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Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps

Nature Neuroscience volume 3, pages 600–607 (2000)Cite this article

Abstract

Are different forms of breathing derived from one or multiple neural networks? We demonstrate that brainstem slices containing the pre-Bötzinger complex generated two rhythms when normally oxygenated, with striking similarities to eupneic (‘normal’) respiration and sighs. Sighs were triggered by eupneic bursts under control conditions, but not in the presence of strychnine (1 μM). Although all neurons received synaptic inputs during both activities, the calcium channel blocker cadmium (4 μM) selectively abolished sighs. In anoxia, sighs ceased, and eupneic activity was reconfigured into gasping, which like eupnea was insensitive to 4 μM cadmium. This reconfiguration was accompanied by suppression of synaptic inhibition. We conclude that a single medullary network underlies multiple breathing patterns.

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Figure 1: Characterization of two activity patterns in vitro representing a fictive form of eupnea and sighs (augmented breaths).
Figure 2: The biphasic sigh can be separated into two distinct components.
Figure 3: Eupnea and sighs are differentially affected by cadmium and substance P (SP).
Figure 4: Characterization of a third activity pattern in vitro representing fictive gasping.
Figure 5: Stereotaxic maps of the distribution of rhythmic population activity during eupnea, sighs and gasping.
Figure 6: Activity of respiratory neurons during sighs.
Figure 7: Characterization of in vitro gasping in inspiratory cells.
Figure 8: Characterization of in vitro gasping: expiratory and post-inspiratory cells.

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References

  1. Kahn, A. et al. Polysomnographic studies of infants who subsequently died of sudden infant death syndrome. Pediatrics 82, 721–727 (1988).

    CAS  PubMed  Google Scholar 

  2. Poets, C. F., Meny, R. G., Chobanian, M. R. & Bonofiglo, R. E. Gasping and other cardiorespiratory patterns during sudden infant deaths. Pediatr. Res. 45, 350–354 (1999).

    Article  CAS  Google Scholar 

  3. Lijowska, A. S., Reed, N. W., Chiodini, B. A. & Thach, B. T. Sequential arousal and airway-defensive behavior of infants in asphyxial sleep environments. J. Appl. Physiol. 83, 219–228 (1997).

    Article  CAS  Google Scholar 

  4. Lumsden, T. Observations on the respiratory centres in the cat. J. Physiol. (Lond.) 57, 153–160 (1923).

    Article  CAS  Google Scholar 

  5. St. John, W. M. Neurogenesis of patterns of automatic ventilatory activity. Prog. Neurobiol. 56, 97–117 (1998).

    Article  CAS  Google Scholar 

  6. 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 

  7. Koshiya, N. & Guyenet. P. G. Tonic sympathetic reflex after blockade of respiratory rhythmogenesis in the cat. J. Physiol. (Lond.) 491, 859–869 (1996).

    Article  CAS  Google Scholar 

  8. Fung, M. L., Wang, W. & St. John, W. M. Medullary loci critical for expression of gasping in adult rats. J. Physiol. (Lond.) 480, 597–611 (1994).

    Article  CAS  Google Scholar 

  9. Huang, Q., Zhou, D. & St. John, W. M. Lesions of regions for in vitro ventilatory genesis eliminate gasping but not eupnea. Respir. Physiol. 107, 111–123 (1997).

    Article  CAS  Google Scholar 

  10. Ramirez, J. M., Schwarzacher, S. W., Pierrefiche, O., Olivera, B. M. & Richter, D. W. Selective lesioning of the cat pre-Bötzinger complex in vivo eliminates breathing but not gasping. J. Physiol. (Lond.) 507, 895–907 (1998).

    Article  CAS  Google Scholar 

  11. Meyrand, P., Simmers, J. & Moulins, M. Construction of a pattern-generating circuit with neurons of different networks. Nature 351, 60–63 (1991).

    Article  CAS  Google Scholar 

  12. Marder, E. Polymorphic neural networks. Curr. Biol. 4, 752–754 (1994).

    Article  CAS  Google Scholar 

  13. Ramirez, J. M. & Pearson, K. G. Generation of motor patterns for walking and flight in motoneurons supplying bifunctional muscles in the locust. J. Neurobiol. 19, 257–282 (1988).

    Article  CAS  Google Scholar 

  14. Ramirez, J. M. Reconfiguration of the respiratory network at the onset of locust flight. J. Neurophysiol. 80, 3137–3147 (1998).

