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The genetic and molecular regulation of sleep: from fruit flies to humans

Nature Reviews Neuroscience volume 10, pages 549–560 (2009)Cite this article

Key Points

  • There are many sleep phenotypes, which reflect the duration and intensity of sleep, as well as its circadian and homeostatic regulation.

  • In flies, mice and humans, at least ten genes have either been linked to a human sleep disorder or have been shown to strongly affect sleep.

  • Genes affecting sleep belong to four major functional categories: circadian regulation, neurotransmission, other signalling pathways and ion channels.

  • Mutations in voltage-dependent potassium channels produce some of the most striking sleep phenotypes described so far in both flies and mammals.

  • Sleep and waking affect the expression of hundreds of brain transcripts.

  • mRNAs with higher expression during waking are related to energy metabolism, cellular stress and synaptic potentiation, suggesting that sleep might serve to maintain synaptic homeostasis by downscaling synapses strengthened during waking.

Abstract

It has been known for a long time that genetic factors affect sleep quantity and quality. Genetic screens have identified several mutations that affect sleep across species, pointing to an evolutionary conserved regulation of sleep. Moreover, it has also been recognized that sleep affects gene expression. These findings have given valuable insights into the molecular underpinnings of sleep regulation and function that might lead the way to more efficient treatments for sleep disorders.

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Figure 1: Sleep phenotypes.
Figure 2: Proposed mechanism for the short-sleeping phenotype caused by loss-of-function mutations of Shaker-encoded potassium channels.
Figure 3: The expression of Period mRNA and protein changes as a function of the 24 h cycle and in response to sleep deprivation.
Figure 4: The major functional categories of genes with increased expression in the rat brain after several hours of wakefulness or after several hours of sleep.

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Acknowledgements

This work was funded by US National Institutes of Health grants P20 MH077967 and R01 GM075315. I thank D. Bushey, S. Maret and G. Tononi for critical comments on the manuscript.

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  1. Department of Psychiatry, University of Wisconsin, Madison, 53719, Wisconsin, USA

    Chiara Cirelli

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Supplementary information

Supplementary information S1 (table)

Twin studies with heritability estimates for sleep phenotypes (% of variance explained by genetic effects) (PDF 206 kb)

Supplementary information S2 (table)

Studies in flies and mice using reverse and forward genetics to show effects of single candidate genes on sleep. (PDF 501 kb)

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Glossary

Hypocretin/orexin system

A group of neurons in the posterior hypothalamus that have diffuse projections to the CNS and release hypocretins or orexins. These neuropeptides have been involved in the regulation of sleep and arousal, feeding and energy metabolism.

Slow waves

Oscillations of cortical origin that have frequencies in the delta band.

Rapid-eye-movement (REM) sleep

The second phase of sleep observed in mammals and birds. In REM sleep the muscle tone is reduced or absent, but the EEG is similar to waking. REM theta activity (4–7 Hz) is also present.

Spindles

Waxing and waning oscillations of thalamic origin, the frequency of which is in the sigma band.

Non-rapid eye movement (NREM) sleep

One of the two types of sleep observed in mammals and birds. NREM sleep includes slow-wave sleep, characterized mainly by large slow waves.

Sleep consolidation

Consolidated sleep is characterized by long sleep episodes, little waking after sleep onset (WASO) and only few brief awakenings.

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Cirelli, C. The genetic and molecular regulation of sleep: from fruit flies to humans. Nat Rev Neurosci 10, 549–560 (2009). https://doi.org/10.1038/nrn2683

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