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.

  • Article
  • Published:

Hypoxia activates a latent circuit for processing gustatory information in C. elegans

Nature Neuroscience volume 13, pages 610–614 (2010)Cite this article

Subjects

Abstract

Dedicated neuronal circuits enable animals to engage in specific behavioral responses to environmental stimuli. We found that hypoxic stress enhanced gustatory sensory perception via previously unknown circuitry in Caenorhabditis elegans. The hypoxia-inducible transcription factor HIF-1 upregulated serotonin (5-HT) expression in specific sensory neurons that are not normally required for chemosensation. 5-HT subsequently promoted hypoxia-enhanced sensory perception by signaling through the metabotropic G protein–coupled receptor SER-7 in an unusual peripheral neuron, the M4 motor neuron. M4 relayed this information back into the CNS via the FMRFamide-related neuropeptide FLP-21 and its cognate receptor, NPR-1. Thus, physiological detection of hypoxia results in the activation of an additional, previously unrecognized circuit for processing sensory information that is not required for sensory processing under normoxic conditions.

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: 5-HT expression is altered in hypoxia through direct HIF-1 regulation of tph-1.
Figure 2: C. elegans shows enhanced sensory perception after hypoxic stress using HIF-1 and 5-HT in a neuron-specific manner.
Figure 3: SER-7, a 5-HT7–like metabotropic receptor, acts in the M4 pharyngeal motorneuron to induce HESP.
Figure 4: Mutations in flp-21 and npr-1 caused defects in the HESP response.

Similar content being viewed by others

References

  1. Joels, M. & Baram, T.Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459–466 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. de Kloet, E.R., Joels, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nat. Rev. Neurosci. 6, 463–475 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. McEwen, B.S. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904 (2007).

    Article  PubMed  Google Scholar 

  4. Chaouloff, F. Serotonin, stress and corticoids. J. Psychopharmacol. 14, 139–151 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Liang, B. et al. Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metab. 4, 429–440 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, Y., Lu, H. & Bargmann, C.I. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438, 179–184 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Chang, A.J. et al. A distributed chemosensory circuit for oxygen preference in C. elegans. PLoS Biol. 4, e274 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hukema, R.K., Rademakers, S. & Jansen, G. Gustatory plasticity in C. elegans involves integration of negative cues and NaCl taste mediated by serotonin, dopamine and glutamate. Learn. Mem. 15, 829–836 (2008).

    Article  PubMed  Google Scholar 

  9. Pocock, R. & Hobert, O. Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans. Nat. Neurosci. 11, 894–900 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Sze, J.Y. et al. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403, 560–564 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Semenza, G.L. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol. Med. 7, 345–350 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Epstein, A.C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Bishop, T. et al. Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. PLoS Biol. 2, e289 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Shen, C. et al. Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans. J. Biol. Chem. 280, 20580–20588 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Semenza, G.L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Rahman, M.S. & Thomas, P. Molecular cloning, characterization and expression of two tryptophan hydroxylase (TPH-1 and TPH-2) genes in the hypothalamus of Atlantic croaker: down-regulation after chronic exposure to hypoxia. Neuroscience 158, 751–765 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Poncet, L. et al. Activity of tryptophan hydroxylase and content of indolamines in discrete brain regions after a long-term hypoxic exposure in the rat. Brain Res. 765, 122–128 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Bargmann, C.I. & Horvitz, H.R. Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans. Neuron 7, 729–742 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Uchida, O. et al. The C. elegans che-1 gene encodes a zinc finger transcription factor required for specification of the ASE chemosensory neurons. Development 130, 1215–1224 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Hobson, R.J. et al. SER-7, a Caenorhabditis elegans 5-HT7-like receptor, is essential for the 5-HT stimulation of pharyngeal pumping and egg laying. Genetics 172, 159–169 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hapiak, V.M. et al. Dual excitatory and inhibitory serotonergic inputs modulate egg laying in Caenorhabditis elegans. Genetics 181, 153–163 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hobson, R.J. et al. SER-7b, a constitutively active Gα-coupled 5-HT7–like receptor expressed in the Caenorhabditis elegans M4 pharyngeal motorneuron. J. Neurochem. 87, 22–29 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Ray, P., Schnabel, R. & Okkema, P.G. Behavioral and synaptic defects in C. elegans lacking the NK-2 homeobox gene ceh-28. Dev. Neurobiol. 68, 421–433 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Mehta, R. et al. Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science 324, 1196–1198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Avery, L. & Horvitz, H.R. Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans. Neuron 3, 473–485 (1989).

