Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Stress response genes protect against lethal effects of sleep deprivation in Drosophila

Nature volume 417, pages 287–291 (2002)Cite this article

Abstract

Sleep is controlled by two processes: a homeostatic drive that increases during waking and dissipates during sleep, and a circadian pacemaker that controls its timing1. Although these two systems can operate independently2,3, recent studies indicate a more intimate relationship4,5. To study the interaction between homeostatic and circadian processes in Drosophila, we examined homeostasis in the canonical loss-of-function clock mutants period (per01), timeless (tim01), clock (Clkjrk) and cycle (cyc01)6,7,8,9. cyc01 mutants showed a disproportionately large sleep rebound and died after 10 hours of sleep deprivation, although they were more resistant than other clock mutants to various stressors. Unlike other clock mutants, cyc01 flies showed a reduced expression of heat-shock genes after sleep loss. However, activating heat-shock genes before sleep deprivation rescued cyc01 flies from its lethal effects. Consistent with the protective effect of heat-shock genes, was the observation that flies carrying a mutation for the heat-shock protein Hsp83 (Hsp8308445)10 showed exaggerated homeostatic response and died after sleep deprivation. These data represent the first step in identifying the molecular mechanisms that constitute the sleep homeostat.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sleep homeostasis is altered in circadian mutants and is markedly increased in cyc01 flies.
Figure 2: cyc01 flies are resistant to stress.
Figure 3: Expression of heat-shock genes is reduced in cyc01 flies after 3 h of sleep deprivation.
Figure 4: Heat protects cyc01 flies from the lethal effects of sleep deprivation.

Similar content being viewed by others

References

  1. Borbely, A. A. & Achermann, P. Sleep homeostasis and models of sleep regulation. J. Biol. Rhythms 14, 557–568 (1999)

    CAS  PubMed  Google Scholar 

  2. Mistlberger, R. E., Bergmann, B. M., Waldenar, W. & Rechtschaffen, A. Recovery sleep following sleep deprivation in intact and suprachiasmatic nuclei-lesioned rats. Sleep 6, 217–233 (1983)

    Article  CAS  PubMed  Google Scholar 

  3. Tobler, I., Borbely, A. A. & Groos, G. The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions. Neurosci. Lett. 42, 49–54 (1983)

    Article  CAS  PubMed  Google Scholar 

  4. Naylor, E. et al. The circadian clock mutation alters sleep homeostasis in the mouse. J. Neurosci. 20, 8138–8143 (2000)

    Article  CAS  PubMed  Google Scholar 

  5. Antle, M. C. & Mistlberger, R. E. Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster. J. Neurosci. 20, 9326–9332 (2000)

    Article  CAS  PubMed  Google Scholar 

  6. Konopka, R. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971)

    Article  ADS  CAS  Google Scholar 

  7. Sehgal, A., Price, J. L., Man, B. & Young, M. W. Loss of circadian behavioural rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–1606 (1994)

    Article  ADS  CAS  Google Scholar 

  8. Allada, R., White, N. E., So, W. V., Hall, J. C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791–804 (1998)

    Article  CAS  Google Scholar 

  9. Rutila, J. E. et al. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–814 (1998)

    Article  CAS  Google Scholar 

  10. Castrillon, D. H. et al. Toward a molecular genetic analysis of spermatogenesis in Drosophila melanogaster: characterization of male-sterile mutants generated by single P element mutagenesis. Genetics 135, 489–505 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shaw, P. J., Cirelli, C., Greenspan, R. J. & Tononi, G. Correlates of sleep and waking in Drosophila melanogaster. Science 287, 1834–1837 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Hendricks, J. C. et al. Rest in Drosophila is a sleep-like state. Neuron 25, 129–138 (2000)

    Article  CAS  Google Scholar 

  13. Edgar, D. M., Dement, W. C. & Fuller, C. A. Effect of SCN lesions on sleep in squirrel monkeys: Evidence for opponent processes in sleep–wake regulation. J. Neurosci. 13, 1065–1079 (1993)

    Article  CAS  PubMed  Google Scholar 

  14. Dijk, D. J. & Czeisler, C. A. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci. Lett. 166, 63–68 (1994)

    Article  CAS  PubMed  Google Scholar 

  15. Homyk, T., Szidonya, J. & Suzuki, D. T. Behavioral mutants of Drosophila melanogaster. Mol. Gen. Genet. 177, 553–565 (1980)

