After a six-week
the REM sleep flip-flop switch theory proposed by Lu et al., both REM-on treatment with melatonin, polysomnographic recordings showed a sig­
and REM-off regions in the mesopontine tegmentum contain GABAergic nificant reduction in REM sleep without muscle atonia, as well as a
neurons and inhibit each other (Lu et al., 2006). This research group also reduction in the number of REM sleep stage-shifts and epochs (Kunz and
found a restricted region in the ventromedial medulla, termed the Bes, 1999). A melatoninergic agonist, ramelteon, has also exhibited
supraolivary medulla, which sends glutamatergic projections to the potential for the treatment of RBD and its related disorders (Kashihara
spinal ventral horn. A study of mice that were modified using loxP et al., 2016). The dopamine receptor agonist, pramipexole, is contra­
showed that lesioning of the supraolivary medulla glutamate but not dictory in RBD treatment (Kumru et al., 2008; Schmidt et al., 2006). The
GABA/glycine release resulted in a loss of muscle atonia (Vetrivelan antidepressant, parexetine, as well as L-3.4-dihydroxyphenylalanine and
et al., 2009). Another investigation showed that antagonistic blockade the acetylcholinesterase inhibitor, donepezil, have also been studied as
of phasic GABAergic/glycinergic drive at the trigeminal motor pool does alternative treatments for RBD; however, the results have been limited.
not prevent or reverse REM atonia. These results might implicate While new insights have been elucidated for dopaminergic agonists,
another inhibitory mechanism mediating REM atonia (Brooks and glutamatergic antagonists, and phytocannabinoids, further evidence is
Peever, 2008). Furthermore, neurochemical lesioning of the caudal needed to support their effectiveness and safety (de Almeida et al.,
ventral mesopontine junction causes an increase in phasic motor activity 2018). The effectiveness of other interventions, such as behavioral
during REM sleep, which suggests that this network is more complicated measures (Alatriste-Booth et al., 2015) or deep brain stimulation (Eug­
than previously estimated (Lai et al., 2008). ster et al., 2016), is still deemed inconclusive.

4.3. Treatment of RBD 4.4. Treatment of narcolepsy

Similar to the other two parasomnias, in which cognitive behavioral In 1960, it was first documented that the tricyclic antidepressant,
therapies and reassurance are regarded as the first-line treatment (Gal­ imipramine, could significantly decrease the occurrence of cataplexy via
biati et al., 2015), maintaining a safe sleep environment is helpful in its active metabolite, desipramine; however, there was no obvious ef­
treating RBD (Aurora et al., 2010). Any situations that trigger or exac­ fects on EDS and irresistible sleep attacks (Akimoto et al., 1960). Tri­
erbate RBD should be avoided in non-pharmacological interventions, cyclic antidepressants—such as imipramine, protriptyline, and

