Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep

Niwa, Yasutaka; Kanda, Genki N.; Yamada, Rikuhiro G.; Shi, Shoi; Sunagawa, Genshiro A.; Ukai-Tadenuma, Maki; Fujishima, Hiroshi; Matsumoto, Naomi; Masumoto, Kouji; Nagano, Mamoru; Kasukawa, Takeya; Galloway, James C.; Perrin, Dimitri; Shigeyoshi, Yasufumi; Ukai, Hideki; Kanazawa, Hiroshi; Sumiyama, Kenta; Ueda, Hiroki R.

doi:10.1016/j.celrep.2018.07.082

Cited by 78 publications

(63 citation statements)

References 69 publications

(90 reference statements)

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“…and Chrm3 (Niwa Y et al 2018). Our results do not indicate the types of muscarinic receptors that might be involved in post-training memory consolidation but evidence obtained from Nissen et al (2006) showed that M1 receptor is not involved as its agonist (RS-86) altered sleep structure without altering declarative or procedural memory consolidation.…”

Section: Discussioncontrasting

confidence: 87%

Low acetylcholine during early sleep is important for motor memory consolidation

Qandeel

2018

Preprint

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The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep is optimal for memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would disrupt motor memory consolidation. We trained separate groups of adult mice on the rotarod walking and skilled reaching for food tasks, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing suggested that physostigmine impaired motor skill acquisition. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eyemovement sleep onset, and reduced slow-wave power in the hippocampus and cortex. The impaired motor performance with physostigmine, however, was not solely due to its effects on sleep structure, as one hour of sleep deprivation after training did not impair rotarod performance. A reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep also affected rotarod performance. Administration of agonists and antagonists of muscarinic and nicotinic acetylcholine receptors revealed that activation of muscarinic receptors during early sleep impaired rotarod performance. The experiments suggest that the increased slow wave activity and inactivation of muscarinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.

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Section: Discussioncontrasting

confidence: 87%

Low acetylcholine during early sleep is important for motor memory consolidation

Qandeel

2018

Preprint

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“…The identification of critical cholinergic receptors has been unfeasible until the recent emergence of the efficient techniques in genetics such as CRISPR and ES-mice (Sunagawa et al, 2016;Ukai et al, 2017). The comprehensive study with these techniques on acetylcholine receptors revealed that DKO mice of G q proteincoupled muscarinic acetylcholine receptors: Chrm1 and Chrm3 abolish REM sleep and the associated enrichment of EEG theta oscillation during sleep, leaving the theta oscillation largely unaffected during wakefulness (Niwa et al, 2018;Figure 4). This work demonstrated the necessity of acetylcholine for REM sleep and the EEG theta oscillation during sleep, which is in line with the previous pharmacological studies that demonstrated that the muscarinic blockers, such as atropine or scopolamine, diminish the EEG theta oscillation in anesthetized animals (Kim and Jeong, 1999;Buzsaki, 2002).…”

Section: The Essential Genes For Rem Sleep and The Associated Eeg Thementioning

confidence: 99%

“…To obtain deeper insights into the molecular mechanism of REM sleep, we need to address two issues: (1) identifying specific molecular components among the family members of acetylcholine receptors and (2) understanding the molecular function in regulating cellular properties of the identified receptors. A recent comprehensive reverse genetic study revealed that the G q protein-coupled muscarinic acetylcholine receptors, Chrm1 and Chrm3, are essential for REM sleep, as REM sleep and its associated enrichment of EEG theta oscillation could be hardly detected in Chrm1 and Chrm3 double-knockout (DKO) mice during sleep (Niwa et al, 2018). Also, a series of our studies suggested that the Ca 2+ -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.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of REM Sleep

Yamada

Ueda

2020

Front. Neurosci.

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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.

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“…It is also a crucial feature for some applications such as studies of complex pathways or functions that require targeting multiple genes (e.g. sleep [6][7][8]) or producing whole-genome maps [9].…”

Section: Introductionmentioning

confidence: 99%

A Benchmark of Computational CRISPR-Cas9 Guide Design Methods

Bradford

Perrin

2018

Preprint

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The popularity of CRISPR-based gene editing has resulted in an abundance of tools to design CRISPR-Cas9 guides. This is also driven by the fact that designing highly specific and efficient guides is a crucial, but not trivial, task in using CRISPR for gene editing. Here, we thoroughly analyse the performance of 17 design tools. They are evaluated based on runtime performance, compute requirements, and guides generated. To achieve this, we implemented a method for auditing system resources while a given tool executes, and tested each tool on datasets of increasing size, derived from the mouse genome. We found that only five tools had a computational performance that would allow them to analyse an entire genome in a reasonable time, and without exhausting computing resources. There was wide variation in the guides identified, with some tools reporting every possible guide while others filtered for predicted efficiency. Some tools also failed to exclude guides that would target multiple positions in the genome. We also considered a collection of over a thousand guides for which experimental data is available. For the tools that attempt to filter based on efficiency, 65% to 85% of the guides they reported were experimentally found to be efficient, but with limited overlap in the sets produced by different tools. Our results show that CRISPR-Cas9 guide design tools need further work in order to achieve rapid whole-genome analysis and that improvements in guide design will likely require combining multiple approaches.

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Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep

Cited by 78 publications

References 69 publications

Low acetylcholine during early sleep is important for motor memory consolidation

Low acetylcholine during early sleep is important for motor memory consolidation

Molecular Mechanisms of REM Sleep

A Benchmark of Computational CRISPR-Cas9 Guide Design Methods

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