Journal of Computational Neuroscience

, Volume 30, Issue 3, pp 515–528 | Cite as

Two types of independent bursting mechanisms in inspiratory neurons: an integrative model



The network of coupled neurons in the pre-Bötzinger complex (pBC) of the medulla generates a bursting rhythm, which underlies the inspiratory phase of respiration. In some of these neurons, bursting persists even when synaptic coupling in the network is blocked and respiratory rhythmic discharge stops. Bursting in inspiratory neurons has been extensively studied, and two classes of bursting neurons have been identified, with bursting mechanism depends on either persistent sodium current or changes in intracellular Ca2+, respectively. Motivated by experimental evidence from these intrinsically bursting neurons, we present a two-compartment mathematical model of an isolated pBC neuron with two independent bursting mechanisms. Bursting in the somatic compartment is modeled via inactivation of a persistent sodium current, whereas bursting in the dendritic compartment relies on Ca2+ oscillations, which are determined by the neuromodulatory tone. The model explains a number of conflicting experimental results and is able to generate a robust bursting rhythm, over a large range of parameters, with a frequency adjusted by neuromodulators.


Respiratory rhythm Dendritic bursting Ca2+ oscillations Pre-Bötzinger complex Intrinsic burster Endogenous neurotransmitters 


  1. Andrews, S. B., Leapman, R. D., Landis, D. M., & Reese, T. S. (1988). Activity-dependent accumulation of calcium in Purkinje cell dendritic spines. Proceedings of the National Academy of Sciences of the United States of America, 85, 1682–1685.PubMedCrossRefGoogle Scholar
  2. Arata, A., Onimaru, H., & Homma, I. (1998). The adrenergic modulation of firings of respiratory rhythm-generating neurons in medulla-spinal cord preparation from newborn rat. Experimental Brain Research, 119, 399–408.CrossRefGoogle Scholar
  3. Bell, H. J., Inoue, T., Shum, K., Luk, C., & Syed, N. I. (2007). Peripheral oxygen-sensing cells directly modulate the output of an identified respiratory central pattern generating neuron. The European Journal of Neuroscience, 25, 3537–3550.PubMedCrossRefGoogle Scholar
  4. Brown, C. H., Ludwig, M., & Leng, G. (1998). kappa-opioid regulation of neuronal activity in the rat supraoptic nucleus in vivo. The Journal of Neuroscience, 18, 9480–9488.PubMedGoogle Scholar
  5. Butera, R. J., Jr., Rinzel, J., & Smith, J. C. (1999). Models of respiratory rhythm generation in the pre-Botzinger complex. I. Bursting pacemaker neurons. Journal of Neurophysiology, 82, 382–397.PubMedGoogle Scholar
  6. Cho, H., Kim, M. S., Shim, W. S., Yang, Y. D., Koo, J., & Oh, U. (2003). Calcium-activated cationic channel in rat sensory neurons. The European Journal of Neuroscience, 17, 2630–2638.PubMedCrossRefGoogle Scholar
  7. Czarnecki, A., Magloire, V., & Streit, J. (2009). Modulation of intrinsic spiking in spinal cord neurons. Journal of Neurophysiology, 102, 2441–2452.PubMedCrossRefGoogle Scholar
  8. Del Negro, C. A., Johnson, S. M., Butera, R. J., & Smith, J. C. (2001). Models of respiratory rhythm generation in the pre-Botzinger complex. III. Experimental tests of model predictions. Journal of Neurophysiology, 86, 59–74.PubMedGoogle Scholar
  9. Del Negro, C. A., Morgado-Valle, C., & Feldman, J. L. (2002a). Respiratory rhythm: an emergent network property? Neuron, 34, 821–830.CrossRefGoogle Scholar
  10. Del Negro, C. A., Koshiya, N., Butera, R. J., Jr., & Smith, J. C. (2002b). Persistent sodium current, membrane properties and bursting behavior of pre-botzinger complex inspiratory neurons in vitro. Journal of Neurophysiology, 88, 2242–2250.CrossRefGoogle Scholar