5
Y.-Q. Wang et al. Progress in Neurobiology xxx (xxxx) xxx

clomipramine—have been shown to control sleep paralysis and hypno­ studies (Black et al., 2017). Moreover, genetic and stem cell therapies,
gogic hallucinations, as well as to inhibit REM sleep. However, their such as viral vector-based delivery of the prepro-HCRT gene, are also
utility is limited by frequent and intolerable side effects, such as seda­ promising choices (Liu et al., 2011).
tion, sweating, constipation, and tachycardia, caused by non-selective
blockage of serotonergic and noradrenergic reuptake (Mignot, 2012). 5. Conclusions
Similarly, selegiline, a monoamine oxidase inhibitor with sympatho­
mimetic side effects, shows a strong suppression of REM sleep and great In this review, we summarized the latest progress on the neurobio­
improvement in EDS (Hublin et al., 1994). logical mechanisms of REM sleep and REM sleep related diseases.
Current treatments for narcolepsy are symptomatic and based on Although there has been much excitement with recent progress in this
management of sleepiness and cataplexy. They include wake-promoting field, further developments and clinical applications are needed to
therapeutics that enhance presynaptic dopaminergic release and anti­ elucidate more details of the corresponding mechanisms and their ef­
cataplectic agents that facilitate monoaminergic neurotransmission. fects in patients. In the future, the following studies are needed for better
First-line medications for EDS are stimulants and include modafinil/ understanding the mechanisms of REM sleep and related diseases: (1)
armodafinil, pitolisant, and sodium oxybate (Black et al., 2016; Darwish loss-of-function experiments are needed to assess the roles of specific
et al., 2009; Dauvilliers et al., 2013; Group, 2005). For cataplexy, so­ nuclei in REM sleep regulation, such as the LDT, PPT, and/or SLD; (2)
dium oxybate, venlafaxine, and pitolisant are regarded as first-choice additional studies are required to investigate the inhibitory mechanism
treatments (Alshaikh et al., 2012; Thorpy, 2015). Sodium oxybate, the mediating REM atonia; and (3) evidence supporting the effectiveness
sodium salt of gamma-hydroxybutyrate, increases slow wave activity of and safety of dopaminergic agonists, glutamatergic antagonists, phyto­
NREM sleep after administration (Black et al., 2010; Walsh et al., 2010). cannabinoids, and/or deep brain stimulation in RBD treatment is
Its therapeutic mechanism might be indirect, involving dopaminergic needed.
transmission and secondary interactions with GABAB receptors (Huang Furthermore, the onset and maintenance of REM sleep and the
and Guilleminault, 2009) possibly through disinhibition of dopami­ transition from NREM to REM sleep still represent critical gaps in our
nergic release via G-protein-coupled inwardly rectifying potassium knowledge. In particular, brain regions in the hypothalamus and
channels (Cruz et al., 2004). Another effective medication is modafinil, brainstem (including the pons and medulla oblongata) are likely
which inhibits dopamine reuptake via the dopamine transporter (Wisor, important regions for further investigation. Therefore, future studies
2013). Modafinil might exert its effects by acting on components of should employ tract-tracing and other specific manipulations of targeted
wake-promoting systems that are facilitated as a compensatory response neurons, combined with EEG and other animal behavioral experiments,
to disrupted HCRT signaling (Willie et al., 2005). Methylphenidate and to determine whether and how NREM-sleep-related nuclei participate in
amphetamines are now second- and third-line therapies, respectively. the generation and transition to REM sleep. Furthermore, the most
They are used to counter EDS in narcolepsy as a supplement to modafinil substantial bottleneck is in successfully translating basic research results
or sodium oxybate (Thorpy and Dauvilliers, 2015). In addition, the in­ into the clinical treatment of REM-related diseases. For example, since
crease of histaminergic tone caused by histamine H3 autoreceptor existing treatments for narcolepsy are all based on mere symptoms,
antagonism is thought to exert therapeutic effects on EDS in narcolepsy future studies are needed to elucidate the mechanisms of such diseases
(Black et al., 2017). Pitolisant has received approval as a new drug for in order to identify and develop more precise and efficacious treatment
the treatment of narcolepsy in Europe via boosting hypothalamic levels strategies.
of histamine (Calik, 2017; Irukayama-Tomobe and Yanagisawa, 2018).
However, adverse reactions still exist, such as headache, anxiety, irri­
tability, and nausea (Yang and Gao, 2019). R-baclofen, a GABAB agonist Declaration of Competing Interest
with an enantiomer-specific form of racemic baclofen, has been
considered a narcolepsy therapeutic in a preclinical study (Black et al., The authors report no declarations of interest.
2014).
Recently, Yang et al. reported that a selective dopamine and
Acknowledgements
norepinephrine reuptake inhibitor, solriamfetol, could strongly reduce
EDS in patients with narcolepsy (Yang and Gao, 2019). Furthermore, it
This study was supported in part by grants-in-aid for scientific
has been approved to be used as a wake-promoting therapy in the USA
research from the National Key Research and Development Program of
(Abad and Guilleminault, 2018). The recommended dose is higher than
China (2020YFC2005300), National Natural Science Foundation of
75 mg but no more than 150 mg once daily (Yang and Gao, 2019).
China (82020108014, 81871037, 32070984, 31871072, and
An underlying auto-immunological mechanism has been proposed
82071491), Shanghai Municipal Science and Technology Major Project
for narcolepsy with cataplexy and/or hypocretin deficiency that is
(2018SHZDZX01) and ZJLab, Program for Shanghai Outstanding Aca­
characterized by the specific loss of a small number of hypothalamic
demic Leaders (to Z.-L.H), Shanghai Science and Technology Innovation
neurons. T-cell function is responsible for related cell death. Immuno­
Action Project (201409001800), and a key laboratory program of the
therapy might be a worthwhile strategy for this type of narcolepsy by
Education Commission of Shanghai Municipality (ZDSYS14005).
suppressing T-cell function (i.e., a specific monoclonal antibody reacts
with human leucocyte antigen attached HCRT fragments). Although
immunotherapy is promising, robust evidence is needed before such Appendix A. The Peer Review Overview and Supplementary
treatments can be used clinically (Reading, 2019). data
When individual management strategies are evaluated, coexisting
morbidities, such as depression and additional symptoms (e.g., obesity), The Peer Review Overview and Supplementary data associated with
should not be neglected (Kallweit and Bassetti, 2017). HCRT replace­ this article can be found in the online version, at doi: https://doi.org/10
ment compounds and immune-modifying medications are likely to be .1016/j.pneurobio.2021.102106.
future treatments (Arias-Carrion and Murillo-Rodriguez, 2014; Baier
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