    Article  PubMed  Google Scholar 

  16. Armitage, R., Smith, C., Thompson, S. & Hoffman, R. Sex differences in slow-wave activity in response to sleep deprivation. Sleep Res. Online 4, 33–41 (2001)

    Google Scholar 

  17. Rechtschaffen, A., Gilliland, M. A., Bergmann, B. M. & Winter, J. B. Physiological correlates of prolonged sleep deprivation in rats. Science 221, 182–184 (1983)

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Sapolsky, R. M. Stress hormones: good and bad. Neurobiol. Dis. 7, 540–542 (2000)

    Article  CAS  PubMed  Google Scholar 

  19. Ashburner, M. Patterns of puffing activity in the salivary gland chromosomes of Drosophila. Chromosoma 31, 356–376 (1970)

    Article  CAS  PubMed  Google Scholar 

  20. Marchler, G. & Wu, C. Modulation of Drosophila heat shock transcription factor activity by the molecular chaperone DROJ1. EMBO J. 20, 499–509 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ornelles, D. A. & Penman, S. Prompt heat-shock and heat-shifted proteins associated with the nuclear matrix–intermediate filament scaffold in Drosophila melanogaster cells. J. Cell Sci. 95, 393–404 (1990)

    CAS  PubMed  Google Scholar 

  22. Cirelli, C. & Tononi, G. Gene expression in the brain across the sleep–waking cycle. Brain Res. 885, 303–321 (2000)

    Article  CAS  PubMed  Google Scholar 

  23. Yoshida, E. N., Benkel, B. F., Fong, Y. & Hickey, D. A. Sequence and phylogenetic analysis of the SNF4/AMPK gamma subunit gene from Drosophila melanogaster. Genome 42, 1077–1087 (1999)

    Article  CAS  PubMed  Google Scholar 

  24. Ma, E. & Haddad, G. G. Isolation and characterization of the hypoxia-inducible factor 1β in Drosophila melanogaster. Brain Res. Mol. Brain Res. 73, 11–16 (1999)

    Article  CAS  PubMed  Google Scholar 

  25. Cornelius, G. & Engel, M. Stress causes induction of MAP kinase-specific phosphatase and rapid repression of MAP kinase activity in Drosophila. Cell Signal. 7, 611–615 (1995)

    Article  CAS  PubMed  Google Scholar 

  26. Ekengren, S. et al. A humoral stress response in Drosophila. Curr. Biol. 11, 714–718 (2001)

    Article  CAS  PubMed  Google Scholar 

  27. Perezgasga, L., Segovia, L. & Zurita, M. Molecular characterization of the 5′ control region and of two lethal alleles affecting the hsp60 gene in Drosophila melanogaster. FEBS Lett. 456, 269–273 (1999)

    Article  CAS  PubMed  Google Scholar 

  28. Hogenesch, J. B. et al. Characterization of a subset of the basic-helix–loop–helix-PAS superfamily that interacts with components of the dioxin signalling pathway. J. Biol. Chem. 272, 8581–8593 (1997)

    Article  CAS  PubMed  Google Scholar 

  29. Rechtschaffen, A. Current perspectives on the function of sleep. Perspect. Biol. Med. 41, 359–390 (1998)

    Article  CAS  PubMed  Google Scholar 

  30. Rechtschaffen, A., Bergmann, B. M., Everson, C. A., Kushida, C. A. & Gilliland, M. A. Sleep deprivation in the rat: X. Integration and discussion of the findings. Sleep 12, 68–87 (1989)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank H. Dierick, R. Andretic and K. Long for helpful comments on the manuscript, and J. Hendricks for sharing data before publication. This work was performed at The Neurosciences Institute, which is supported by the Neurosciences Research Foundation.

Author information

Author notes

  1. Giulio Tononi

    Present address: Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Boulevard, Madison, Wisconsin, 53711, USA

Authors and Affiliations

  1. The Neurosciences Institute, 10640 John J. Hopkins Drive, San Diego, California, 92121, USA

    Paul J. Shaw, Giulio Tononi, Ralph J. Greenspan & Donald F. Robinson

Authors
  1. Paul J. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giulio Tononi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ralph J. Greenspan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donald F. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shaw, P., Tononi, G., Greenspan, R. et al. Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417, 287–291 (2002). https://doi.org/10.1038/417287a

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/417287a

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing