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Review
. 2020 Jan 14:13:1402.
doi: 10.3389/fnins.2019.01402. eCollection 2019.

Molecular Mechanisms of REM Sleep

Rikuhiro G Yamada  1 , Hiroki R Ueda  1   2
Affiliations
Review

Molecular Mechanisms of REM Sleep

Rikuhiro G Yamada et al. Front Neurosci. .

Abstract

Rapid-eye movement (REM) sleep is a paradoxical sleep state characterized by brain activity similar to wakefulness, rapid-eye-movement, and lack of muscle tone. REM sleep is a fundamental brain function, evolutionary conserved across species, including human, mouse, bird, and even reptiles. The physiological importance of REM sleep is highlighted by severe sleep disorders incurred by a failure in REM sleep regulation. Despite the intense interest in the mechanism of REM sleep regulation, the molecular machinery is largely left to be investigated. In models of REM sleep regulation, acetylcholine has been a pivotal component. However, even newly emerged techniques such as pharmacogenetics and optogenetics have not fully clarified the function of acetylcholine either at the cellular level or neural-circuit level. Recently, we discovered that the G q type muscarinic acetylcholine receptor genes, Chrm1 and Chrm3, are essential for REM sleep. In this review, we develop the perspective of current knowledge on REM sleep from a molecular viewpoint. This should be a starting point to clarify the molecular and cellular machinery underlying REM sleep regulation and will provide insights to explore physiological functions of REM sleep and its pathological roles in REM-sleep-related disorders such as depression, PTSD, and neurodegenerative diseases.

Keywords: REM sleep; bursting; hippocampus; muscarinic acetylcholine receptors; theta oscillation.

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Figures

FIGURE 1
FIGURE 1
The brain region and the neural connections in the MS-DBB–hippocampus system. (A) The MS-DBB–hippocampus system depicted in 3D space. The blue region is the hippocampal formation; the orange region is the medial septal complex (including MS-DBB). The purple region is the somatomotor areas in the neocortex (isocortex) presented for visual aid to highlight the deep locations of the hippocampus and the medial septal complex. (B) The thalamocortical system depicted in 3D space. The transparent blue region represents the neocortex. The orange region represents thalamus. The purple region is the somatomotor areas in the neocortex presented for visual aid to highlight the deep location of the thalamus. (C) Schematic diagram of the MS-DBB–hippocampus system. The hippocampal pyramidal neurons (blue triangles) are aligned in parallel so that they produce the strong alteration in the electrical field measurable by EEG. The pyramidal neurons receive excitatory cholinergic and glutamatergic inputs from the MS-DBB and inhibitory inputs from hippocampal interneurons. The pyramidal neurons innervate cholinergic and GABAergic neurons in MS-DBB. Dark brown ellipsoids represent GABAergic neurons; light brown ellipsoids represent cholinergic neurons; blue ellipsoids and triangles represent glutaminergic neurons. Red connection and blue connections represent excitatory and inhibitory connections, respectively. The 3D plots were drawn with cocoframer available at a public mouse brain atlas for parts (A) and (B) (Allen Institute for Brain Science, 2018).
FIGURE 2
FIGURE 2
Bursting and intracellular Ca2+ concentration in a simple model. The membrane potential (orange line) and the intracellular Ca2+ concentration (blue line) are plotted. The bursting consists of UP and DOWN states alternating with each other. In the DOWN state (light blue background), the membrane potential is hyperpolarized to be quiet, and in the UP state (light orange background), the membrane potential is depolarized to generate a series of fast action potentials. In the first DOWN state, deactivation of the Ca2+-dependent potassium outward current (IK[Ca]) raise the membrane potential toward the threshold of Na+ and K+ dependent fast action potentials (INa/K), entering the UP state. In the UP state, the fast Na+ spikes also activate high-threshold Ca2+ current (ICa), building up the intracellular Ca2+ concentration. At the end of the UP state, due to the activation of the Ca2+-dependent potassium current (IK[Ca]), the membrane potential repolarizes, going to the DOWN state. In the second DOWN state, the hyperpolarized membrane then deactivates the IK[Ca] to evoke another raise of membrane potential. The plot was calculated by the simplified-average neuron (SAN) model with arbitrary y-axis scales for visual aid (Yoshida et al., 2018).
FIGURE 3
FIGURE 3
Schematic diagram of the neural circuit for EEG theta oscillation. Light brown ellipsoids represent cholinergic neurons, blue ellipsoids represent glutaminergic neurons, dark brown ellipsoids represent GABAergic neurons, and green ellipsoid represents monoaminergic neurons. Blue connections and red connections represent excitatory and inhibitory connections, respectively. Blue and dark brown letters for neurons represent glutamatergic and GABAergic neurons, respectively. The neurons represented by only letters are not depicted in ellipsoid because the definition of their residing brain regions has not been established yet.
FIGURE 4
FIGURE 4
Power of EEG theta and delta oscillations in Chrm1 and Chrm3 DKO mice. (A) Pie charts presenting the proportions of sleep stages detected in wild-type mice (top) and double knockout (DKO) mice (bottom). REM sleep in wild-type mice was 72 min a day while almost undetected in DKO mice. (B) Hypnogram of a wild-type mouse. Delta power (normalized mV2), the ratio of theta/delta power, and total power of EMG signal. (C) Hypnogram of a Chrm1 and Chrm3 DKO mice. Orange for wakefulness, yellow for REM, and blue for NREM are shown. The enrichment of theta oscillation (increase in the value of θ/δ), that is associated with REM sleep in (A), was hardly detected during sleep in the DKO mice (C). The plots were reproduced from the data published in the literature (Niwa et al., 2018).
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