Breathing matters

Abstract

Breathing is a well-described, vital and surprisingly complex behaviour, with behavioural and physiological outputs that are easy to directly measure. Key neural elements for generating breathing pattern are distinct, compact and form a network amenable to detailed interrogation, promising the imminent discovery of molecular, cellular, synaptic and network mechanisms that give rise to the behaviour. Coupled oscillatory microcircuits make up the rhythmic core of the breathing network. Primary among these is the preBötzinger Complex (preBötC), which is composed of excitatory rhythmogenic interneurons and excitatory and inhibitory pattern-forming interneurons that together produce the essential periodic drive for inspiration. The preBötC coordinates all phases of the breathing cycle, coordinates breathing with orofacial behaviours and strongly influences, and is influenced by, emotion and cognition. Here, we review progress towards cracking the inner workings of this vital core.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The anatomy and physiology of respiration.
Fig. 2: Elements of the breathing central pattern generator.
Fig. 3: Emergent network rhythms and burstlet theory.
Fig. 4: A circuit that generates and modulates sighs.

References

  1. 1.

    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). This seminal work announced the preBötC, which was identified and named in reference 15 cited therein.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Schwarzacher, S. W., Smith, J. C. & Richter, D. W. Pre-Bötzinger complex in the cat. J. Neurophysiol. 73, 1452–1461 (1995).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Schwarzacher, S. W., Rüb, U. & Deller, T. Neuroanatomical characteristics of the human pre-Bötzinger Complex and its involvement in neurodegenerative brainstem diseases. Brain J. Neurol. 134, 24–35 (2011).

    Article  Google Scholar 

  4. 4.

    Tupal, S. et al. Testing the role of preBötzinger complex somatostatin neurons in respiratory and vocal behaviors. Eur. J. Neurosci. 40, 3067–3077 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Wenninger, J. M. et al. Large lesions in the pre-Bötzinger complex area eliminate eupneic respiratory rhythm in awake goats. J. Appl. Physiol. 97, 1629–1636 (2004).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Pantaleo, T., Mutolo, D., Cinelli, E. & Bongianni, F. Respiratory responses to somatostatin microinjections into the Bötzinger complex and the pre-Bötzinger complex of the rabbit. Neurosci. Lett. 498, 26–30 (2011).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Bongianni, F., Mutolo, D., Cinelli, E. & Pantaleo, T. Respiratory responses induced by blockades of GABA and glycine receptors within the Bötzinger complex and the pre-Bötzinger complex of the rabbit. Brain Res. 1344, 134–147 (2010).

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Smith, J. C., Morrison, D. E., Ellenberger, H. H., Otto, M. R. & Feldman, J. L. Brainstem projections to the major respiratory neuron populations in the medulla of the cat. J. Comp. Neurol. 281, 69–96 (1989).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

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

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Wu, J. et al. A V0 core neuronal circuit for inspiration. Nat. Commun. 8, 544 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Tan, W., Pagliardini, S., Yang, P., Janczewski, W. A. & Feldman, J. L. Projections of preBötzinger Complex neurons in adult rats. J. Comp. Neurol. 518, 1862–1878 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Yackle, K. et al. Breathing control center neurons that promote arousal in mice. Science 355, 1411–1415 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Yang, C. & Feldman, J. Efferent projections of excitatory and inhibitory preBötzinger Complex neurons. J. Comp. Neurol. 526, 1389–1402 (2018).

  14. 14.

    Funk, G. D., Smith, J. C. & Feldman, J. L. Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids. J. Neurophysiol. 70, 1497–1515 (1993).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Johnson, S. M., Smith, J. C. & Feldman, J. L. Modulation of respiratory rhythm in vitro: role of Gi/o protein-mediated mechanisms. J. Appl. Physiol. 80, 2120–2133 (1996).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    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). This report demonstrates that neuropeptide receptor expression characterizes constituent preBötC rhythmogenic neurons and demarcates the borders of the preBötC.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Stornetta, R. L. et al. A group of glutamatergic interneurons expressing high levels of both neurokinin-1 receptors and somatostatin identifies the region of the pre-Bötzinger Complex. J. Comp. Neurol. 455, 499–512 (2003).

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    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).

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    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).