    Article  CAS  Google Scholar 

  15. Grélot, L. & Bianchi, A. L. in Neural Control of the Respiratory Muscles (eds. Miller, A. D., Bianchi, A. L. & Bishop, B. P.) 297–304 (CRC Press, New York, 1997).

    Google Scholar 

  16. Ramirez, J. M., Quellmalz, U. J. & Wilken, B. Developmental changes in the hypoxic response of the hypoglossus respiratory motor output in vitro. J. Neurophysiol. 78, 383–392 (1997).

    Article  CAS  Google Scholar 

  17. Ramirez, J. M., Telgkamp, P., Elsen, F. P., Quellmalz, U. J. & Richter, D. W. Respiratory rhythm generation in mammals: synaptic and membrane properties. Respir. Physiol. 110, 71–85 (1997).

    Article  CAS  Google Scholar 

  18. Telgkamp, P. & Ramirez, J. M. Differential response of respiratory nuclei to anoxia in rhythmic brainstem slices of mice. J. Neurophysiol. 82, 2163–2170 (1999).

    Article  CAS  Google Scholar 

  19. Orem, J. & Trotter, R. H. Medullary respiratory neuronal activity during augmented breaths in intact unanesthetized cats. J. Appl. Physiol. 74, 761–769 (1993).

    Article  CAS  Google Scholar 

  20. Cherniack, N. S., von Euler, C., Glogowska, M. & Homma, I. Characteristics and rate of occurrence of spontaneous and provoked augmented breaths. Acta Physiol. Scand. 111, 349–360 (1981).

    Article  CAS  Google Scholar 

  21. Haddad, G. G. & Jiang, C. O2 deprivation in the central nervous system: on mechanisms of neuronal response, differential sensitivity and injury. Prog. Neurobiol. 40, 277–318 (1993).

    Article  CAS  Google Scholar 

  22. Neubauer, J. A., Melton, J. E. & Edelman, N. H. Modulation of respiration during brain hypoxia. J. Appl. Physiol. 68, 441–451 (1990).

    Article  CAS  Google Scholar 

  23. Bartlett, D. Jr. Origin and regulation of spontaneous deep breaths. Respir. Physiol. 12, 230–238 (1971).

    Article  Google Scholar 

  24. Wang, W., Fung, M. L., Darnall, R. A. & St. John, W. M. Characterizations and comparisons of eupnoea and gasping in neonatal rats. J. Physiol. (Lond.) 490, 277–292 (1996).

    Article  CAS  Google Scholar 

  25. Wang, W., Fung, M. L. & St. John, W. M. Pontile regulation of ventilatory activity in the adult rat. J. Appl. Physiol. 74, 2801–2811 (1993).

    Article  CAS  Google Scholar 

  26. Fung, M. L., Wang, W. & St. John W. M. Medullary loci critical for expression of gasping in adult rats. J. Physiol. 480, 597–611 (1994).

    Article  CAS  Google Scholar 

  27. Lawson, E. E. & Thach, B. T. Respiratory patterns during progressive asphyxia in newborn rabbits. J. Appl. Physiol. 43, 468–474 (1977).

    Article  CAS  Google Scholar 

  28. Macefield, G. & Nail, B. Phrenic and external intercostal motoneuron activity during progressive asphyxia. J. Appl. Physiol. 63, 1413–1420 (1987).

    Article  CAS  Google Scholar 

  29. Ellenberger, H. H. Nucleus ambiguus and bulbospinal ventral respiratory group neurons in the neonatal rat. Brain Res. Bull. 50, 1–13 (1999).

    Article  CAS  Google Scholar 

  30. Johnson, S. M., Smith, J. C., Funk, G. D. & Feldman, J. L. Pacemaker behavior of respiratory neurons in medullary slices from neonatal rat. J. Neurophysiol. 72, 2598–2608 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Koshiya, N. & Smith, J. C. Neuronal pacemaker for breathing visualized in vitro. Nature 400, 360–363 (1999).

    Article  CAS  Google Scholar 

  33. St. John, W. M. Rostral medullary respiratory neuronal activities of decerebrate cats in eupnea, apneusis and gasping. Respir. Physiol. 116, 47–65 (1999).

    Article  CAS  Google Scholar 

  34. Ramirez, J. M., Quellmalz, U. J., Wilken, B. & Richter, D. W. The hypoxic response of neurones within the in vitro mammalian respiratory network. J. Physiol. (Lond.) 507, 571–582 (1998).

    Article  CAS  Google Scholar 

  35. Schmidt, C., Bellingham, M. C. & Richter, D. W. Adenosinergic modulation of respiratory neurones and hypoxic responses in the anaesthetized cat. J. Physiol. (Lond.) 483, 769–781 (1995).