  11. Del Negro, C. A., Morgado-Valle, C., Hayes, J. A., Mackay, D. D., Pace, R. W., Crowder, E. A., et al. (2005). Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation. The Journal of Neuroscience, 25, 446–453.PubMedCrossRefGoogle Scholar
  12. Doi, A., & Ramirez, J. M. (2008). Neuromodulation and the orchestration of the respiratory rhythm. Respiratory Physiology & Neurobiology, 164, 96–104.CrossRefGoogle Scholar
  13. Elsen, F. P., & Ramirez, J. M. (1998). Calcium currents of rhythmic neurons recorded in the isolated respiratory network of neonatal mice. The Journal of Neuroscience, 18, 10652–10662.PubMedGoogle Scholar
  14. Elsen, F. P., & Ramirez, J. M. (2005). Postnatal development differentially affects voltageactivated calcium currents in respiratory rhythmic versus nonrhythmic neurons of the pre-Botzinger complex. Journal of Neurophysiology, 94, 1423–1431.PubMedCrossRefGoogle Scholar
  15. Ermentrout, B. (2002). Simulating, analyzing, and animating dynamical systems: a guide to XPPAUT for researchers and students. Philadelphia: Society for Industrial and Applied Mathematics.CrossRefGoogle Scholar
  16. Fujii, M., Umezawa, K., & Arata, A. (2004). Dopaminergic modulation on respiratory rhythm in rat brainstem-spinal cord preparation. Neuroscience Research, 50, 355–359.PubMedCrossRefGoogle Scholar
  17. Funk, G. D., Smith, J. C., & Feldman, J. L. (1993). Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids. Journal of Neurophysiology, 70, 1497–1515.PubMedGoogle Scholar
  18. Helliwell, R. M., & Large, W. A. (1997). Alpha 1-adrenoceptor activation of a non-selective cation current in rabbit portal vein by 1, 2-diacyl-sn-glycerol. Journal de Physiologie, 499(Pt 2), 417–428.Google Scholar
  19. Herlenius, E., & Lagercrantz, H. (1999). Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro. Journal de Physiologie, 518(Pt 1), 159–172.CrossRefGoogle Scholar
  20. Hilaire, G., Viemari, J. C., Coulon, P., Simonneau, M., & Bevengut, M. (2004). Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents. Respiratory Physiology & Neurobiology, 143, 187–197.CrossRefGoogle Scholar
  21. Hill, A. J., Hinton, J. M., Cheng, H., Gao, Z., Bates, D. O., Hancox, J. C., et al. (2006). A TRPC-like non-selective cation current activated by alpha 1-adrenoceptors in rat mesenteric artery smooth muscle cells. Cell Calcium, 40, 29–40.PubMedCrossRefGoogle Scholar
  22. Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal de Physiologie, 117, 500–544.Google Scholar
  23. Johnson, S. M., Smith, J. C., Funk, G. D., & Feldman, J. L. (1994). Pacemaker behavior of respiratory neurons in medullary slices from neonatal rat. Journal of Neurophysiology, 72, 2598–2608.PubMedGoogle Scholar
  24. Johnson, R. A., Johnson, S. M., & Mitchell, G. S. (1998). Catecholaminergic modulation of respiratory rhythm in an in vitro turtle brain stem preparation. Journal of Applied Physiology, 85, 105–114.PubMedGoogle Scholar
  25. Koizumi, H., & Smith, J. C. (2008). Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Botzinger complex in vitro. The Journal of Neuroscience, 28, 1773–1785.PubMedCrossRefGoogle Scholar
  26. Krnjevic, K. (1999). Early effects of hypoxia on brain cell function. Croatian Medical Journal, 40, 375–380.PubMedGoogle Scholar
  27. Li, Y. X., & Rinzel, J. (1994). Equations for InsP3 receptor-mediated [Ca2+]i oscillations derived from a detailed kinetic model: a Hodgkin-Huxley like formalism. Journal of Theoretical Biology, 166, 461–473.PubMedCrossRefGoogle Scholar