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Hayes, J. A. & Del Negro, C. A. Neurokinin receptor-expressing pre-Bötzinger complex neurons in neonatal mice studied in vitro. J. Neurophysiol. 97, 4215–4224 (2007).

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Liu, Y.-Y. et al. Substance P and enkephalinergic synapses onto neurokinin-1 receptor-immunoreactive neurons in the pre-Bötzinger complex of rats. Eur. J. Neurosci. 19, 65–75 (2004).

    PubMed  Article  Google Scholar 

  22. 22.

    Peña, F. & Ramirez, J.-M. Substance P-mediated modulation of pacemaker properties in the mammalian respiratory network. J. Neurosci. 24, 7549–7556 (2004).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Ramírez-Jarquín, J. O. et al. Somatostatin modulates generation of inspiratory rhythms and determines asphyxia survival. Peptides 34, 360–372 (2012).

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Llona, I. & Eugenín, J. Central actions of somatostatin in the generation and control of breathing. Biol. Res. 38, 347–352 (2005).

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Rekling, J. C., Champagnat, J. & Denavit-Saubié, M. Thyrotropin-releasing hormone (TRH) depolarizes a subset of inspiratory neurons in the newborn mouse brain stem in vitro. J. Neurophysiol. 75, 811–819 (1996).

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Gray, P. A., Janczewski, W. A., Mellen, N., McCrimmon, D. R. & Feldman, J. L. Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons. Nat. Neurosci. 4, 927–930 (2001).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    McKay, L. C., Janczewski, W. A. & Feldman, J. L. Sleep-disordered breathing after targeted ablation of preBötzinger complex neurons. Nat. Neurosci. 8, 1142–1144 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Wenninger, J. M. et al. Small reduction of neurokinin-1 receptor-expressing neurons in the pre-Bötzinger complex area induces abnormal breathing periods in awake goats. J. Appl. Physiol. 97, 1620–1628 (2004).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Tan, W. et al. Silencing preBötzinger Complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat. Neurosci. 11, 538–540 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Stornetta, R. L., Sevigny, C. P. & Guyenet, P. G. Inspiratory augmenting bulbospinal neurons express both glutamatergic and enkephalinergic phenotypes. J. Comp. Neurol. 455, 113–124 (2003).

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Guyenet, P. G., Sevigny, C. P., Weston, M. C. & Stornetta, R. L. Neurokinin-1 receptor-expressing cells of the ventral respiratory group are functionally heterogeneous and predominantly glutamatergic. J. Neurosci. 22, 3806–3816 (2002).

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Coveñas, R. et al. Mapping of neurokinin-like immunoreactivity in the human brainstem. BMC Neurosci. 4, 3 (2003).

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Liu, Y. Y., Ju, G. & Wong-Riley, M. T. Distribution and colocalization of neurotransmitters and receptors in the pre-Bötzinger complex of rats. J. Appl. Physiol. 91, 1387–1395 (2001).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Fukuda, H., Nakamura, E., Koga, T., Furukawa, N. & Shiroshita, Y. The site of the anti-emetic action of tachykinin NK1 receptor antagonists may exist in the medullary area adjacent to the semicompact part of the nucleus ambiguus. Brain Res. 818, 439–449 (1999).

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Nakaya, Y., Kaneko, T., Shigemoto, R., Nakanishi, S. & Mizuno, N. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J. Comp. Neurol. 347, 249–274 (1994).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Yamamoto, Y., Onimaru, H. & Homma, I. Effect of substance P on respiratory rhythm and pre-inspiratory neurons in the ventrolateral structure of rostral medulla oblongata: an in vitro study. Brain Res. 599, 272–276 (1992).

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Le Gal, J.-P., Juvin, L., Cardoit, L., Thoby-Brisson, M. & Morin, D. Remote control of respiratory neural network by spinal locomotor generators. PLOS ONE 9, e89670 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Tan, W. et al. Reelin demarcates a subset of pre-Bötzinger complex neurons in adult rat. J. Comp. Neurol. 520, 606–619 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Cui, Y. et al. Defining preBötzinger Complex rhythm- and pattern-generating neural microcircuits in vivo. Neuron 91, 602–614 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Koizumi, H. et al. Voltage-dependent rhythmogenic property of respiratory pre-Bötzinger complex glutamatergic, Dbx1-derived, and somatostatin-expressing neuron populations revealed by graded optogenetic inhibition. eNeuro https://doi.org/10.1523/eneuro.0081-16.2016 (2016).