    Article  CAS  Google Scholar 

  36. England, S. J., Melton, J. E., Douse, M. A. & Duffin, J. Activity of respiratory neurons during hypoxia in the chemodenervated cat. J. Appl. Physiol. 78, 856–861 (1995).

    Article  CAS  Google Scholar 

  37. Tomori, Z., Benacka, R. & Donic, V. Mechanisms and clinicophysiological implications of the sniff- and gasp-like aspiration reflex. Respir. Physiol. 114, 83–98 (1998).

    Article  CAS  Google Scholar 

  38. Li, Y. Q., Takada, M., Kaneko, T. & Mizuno, N. Distribution of GABAergic and glycinergic premotor neurons projecting to the facial and hypoglossal nuclei in the rat. J. Comp. Neurol. 378, 283–294 (1997).

    Article  CAS  Google Scholar 

  39. Solomon, I. C., Edelman, N. H. & Neubauer, J. A. Patterns of phrenic motor output evoked by chemical stimulation of neurons located in the pre-Bötzinger complex in vivo. J. Neurophysiol. 81, 1150–1161 (1999).

    Article  CAS  Google Scholar 

  40. Dogas, Z. et al. Differential effects of GABAA receptor antagonists in the control of respiratory neuronal discharge patterns. J. Neurophysiol. 80, 2368–2377 (1998).

    Article  CAS  Google Scholar 

  41. Richter, D. W. Generation and maintenance of the respiratory rhythm. J. Exp. Biol. 100, 93–107 (1982).

    CAS  PubMed  Google Scholar 

  42. Haji, A., Takeda, R. & Remmers, J. E. Evidence that glycine and GABA mediate postsynaptic inhibition of bulbar respiratory neurons in the cat. J. Appl. Physiol. 73, 2333–2342 (1992).

    Article  CAS  Google Scholar 

  43. Schmid, K., Foutz, A. S. & Denavit-Saubie, M. Inhibitions mediated by glycine and GABAA receptors shape the discharge pattern of bulbar respiratory neurons. Brain Res. 710, 150–160 (1996).

    Article  CAS  Google Scholar 

  44. Brockhaus, J. & Ballanyi, K. Synaptic inhibition in the isolated respiratory network of neonatal rats. Eur. J. Neurosci. 10, 3823–3839 (1998).

    Article  CAS  Google Scholar 

  45. St. John, W. M., Zhou, D. & Fregosi, R. F. Expiratory neural activities in gasping. J. Appl. Physiol. 66, 223–231 (1989).

    Article  CAS  Google Scholar 

  46. Butera, R. J. Jr., Rinzel, J. & Smith, J. C. Models of respiratory rhythm generation in the pre-Bötzinger complex. I. Bursting pacemaker neurons. J. Neurophysiol. 82, 382–397 (1999).

    Article  Google Scholar 

  47. Elsen, F. P. & Ramirez, J. M. Calcium currents of rhythmic neurons recorded in the isolated respiratory network of neonatal mice. J. Neurosci. 18, 10652–10662 (1998).

    Article  CAS  Google Scholar 

  48. 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 

  49. Matsuishi, T. et al. Decreased cerebrospinal fluid levels of substance P in patients with Rett syndrome. Ann. Neurol. 42, 978–981 (1997).

    Article  CAS  Google Scholar 

  50. Obonai, T. et al. Relationship of substance P and gliosis in medulla oblongata in neonatal sudden infant death syndrome. Pediatr. Neurol. 15, 189–192 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Dawn Blitz for reading an earlier draft of this manuscript. We would also like to thank Katherine Nagel for her contribution to some earlier strychnine experiments. This work was supported by NIH RO1-HL 60120-01A1. S.P.L. was supported by NIGMS Medical Scientist National Research Award 5 T32 GM07281.

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Authors and Affiliations

  1. Committee on Neurobiology, The University of Chicago, 1027 East 57th Street, Chicago, 60637, Illinois, USA

    S. P. Lieske & J. M. Ramirez

  2. Department of Organismal Biology and Anatomy, The University of Chicago, 1027 East 57th Street, Chicago, 60637, Illinois, USA

    M. Thoby-Brisson, P. Telgkamp & J. M. Ramirez

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  1. S. P. Lieske
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Correspondence to J. M. Ramirez.

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Lieske, S., Thoby-Brisson, M., Telgkamp, P. et al. Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps. Nat Neurosci 3, 600–607 (2000). https://doi.org/10.1038/75776

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