  28. Llona, I., & Eugenin, J. (2005). Central actions of somatostatin in the generation and control of breathing. Biological Research, 38, 347–352.PubMedCrossRefGoogle Scholar
  29. Lopez-Barneo, J., Ortega-Saenz, P., Pardal, R., Pascual, A., & Piruat, J. I. (2008). Carotid body oxygen sensing. The European Respiratory Journal, 32, 1386–1398.PubMedCrossRefGoogle Scholar
  30. Marder, E. (1988). Modulating a neuronal network. Nature, 335, 296–297.PubMedCrossRefGoogle Scholar
  31. Martin, E. D., Fernandez, M., Perea, G., Pascual, O., Haydon, P. G., Araque, A., et al. (2007). Adenosine released by astrocytes contributes to hypoxia-induced modulation of synaptic transmission. Glia, 55, 36–45.PubMedCrossRefGoogle Scholar
  32. Martone, M. E., Zhang, Y., Simpliciano, V. M., Carragher, B. O., & Ellisman, M. H. (1993). Threedimensional visualization of the smooth endoplasmic reticulum in Purkinje cell dendrites. The Journal of Neuroscience, 13, 4636–4646.PubMedGoogle Scholar
  33. Mironov, S. L. (2008). Metabotropic glutamate receptors activate dendritic calcium waves and TRPM channels which drive rhythmic respiratory patterns in mice. Journal de Physiologie, 586, 2277–2291.CrossRefGoogle Scholar
  34. Morgado-Valle, C., Beltran-Parrazal, L., DiFranco, M., Vergara, J. L., & Feldman, J. L. (2008). Somatic Ca2+ transients do not contribute to inspiratory drive in preBotzinger Complex neurons. Journal de Physiologie, 586, 4531–4540.CrossRefGoogle Scholar
  35. Nieber, K. (1999). Hypoxia and neuronal function under in vitro conditions. Pharmacology & Therapeutics, 82, 71–86.CrossRefGoogle Scholar
  36. Onimaru, H., Ballanyi, K., & Richter, D. W. (1996). Calcium-dependent responses in neurons of the isolated respiratory network of newborn rats. Journal de Physiologie, 491(Pt 3), 677–695.Google Scholar
  37. Onimaru, H., Shamoto, A., & Homma, I. (1998). Modulation of respiratory rhythm by 5-HT in the brainstem-spinal cord preparation from newborn rat. Pflugers Archiv, 435, 485–494.PubMedCrossRefGoogle Scholar
  38. Pace, R. W., Mackay, D. D., Feldman, J. L., & Del Negro, C. A. (2007). Inspiratory bursts in the preBotzinger complex depend on a calcium-activated non-specific cation current linked to glutamate receptors in neonatal mice. Journal de Physiologie, 582, 113–125.CrossRefGoogle Scholar
  39. Pena, F., & Aguileta, M. A. (2007). Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo. Neuroscience Letters, 415, 288–293.PubMedCrossRefGoogle Scholar
  40. Pena, F., Parkis, M. A., Tryba, A. K., & Ramirez, J. M. (2004). Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron, 43, 105–117.PubMedCrossRefGoogle Scholar
  41. Pena, F., & Ramirez, J. M. (2005). Hypoxia-induced changes in neuronal network properties. Molecular Neurobiology, 32, 251–283.PubMedCrossRefGoogle Scholar
  42. Ptak, K., & Hilaire, G. (1999). Central respiratory effects of substance P in neonatal mice: an in vitro study. Neuroscience Letters, 266, 189–192.PubMedCrossRefGoogle Scholar
  43. Ptak, K., Yamanishi, T., Aungst, J., Milescu, L. S., Zhang, R., Richerson, G. B., et al. (2009). Raphe neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P. The Journal of Neuroscience, 29, 3720–3737.PubMedCrossRefGoogle Scholar
  44. Purvis, L. K., Smith, J. C., Koizumi, H., & Butera, R. J. (2007). Intrinsic bursters increase the robustness of rhythm generation in an excitatory network. Journal of Neurophysiology, 97, 1515–1526.PubMedCrossRefGoogle Scholar
  45. Ramirez, J. M., Quellmalz, U. J., & Wilken, B. (1997). Developmental changes in the hypoxic response of the hypoglossus respiratory motor output in vitro. Journal of Neurophysiology, 78, 383–392.PubMedGoogle Scholar
