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Sleep and circadian rhythmicity as entangled processes serving homeostasis

Nature Reviews Neuroscience volume 25, pages 43–59 (2024)Cite this article

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Abstract

Sleep is considered essential for the brain and body. A predominant concept is that sleep is regulated by circadian rhythmicity and sleep homeostasis, processes that were posited to be functionally and mechanistically separate. Here we review and re-evaluate this concept and its assumptions using findings from recent human and rodent studies. Alterations in genes that are central to circadian rhythmicity affect not only sleep timing but also putative markers of sleep homeostasis such as electroencephalogram slow-wave activity (SWA). Perturbations of sleep change the rhythmicity in the expression of core clock genes in tissues outside the central clock. The dynamics of recovery from sleep loss vary across sleep variables: SWA and immediate early genes show an early response, but the recovery of non-rapid eye movement and rapid eye movement sleep follows slower time courses. Changes in the expression of many genes in response to sleep perturbations outlast the effects on SWA and time spent asleep. These findings are difficult to reconcile with the notion that circadian- and sleep–wake-driven processes are mutually independent and that the dynamics of sleep homeostasis are reflected in a single variable. Further understanding of how both sleep and circadian rhythmicity contribute to the homeostasis of essential physiological variables may benefit from the assessment of multiple sleep and molecular variables over longer time scales.

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Fig. 1: Phenomenology of sleep.
Fig. 2: Responses to sleep loss: different dynamics for REM sleep, NREM sleep and SWA.
Fig. 3: Generation of circadian rhythmicity.
Fig. 4: Modelling sleep–wake-driven and circadian-driven aspects of sleep–wake regulation.
Fig. 5: Clock genes and their variants affect aspects of sleep regulation.
Fig. 6: Effect of circadian clock and sleep–wake history on rhythmic transcription varies across genes.

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Data availability

The example graphs depicted in Figs. 1 and 2 are based on the publicly accessible data resource https://bxd.vital-it.ch/, published first in ref. 39 and then as a digital research object describing the analyses pipe-line and links to data and analyses scripts98. Simulations of the sleep–wake-driven process in the mouse (Fig. 4b,d) were performed using parameters and methods described in ref. 99 and illustrated in Fig. 4a, on data from ref. 100.

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Acknowledgements

This publication and some of the research highlighted by P.F. was supported by the Swiss National Science Foundation (grants CRSII3_136201, 31003A_173182, 310030B_192805 and 310030_214847) and the State of Vaud, Switzerland. Research by D.-J.D. is supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd, the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The authors thank S. Archer for comments on the manuscript, and A. C. Skeldon for preparing Fig. 4c.

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  1. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

    Paul Franken

  2. Surrey Sleep Research Centre, University of Surrey, Guildford, UK

    Derk-Jan Dijk

  3. UK Dementia Research Institute, Care Research and Technology Centre, Imperial College London and the University of Surrey, Guildford, UK

    Derk-Jan Dijk

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Franken, P., Dijk, DJ. Sleep and circadian rhythmicity as entangled processes serving homeostasis. Nat. Rev. Neurosci. 25, 43–59 (2024). https://doi.org/10.1038/s41583-023-00764-z

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