Bmal1 function in skeletal muscle regulates sleep
- Morehouse School of Medicine, United States
- University of Florida, United States
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
Abstract
Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle.
Article and author information
Author details
J Christopher Ehlen
Joseph S Takahashi
Funding
National Institute on Minority Health and Health Disparities (G12 MD007602)
- J Christopher Ehlen
- Jason P DeBruyne
National Institute of Neurological Disorders and Stroke (R01 NS078410)
- Ketema N Paul
National Heart, Lung, and Blood Institute (T32 HL116077)
- Allison J Brager
National Institute of Mental Health (P50 MH074924)
- Joseph S Takahashi
National Institute of General Medical Sciences (SC1 GM109861)
- Jason P DeBruyne
Howard Hughes Medical Institute
- Joseph S Takahashi
National Heart, Lung, and Blood Institute (T32 HL007609)
- Cloe L Gray
National Institute of Neurological Disorders and Stroke (U54 NS060659)
- Ketema N Paul
National Institute of Neurological Disorders and Stroke (U54 NS083932)
- J Christopher Ehlen
- Jason P DeBruyne
- Ketema N Paul
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense.
Ethics
Animal experimentation: All procedures involving animals were approved by the Morehouse School of Medicine institutional animal care and use committee, protocol reference number 15-17. Animal studies conformed to recommendations published in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Bmal1 function in skeletal muscle regulates sleep
eLife 6:e26557.
https://doi.org/10.7554/eLife.26557
Further reading
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A specific gene in skeletal muscle helps to regulate sleep.
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- Neuroscience
When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
