Sleep: It's not all in the brain
A clock gene expressed in skeletal muscle plays a bigger role in regulating sleep than it does in the brain.
- Cincinnati Children's Hospital Medical Center, United States
“Great workout, I’m going to sleep like a baby tonight!” Ever wondered why strenuous exercise often leads to a great night’s sleep? A new study in eLife could help researchers explain this (Ehlen et al., 2017).
All mammals need to sleep, but why and how we sleep still remains largely a mystery. According to the ‘two-process model’, first proposed 35 years ago, the sleep-wake cycle is a product of two distinct mechanisms: the sleep homeostat that governs how much sleep you need, and the circadian clock that dictates when you get it (Borbély, 1982).
Sleep is regulated by different regions in the brain and by a number of different chemical messengers and genes. In the last three decades, circadian clock genes were identified that regulate sleep timing (for a recent review, see (Takahashi, 2017)). Experiments in humans and animal models revealed that, far from being distinct, many core clock genes, for example, Clock or Npas2, also regulate sleep homeostasis (Laposky et al., 2005; Franken et al., 2006; Viola et al., 2007; Allebrandt et al., 2010; Zhou et al., 2014; Mang et al., 2016). Further, some of the genes that regulate the sleep homeostat, such as Dec2, also control the expression of clock genes (He et al., 2009; Pellegrino et al., 2014).
The Bmal1 gene is the only clock gene required for circadian rhythms in mammals. Under conditions of constant darkness – how circadian rhythms are typically studied – mice that completely lacked Bmal1 lost their 24-hour rhythms and slept longer than mice that still had the gene. These mice also responded differently to sleep deprivation (Laposky et al., 2005). The standard response to sleep deprivation is to sleep longer and more deeply. However, silencing Bmal1 throughout the brain and body impaired the ability of the mice to rebound from sleep deprivation. Conventional wisdom suggests that Bmal1 exerts its influence in the brain. Indeed, when Bmal1 was selectively deleted in histaminergic neurons, the mice had fragmented sleep and didn’t recover from sleep deprivation as well (Yu et al., 2014).
Now in eLife, Ketema Paul and colleagues – including Christopher Ehlen and Allison Brager as co-first authors – report that conventional wisdom is wrong (Ehlen et al., 2017). Ehlen et al. decided to test whether restoring the expression of the Bmal1 gene selectively in the brain of Bmal1-deficient mice would rescue their response to sleep deprivation: it didn’t. However, restoring Bmal1 in skeletal muscle did. Mice with Bmal1 expressed in the skeletal muscle slept normally, whereas mice with Bmal1 expressed in the brain slept abnormally.
Moreover, when the researchers selectively knocked-out Bmal1 in the skeletal muscle, the mice couldn’t recover from sleep deprivation as well, similar to mice that completely lacked the gene. Conversely, when Bmal1 was over-expressed in skeletal muscle, it made them resistant to even longer periods of sleep deprivation.
Collectively, these results show that the Bmal1 gene in the skeletal muscle regulates responses to sleep deprivation. Not only is the two-process model obsolete – the dogma that sleep is governed solely by the brain has been upended. However, important questions remain. For example, does Bmal1 in the skeletal muscle regulate the response to sleep deprivation on its own, or are its partners Clock and Npas2 also involved? What specific signals does the skeletal muscle send to the brain to trigger the onset of sleep and how are they conveyed? Could timed exercise be used to amp up Bmal1 expression and lead to better sleep?
For decades, we’ve known that the body influences sleep. Think about how you felt the last time you had ‘food coma’, how tired you feel when you are sick or after a day in the sun, or how well you sleep after a great workout (provided sore muscles don't keep you awake all night as it does me -- JBH). For the first time, Ehlen et al. – who are based at Morehouse School of Medicine, the University of Florida, the Walter Reed Army Institute of Research, the University of Texas Southwestern Medical Center, and the University of California Los Angeles – show that a gene outside of the brain controls how mammals rebound from sleep deprivation. These findings may open new avenues for treating sleep disorders, potentially through exercise. “Eat well, exercise, and get lots of sleep” may be old advice, but now it’s supported by modern genetics.
References
-
CLOCK gene variants associate with sleep duration in two independent populationsBiological Psychiatry 67:1040–1047.https://doi.org/10.1016/j.biopsych.2009.12.026
-
A two process model of sleep regulationHuman Neurobiology 1:195–204.https://doi.org/10.1007/978-3-540-29678-2_6166
-
Transcriptional architecture of the mammalian circadian clockNature Reviews Genetics 18:164–179.https://doi.org/10.1038/nrg.2016.150
Article and author information
Author details
Publication history
Copyright
© 2017, Francey et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,208
- views
-
- 278
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Sleep: It's not all in the brain
eLife 6:e30561.
https://doi.org/10.7554/eLife.30561
Further reading
-
A specific gene in skeletal muscle helps to regulate sleep.
-
- Neuroscience
The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.
