REM Sleep at its Core - Circuits, Neurotransmitters, and Pathophysiology

Abstract

Rapid eye movement (REM) sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain, and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC) or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC cells activate neurons in the ventral medial medulla, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray and dorsal paragigantocellular reticular nucleus as well as melanin-concentrating hormone neurons in the hypothalamus and cholinergic cells in the laterodorsal and pedunculo-pontine tegmentum in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie narcolepsy/cataplexy and REM sleep behavior disorder (RBD). This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD.

Keywords: REM sleep; REM sleep behavior disorder; amygdala; brainstem; cataplexy; dopamine; hypothalamus; narcolepsy.

Figure 1

Schematic representation of circuits and pathways regulating muscle activity during “normal” wakefulness and cataplexy in the rodent brain. Inappropriate activation of rapid eye movement (REM) sleep muscle paralysis circuitry during wakefulness is thought to produce cataplexy. Glutamatergic REM-active SubC neurons trigger the paralysis of REM sleep via stimulation of the GABAergic/glycinergic cells in the VMM. These VMM neurons send inhibitory projections to skeletal motor neurons. Under normal condition, strong positive emotions are processed via GABAergic neurons of the CeA, which then inhibit cells in the LC and vlPAG. However, in the absence of the LH hypocretinergic neurons in cataplexy, this inhibition is left unbalanced and the REM sleep core circuit (i.e., SubC) is released from inhibition and triggers untimely muscle paralysis while the individual remains conscious. The inhibition of LC neurons during cataplexy removes noradrenergic inputs to motorneurons, thereby enhancing the muscle paralysis of cataplexy. Lower inset represents the brain (EEG) and muscle (EMG) activity in a narcoleptic mouse (i.e., orexin knockout mouse) at the transition into cataplexy [adapted from Burgess and Peever (17)]. Abbreviations: CeA, central nucleus of the amygdala; GABA, γ-aminobutyric acid; LC, locus coeruleus; LH, lateral hypothalamus; VMM, ventral medial medulla; SubC, subcoeruleus; vlPAG, ventrolateral periaqueductal gray; MNs, motoneurons; EEG, electroencephalogram; EMG, electromyogram; a.u., arbitrary unit.

Figure 2

Schematic representation of circuits and pathways regulating muscle activity during “normal” rapid eye movement (REM) sleep and REM sleep behavior disorder (RBD) in the rodent brain. During REM sleep, REM-active glutamatergic SubC neurons trigger REM sleep paralysis through activation of GABAergic/glycinergic cells in the VMM, which carry inhibitory projections to skeletal motor neurons. Under normal REM sleep conditions, the SubC → VMM circuit inhibits motoneurons, which produces paralysis and limits the intrusion of muscle twitches and movement generated by the red nucleus (RN). However, in patients with RBD, degeneration of the SubC → VMM circuit releases motoneurons from their normal source of inhibition, which allows excitatory inputs to produce motor behaviors during REM sleep. Lower inset represents the brain (EEG) and muscle (EMG) activity during REM sleep in a healthy mouse (left) vs. a transgenic mouse model of RBD (right) [adapted from Brooks and Peever (18)]. Abbreviations: GABA, γ-aminobutyric acid; VMM, ventral medial medulla; SubC, subcoeruleus; vlPAG, ventrolateral periaqueductal gray; MNs, motoneurons; RN, red nucleus; EEG, electroencephalogram; EMG, electromyogram.