  46. Ramirez, J. M., Quellmalz, U. J., Wilken, B., & Richter, D. W. (1998). The hypoxic response of neurones within the in vitro mammalian respiratory network. Journal de Physiologie, 507(Pt 2), 571–582.CrossRefGoogle Scholar
  47. Richter, D. W., Bischoff, A., Anders, K., Bellingham, M., & Windhorst, U. (1991). Response of the medullary respiratory network of the cat to hypoxia. Journal de Physiologie, 443, 231–256.Google Scholar
  48. Rubin, J. E. (2006). Bursting induced by excitatory synaptic coupling in nonidentical conditional relaxation oscillators or square-wave bursters. Physical Review E—Statistical, Nonlinear and Soft Matter Physics, 74, 021917.CrossRefGoogle Scholar
  49. Rubin, J. E. (2008). Emergent bursting in small networks of model conditional pacemakers in the pre-Botzinger complex. Advances in Experimental Medicine and Biology, 605, 119–124.PubMedCrossRefGoogle Scholar
  50. Rubin, J. E., Hayes, J. A., Mendenhall, J. L., & Del Negro, C. A. (2009). Calcium-activated nonspecific cation current and synaptic depression promote network-dependent burst oscillations. Proceedings of the National Academy of Sciences of the United States of America, 106, 2939–2944.PubMedCrossRefGoogle Scholar
  51. Rybak, I. A., Paton, J. F., & Schwaber, J. S. (1997). Modeling neural mechanisms for genesis of respiratory rhythm and pattern. I. Models of respiratory neurons. J Neurophysiol, 77, 1994–2006.PubMedGoogle Scholar
  52. Saito, Y., Ezure, K., Kobayashi, M., Ito, M., Saito, K., & Osawa, M. (2002). A review of functional and structural components of the respiratory center involved in the arousal response. Sleep Medicine, 3(Suppl 2), S71–74.PubMedCrossRefGoogle Scholar
  53. Smith, J. C., Ellenberger, H. H., Ballanyi, K., Richter, D. W., & Feldman, J. L. (1991). Pre-Botzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science, 254, 726–729.PubMedCrossRefGoogle Scholar
  54. Spacek, J., & Harris, K. M. (1997). Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. The Journal of Neuroscience, 17, 190–203.PubMedGoogle Scholar
  55. Thoby-Brisson, M., & Ramirez, J. M. (2000). Role of inspiratory pacemaker neurons in mediating the hypoxic response of the respiratory network in vitro. The Journal of Neuroscience, 20, 5858–5866.PubMedGoogle Scholar
  56. Thoby-Brisson, M., & Ramirez, J. M. (2001). Identification of two types of inspiratory pacemaker neurons in the isolated respiratory neural network of mice. Journal of Neurophysiology, 86, 104–112.PubMedGoogle Scholar
  57. Viemari, J. C., & Ramirez, J. M. (2006). Norepinephrine differentially modulates different types of respiratory pacemaker and nonpacemaker neurons. Journal of Neurophysiology, 95, 2070–2082.PubMedCrossRefGoogle Scholar
  58. Viemari, J. C., Bevengut, M., Burnet, H., Coulon, P., Pequignot, J. M., Tiveron, M. C., et al. (2004). Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice. The Journal of Neuroscience, 24, 928–937.PubMedCrossRefGoogle Scholar
  59. Villa, A., Sharp, A. H., Racchetti, G., Podini, P., Bole, D. G., Dunn, W. A., et al. (1992). The endoplasmic reticulum of Purkinje neuron body and dendrites: molecular identity and specializations for Ca2+ transport. Neuroscience, 49, 467–477.PubMedCrossRefGoogle Scholar
  60. Wagner, J., & Keizer, J. (1994). Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations. Biophysical Journal, 67, 447–456.PubMedCrossRefGoogle Scholar
  61. Xia, Y., & Haddad, G. G. (1999). Effect of prolonged O2 deprivation on Na+ channels: differential regulation in adult versus fetal rat brain. Neuroscience, 94, 1231–1243.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratory for NeuroengineeringSchool of Electrical and Computer EngineeringAtlantaUSA

Personalised recommendations