    Article  CAS  PubMed  Google Scholar 

  26. Albertson, D.G. & Thomson, J.N. The pharynx of Caenorhabditis elegans. Phil. Trans. R. Soc. Lond. B 275, 299–325 (1976).

    Article  CAS  Google Scholar 

  27. Kim, K. & Li, C. Expression and regulation of an FMRFamide-related neuropeptide gene family in Caenorhabditis elegans. J. Comp. Neurol. 475, 540–550 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Rogers, C. et al. Inhibition of Caenorhabditis elegans social feeding by FMRFamide-related peptide activation of NPR-1. Nat. Neurosci. 6, 1178–1185 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Gloria-Soria, A. & Azevedo, R.B. npr-1 regulates foraging and dispersal strategies in Caenorhabditis elegans. Curr. Biol. 18, 1694–1699 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. de Bono, M. & Bargmann, C.I. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 94, 679–689 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Coates, J.C. & de Bono, M. Antagonistic pathways in neurons exposed to body fluid regulate social feeding in Caenorhabditis elegans. Nature 419, 925–929 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Hukema, R.K. et al. Antagonistic sensory cues generate gustatory plasticity in Caenorhabditis elegans. EMBO J. 25, 312–325 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheung, B.H. et al. Experience-dependent modulation of C. elegans behavior by ambient oxygen. Curr. Biol. 15, 905–917 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Pierce-Shimomura, J.T., Morse, T.M. & Lockery, S.R. The fundamental role of pirouettes in Caenorhabditis elegans chemotaxis. J. Neurosci. 19, 9557–9569 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chang, A.J. & Bargmann, C.I. Hypoxia and the HIF-1 transcriptional pathway reorganize a neuronal circuit for oxygen-dependent behavior in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 105, 7321–7326 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Poncet, L. et al. Alteration in central and peripheral substance P- and neuropeptide Y–like immunoreactivity after chronic hypoxia in the rat. Brain Res. 733, 64–72 (1996).

    CAS  PubMed  Google Scholar 

  37. Sarafi-Reinach, T.R. et al. The lin-11 LIM homeobox gene specifies olfactory and chemosensory neuron fates in C. elegans. Development 128, 3269–3281 (2001).

    CAS  PubMed  Google Scholar 

  38. Sagasti, A. et al. Alternative olfactory neuron fates are specified by the LIM homeobox gene lim-4. Genes Dev. 13, 1794–1806 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aspöck, G., Ruvkun, G. & Burglin, T.R. The Caenorhabditis elegans ems class homeobox gene ceh-2 is required for M3 pharynx motoneuron function. Development 130, 3369–3378 (2003).

    Article  PubMed  Google Scholar 

  40. Macosko, E.Z. et al. A hub-and-spoke circuit drives pheromone attraction and social behavior in C. elegans. Nature 458, 1171–1175 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bargmann, C.I. & Horvitz, H.R. Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans. Neuron 7, 729–742 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Sze, J.Y. et al. Food and metabolic signaling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403, 560–564 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71 (1974).

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Boyanov and G. Baison for technical assistance, Q. Chen for expert microinjection help, I. Greenwald, M. De Bono and members of the Hobert laboratory for comments on the manuscript, and the Caenorhabditis Genetics Center and C. Bargmann for providing strains. This work was supported by the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University Medical Center, New York, New York, USA

    Roger Pocock & Oliver Hobert

Authors
  1. Roger Pocock
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Hobert
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.P. initiated this study and conducted all of the experiments. R.P. and O.H. designed and discussed the experiments and wrote the paper.

Corresponding author

Correspondence to Roger Pocock.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 1634 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pocock, R., Hobert, O. Hypoxia activates a latent circuit for processing gustatory information in C. elegans. Nat Neurosci 13, 610–614 (2010). https://doi.org/10.1038/nn.2537

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2537

This article is cited by

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