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 Gq 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.
Highlights
Rapid-eye movement (REM) sleep is a prominent brain state which is accompanied with multiple features such as random movements of eyes, vivid dreaming, quiet muscle tone, lessened homeostatic regulation of body, and brain activity marked by the enhancement of specific brain oscillation
A series of our studies suggested that the Ca2+-hyperpolarization pathway plays an important role in regulating cellular properties for the synchronized activity for NREM sleep, i.e., for the SWO and the delta oscillation
The fast Na+ spikes activate high-threshold Ca2+ current (ICa), (3) after the burst of action potentials, the membrane repolarizes as the low-threshold Ca2+ spike (IT) ceases, (4) and the reduced depolarizing effect of IT is followed by the overshooting after-hyperpolarization which is caused by the outflows of K+ due to the activation of Ca2+ dependent potassium channels (IK[Ca]) (Jahnsen and Llinas, 1984; 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
Summary
Reviewed by: Akihiro Yamanaka, Nagoya University, Japan Hiroaki Norimoto, Max-Planck-Institut für Hirnforschung, Germany. REM sleep is a fundamental brain function, evolutionary conserved across species, including human, mouse, bird, and even reptiles. 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. 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
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