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Lethargus is a Caenorhabditis elegans sleep-like state

Nature volume 451, pages 569–572 (2008)Cite this article

A Corrigendum to this article was published on 12 June 2008

Abstract

There are fundamental similarities between sleep in mammals and quiescence in the arthropod Drosophila melanogaster, suggesting that sleep-like states are evolutionarily ancient1,2,3. The nematode Caenorhabditis elegans also has a quiescent behavioural state during a period called lethargus, which occurs before each of the four moults4. Like sleep, lethargus maintains a constant temporal relationship with the expression of the C. elegans Period homologue LIN-42 (ref. 5). Here we show that quiescence associated with lethargus has the additional sleep-like properties of reversibility, reduced responsiveness and homeostasis. We identify the cGMP-dependent protein kinase (PKG) gene egl-4 as a regulator of sleep-like behaviour, and show that egl-4 functions in sensory neurons to promote the C. elegans sleep-like state. Conserved effects on sleep-like behaviour of homologous genes in C. elegans and Drosophila suggest a common genetic regulation of sleep-like states in arthropods and nematodes. Our results indicate that C. elegans is a suitable model system for the study of sleep regulation. The association of this C. elegans sleep-like state with developmental changes that occur with larval moults suggests that sleep may have evolved to allow for developmental changes.

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Figure 1: Behavioural quiescence is concentrated during the lethargus periods.
Figure 2: Responsiveness is reduced during lethargus.
Figure 3: Homeostatic regulation of lethargus.
Figure 4: The egl-4 cGMP-dependent protein kinase promotes sleep-like behaviour.

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Acknowledgements

We thank G. Maislin for statistical advice, A. Hart for discussions, A. Sehgal for comments on the manuscript, and the C. elegans Genetic Center, M. Sokolowski, N. L’Etoile, M. Fujiwara and K. Miller for reagents. This work was supported by grants from the National Institutes of Health (to D.M.R, M.V.S and A.I.P.) and from the National Alliance for Research on Schizophrenia and Depression (to D.M.R.).

Author Contributions D.M.R. designed and performed research, J.E.Z. performed Drosophila experiments, M.H.M. wrote computer programs, U.D.T. performed behavioural experiments involving 1-octanol response measurements, Y.Y. showed that tax-4p::egl-4 can rescue sleep-like behaviours of egl-4(lf), and M.V.S. and A.I.P. provided input into research design and drafted this manuscript along with D.M.R.

Author information

Authors and Affiliations

  1. Center for Sleep and Respiratory Neurobiology,,

    David M. Raizen, John E. Zimmerman, Matthew H. Maycock, Uyen D. Ta & Allan I. Pack

  2. Department of Neurology,,

    David M. Raizen & Uyen D. Ta

  3. Department of Genetics,,

    Meera V. Sundaram

  4. Division of Sleep Medicine, Department of Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA,

    Allan I. Pack

  5. Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA,

    Young-jai You

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Corresponding author

Correspondence to David M. Raizen.

Supplementary information

Supplementary Information 1

This file contains Supplementary Figures 1-4 with Legends, Supplementary Methods, Supplementary Tables 1-2 additional references and Legends to Supplementary Videos 1-7. (PDF 449 kb)

Behaviour during the middle of the L4 stage, before lethargus.

Shown is a video in 50x time lapse of a wild type worm on an agar surface in a lawn of bacteria during the middle of the fourth larval stage, before lethargus. Although the worm is continuously active, many movements are small with frequent changes in shape and direction. Therefore, the frame subtraction method (FIGURE S1) was developed to distinguish a moving animal from a quiescent one. (MOV 33728 kb)

Behaviour during the end of the L4 stage, during lethargus.

Shown is a video in 50x time lapse of the same wild type worm shown in Supplementary Video 1, only four hours later as it enters lethargus. Between quiescence periods, the animal appears to have brief normal movements of 10-30 second duration. (MOV 4269 kb)

Response to dish tap. Brief backing.

Shown is a 15 second video in 5x time lapse of a wild-type worm during lethargus. Following the dish tap, which is identified by movement of the shadow made by the mechanical lever, the worm backs briefly for a length less than that of its pharynx. (MOV 634 kb)

Response to dish tap. Sustained backing.

Shown is a 15 second video in 5x time lapse of a wild-type worm outside lethargus. Following the dish tap, which is identified by movement of the shadow made by the mechanical lever, the worm backs for a length greater than that of its pharynx. (MOV 7838 kb)

Response to dish tap. Complex response.

Shown is a 15 second video in 5x time lapse of a wild-type worm outside lethargus. Following the dish tap, which is identified by movement of the shadow made by the mechanical lever, the worm backs for a length greater than that of its pharynx, then changes direction and moves forward in a new direction. (MOV 635 kb)

Response to dish tap. Acceleration.

Shown is a 15 second video in 5x time lapse of a wild-type worm outside lethargus. Following the dish tap, which is identified by movement of the shadow made by the mechanical lever, the worm, which had been moving forward slowly, accelerates and moves forward faster. (MOV 8437 kb)

Response to dish tap. Shrinking response.

Shown is a 15 second video in 5x time lapse of a wild-type worm outside lethargus. Following the dish tap, which is identified by movement of the shadow made by the mechanical lever, the worm shrinks briefly. This type of response was seen only once. (MOV 694 kb)

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Raizen, D., Zimmerman, J., Maycock, M. et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature 451, 569–572 (2008). https://doi.org/10.1038/nature06535

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