  41. 41.

    Moore, J. D. et al. Hierarchy of orofacial rhythms revealed through whisking and breathing. Nature 497, 205–210 (2013). This work shows that preBötC-driven inspiratory rhythms act as a master oscillator for orofacial behaviours.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Moore, J. D., Kleinfeld, D. & Wang, F. How the brainstem controls orofacial behaviors comprised of rhythmic actions. Trends Neurosci. 37, 370–380 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Kottick, A., Martin, C. A. & Del Negro, C. A. Fate mapping neurons and glia derived from Dbx1-expressing progenitors in mouse preBötzinger complex. Physiol. Rep. 5, e13300 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Bouvier, J. et al. Hindbrain interneurons and axon guidance signaling critical for breathing. Nat. Neurosci. 13, 1066–1074 (2010).

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Gray, P. A. et al. Developmental origin of preBötzinger Complex respiratory neurons. J. Neurosci. 30, 14883–14895 (2010). This work, in conjunction with Ref. 44, shows that rhythmogenic preBötC neurons in perinatal mice are derived from DBX1-expressing precursors.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Picardo, M. C. D., Weragalaarachchi, K. T. H., Akins, V. T. & Del Negro, C. A. Physiological and morphological properties of Dbx1-derived respiratory neurons in the pre-Bötzinger complex of neonatal mice. J. Physiol. 591, 2687–2703 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Vann, N. C., Pham, F. D., Hayes, J. A., Kottick, A. & Del Negro, C. A. Transient suppression of Dbx1 preBötzinger interneurons disrupts breathing in adult mice. PLOS ONE 11, e0162418 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Wang, X. et al. Laser ablation of Dbx1 neurons in the pre-Bötzinger complex stops inspiratory rhythm and impairs output in neonatal mice. eLife 3, e03427 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Pagliardini, S., Greer, J. J., Funk, G. D. & Dickson, C. T. State-dependent modulation of breathing in urethane-anesthetized rats. J. Neurosci. 32, 11259–11270 (2012).

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Saini, J. K. & Pagliardini, S. Breathing during sleep in the postnatal period of rats: the contribution of active expiration. Sleep https://doi.org/10.1093/sleep/zsx172 (2017).

  51. 51.

    Andrews, C. G. & Pagliardini, S. Expiratory activation of abdominal muscle is associated with improved respiratory stability and an increase in minute ventilation in REM epochs of adult rats. J. Appl. Physiol. 119, 968–974 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Rekling, J. C., Funk, G. D., Bayliss, D. A., Dong, X. W. & Feldman, J. L. Synaptic control of motoneuronal excitability. Physiol. Rev. 80, 767–852 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Burke, P. G. R. et al. State-dependent control of breathing by the retrotrapezoid nucleus. J. Physiol. 593, 2909–2926 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Boutin, R. C. T., Alsahafi, Z. & Pagliardini, S. Cholinergic modulation of the parafacial respiratory group. J. Physiol. 595, 1377–1392 (2016).

  55. 55.

    Mellen, N. M., Janczewski, W. A., Bocchiaro, C. M. & Feldman, J. L. Opioid-induced quantal slowing reveals dual networks for respiratory rhythm generation. Neuron 37, 821–826 (2003).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Janczewski, W. A. & Feldman, J. L. Distinct rhythm generators for inspiration and expiration in the juvenile rat. J. Physiol. 570, 407–420 (2006).

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Huckstepp, R. T. R., Cardoza, K. P., Henderson, L. E. & Feldman, J. L. Role of parafacial nuclei in control of breathing in adult rats. J. Neurosci. 35, 1052–1067 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Huckstepp, R. T., Henderson, L. E., Cardoza, K. P. & Feldman, J. L. Interactions between respiratory oscillators in adult rats. eLife 5, e14203 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Guyenet, P. G. & Bayliss, D. A. Neural control of breathing and CO2 homeostasis. Neuron 87, 946–961 (2015). This is a comprehensive review of chemosensation in the pF V (that is, the RTN).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60.

