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.

Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons

Abstract

The normal breathing rhythm in mammals is hypothesized to be generated by neurokinin-1 receptor (NK1R)-expressing neurons in the preBötzinger complex (preBötC), a medullary region proposed to contain the kernel of the circuits generating respiration. If this hypothesis is correct, then complete destruction of preBötC NK1R neurons should severely perturb and perhaps even fatally arrest breathing. Here we show that specific and near complete bilateral (but not unilateral) destruction of preBötC NK1R neurons results in both an ataxic breathing pattern with markedly altered blood gases and pH, and pathological responses to challenges such as hyperoxia, hypoxia and anesthesia. Thus, these 600 neurons seem necessary for the generation of normal breathing in rats.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Local injection of SP-SAP selectively ablates preBötC NK1R neurons.
Figure 2: PreBötC rats breathe with an ataxic pattern.
Figure 3: PreBötC rats (3–5 days after injection) and control rats breathe differently.
Figure 4: Anesthetized (fluorothane, 1–2%) PreBötC rats do not have spontaneous respiratory activity.

References

  1. Rekling, J. C. & Feldman, J. L. PreBötzinger Complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu. Rev. Physiol. 60, 385–405 (1998).

    Article  CAS  Google Scholar 

  2. Smith, J. C., Ellenberger, H. H., Ballanyi, K., Richter, D. W. & Feldman, J. L. Pre-Bötzinger Complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254, 726–729 (1991).

    Article  CAS  Google Scholar 

  3. Gray, P. A., Rekling, J. C., Bocchiaro, C. M. & Feldman, J. L. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger Complex. Science 286, 1566–1568 (1999).

    Article  CAS  Google Scholar 

  4. Wang, H., Stornetta, R. L., Rosin, D. L. & Guyenet, P. G. Neurokinin-1 receptor-immunoreactive neurons of the ventral respiratory group in the rat. J. Comp. Neurol. 434, 128–146 (2001).

    Article  CAS  Google Scholar 

  5. Guyenet, P. G. & Wang, H. Pre-Bötzinger neurons with preinspiratory discharges “in vivo” express NK1 receptors in the rat. J. Neurophysiol. 86, 438–446 (2001).

    Article  CAS  Google Scholar 

  6. Mantyh, P. W. et al. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278, 275–279 (1997).

    Article  CAS  Google Scholar 

  7. Lieske, S. P., Thoby-Brisson, M., Telgkamp, P. & Ramirez, J. M. Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps. Nat. Neurosci. 3, 600–607 (2000).

    Article  CAS  Google Scholar 

  8. Mantyh, P. W. et al. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268, 1629–1632 (1995).

    Article  CAS  Google Scholar 

  9. Habre, W., Sims, C. & D' Souza, M. Anaesthetic management of children with Joubert syndrome. Paediatr. Anaesth. 7, 251–253 (1997).

    Article  CAS  Google Scholar 

  10. Ballayni, K., Onimaru, H. & Homma, I. Respiratory network function in the isolated brainstem-spinal cord of newborn rats. Prog. Neurobiol. 59, 583–684 (1999).

    Article  Google Scholar 

  11. Remmers, J. E. Central neural control of breathing. in Lung Biology in Health and Disease: Control of Breathing in Health and Disease (eds. Altose, M. & Kawakami, Y.) 1–41 (M. Dekker, New York, 1999).

    Google Scholar 

  12. McCrimmon, D. R., Monnier, A., Hayashi, F. & Zuperku, E. J. Pattern formation and rhythm generation in the ventral respiratory group. Clin. Exp. Pharmacol. Physiol. 27, 126–131 (2000).

    Article  CAS  Google Scholar 

  13. Dobbins, E. G. & Feldman, J. L. Brainstem network controlling descending drive to phrenic motoneurons in rat. J. Comp. Neurol. 347, 64–86 (1994).

    Article  CAS  Google Scholar 

  14. Speck, D. F. & Feldman, J. L. Effects of microstimulation and microlesion in the ventral and dorsal respiratory groups in medulla of cat. J. Neurosci. 2, 744–757 (1982).

    Article  CAS  Google Scholar 

  15. Champagnat, J. & Fortin, G. Primordial respiratory-like rhythm generation in the vertebrate embryo. Trends Neurosci. 20, 119–124 (1997).

    Article  CAS  Google Scholar 

  16. Gdovin, M. J., Torgerson, C. S. & Remmers, J. E. The fictively breathing tadpole brainstem preparation as a model for the development of respiratory pattern generation and central chemoreception. Comp. Biochem. Physiol. A. Mol. Integr. Physiol. 124, 275–286 (1999).

    Article  CAS  Google Scholar 

  17. Guilleminault, C. & Robinson, A. Central sleep apnea. Neurol. Clin. 14, 611–628 (1996).

    Article  CAS  Google Scholar 

  18. Thalhofer, S. & Dorow, P. Central sleep apnea. Respiration 64, 2–9 (1997).

    Article  CAS  Google Scholar 

  19. Gozal, D. Congenital central hypoventilation syndrome: an update. Pediatr. Pulmonol. 26, 273–282 (1998).

    Article  CAS  Google Scholar 

  20. Nattie, E., Bartlett, D. Jr. & Rozycki, A. Central alveolar hypoventilation in a child: an evaluation using a whole body plethysmograph. Amer. Rev. Resp. Dis. 112, 259–265 (1975).

    CAS  PubMed  Google Scholar 

  21. Maria, B. L., Boltshauser, E., Palmer, S. C. & Tran, T. X. Clinical features and revised diagnostic criteria in Joubert syndrome. J. Child Neurol. 14, 583–590 (1999).

    Article  CAS  Google Scholar 

  22. Guilleminault, C. & Robinson, A. Developmental aspects of sleep and breathing. Curr. Opin. Pulm. Med. 2, 492–499 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Sofroniew, N. Brecha, T. Otis, R. Fregosi and L. Kruger for assistance and G. Li for histological work. A. Monnier participated in early experiments. Funding was provided by a Ford Foundation Pre-Doctoral Fellowship for Minorities and the Porter Physiology Development Program of the American Physiological Society to P.A.G., and by the National Institutes of Health (HL40959). W.A.J. is on leave of absence from the Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jack L. Feldman.

Supplementary information

Control.mov:

A rat 2 days after injection of SP-SAP that would ultimately produce ~100% bilateral destruction of preB&246;tC NK1R neurons. Because the SP-SAP lesions do not seem to affect breathing before 4-5 days after injection, this rat breathes with an essentially normal pattern. The rat is undrugged and unrestrained. Trace at top is plethysmograph recording; sound is diaphragmatic EMG. (MOV 3546 kb)

Ataxic.mov:

The same rat as in control.mov 8 days after injection, after about 3 days of pathological breathing. The rat is undrugged and unrestrained. Trace at top is integrated diaphragmatic EMG; sound is diaphragmatic EMG. (MOV 7087 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gray, P., Janczewski, W., Mellen, N. et al. Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons. Nat Neurosci 4, 927–930 (2001). https://doi.org/10.1038/nn0901-927

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn0901-927

This article is cited by

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