    Guyenet, P. G. et al. Proton detection and breathing regulation by the retrotrapezoid nucleus. J. Physiol. 594, 1529–1551 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Feldman, J. L., Mitchell, G. S. & Nattie, E. E. Breathing: rhythmicity, plasticity, chemosensitivity. Annu. Rev. Neurosci. 26, 239–266 (2003).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Gourine, A. V. et al. Astrocytes control breathing through pH-dependent release of ATP. Science 329, 571–575 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Wenker, I. C., Kréneisz, O., Nishiyama, A. & Mulkey, D. K. Astrocytes in the retrotrapezoid nucleus sense H+ by inhibition of a Kir4.1-Kir5.1-like current and may contribute to chemoreception by a purinergic mechanism. J. Neurophysiol. 104, 3042–3052 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Rose, M. F. et al. Math1 is essential for the development of hindbrain neurons critical for perinatal breathing. Neuron 64, 341–354 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Dubreuil, V. et al. Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting retrotrapezoid nucleus neurons. J. Neurosci. 29, 14836–14846 (2009).

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Onimaru, H. & Homma, I. A novel functional neuron group for respiratory rhythm generation in the ventral medulla. J. Neurosci. 23, 1478–1486 (2003).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  67. 67.

    Onimaru, H., Ikeda, K. & Kawakami, K. CO2-sensitive preinspiratory neurons of the parafacial respiratory group express Phox2b in the neonatal rat. J. Neurosci. 28, 12845–12850 (2008).

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Ruffault, P.-L. et al. The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO2. eLife 4, e07051 (2015).

    PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Thoby-Brisson, M. et al. Genetic identification of an embryonic parafacial oscillator coupling to the preBötzinger complex. Nat. Neurosci. 12, 1028–1035 (2009).

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Fortuna, M. G., West, G. H., Stornetta, R. L. & Guyenet, P. G. Bötzinger expiratory-augmenting neurons and the parafacial respiratory group. J. Neurosci. 28, 2506–2515 (2008).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  71. 71.

    Stornetta, R. L. et al. Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. J. Neurosci. 26, 10305–10314 (2006).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Kang, B. J. et al. Central nervous system distribution of the transcription factor Phox2b in the adult rat. J. Comp. Neurol. 503, 627–641 (2007).

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Abbott, S. B. G. et al. Selective optogenetic activation of rostral ventrolateral medullary catecholaminergic neurons produces cardiorespiratory stimulation in conscious mice. J. Neurosci. 33, 3164–3177 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Abbott, S. B. G., Stornetta, R. L., Coates, M. B. & Guyenet, P. G. Phox2b-expressing neurons of the parafacial region regulate breathing rate, inspiration, and expiration in conscious rats. J. Neurosci. 31, 16410–16422 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Holloway, B. B., Viar, K. E., Stornetta, R. L. & Guyenet, P. G. The retrotrapezoid nucleus stimulates breathing by releasing glutamate in adult conscious mice. Eur. J. Neurosci. 42, 2271–2282 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Ikeda, K. et al. A Phox2b BAC transgenic rat line useful for understanding respiratory rhythm generator neural circuitry. PLOS ONE 10, e0132475 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Abbott, S. B. G. et al. Photostimulation of retrotrapezoid nucleus Phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats. J. Neurosci. 29, 5806–5819 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Bochorishvili, G., Stornetta, R. L., Coates, M. B. & Guyenet, P. G. Pre-Bötzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J. Comp. Neurol. 520, 1047–1061 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79.

    Rosin, D. L., Chang, D. A. & Guyenet, P. G. Afferent and efferent connections of the rat retrotrapezoid nucleus. J. Comp. Neurol. 499, 64–89 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Abdala, A. P. L., Rybak, I. A., Smith, J. C. & Paton, J. F. R. Abdominal expiratory activity in the rat brainstem–spinal cord in situ: patterns, origins and implications for respiratory rhythm generation. J. Physiol. 587, 3539–3559 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. 81.

    Moraes, D. J. A., Dias, M. B., Cavalcanti-Kwiatkoski, R., Machado, B. H. & Zoccal, D. B. Contribution of the retrotrapezoid nucleus/parafacial respiratory region to the expiratory-sympathetic coupling in response to peripheral chemoreflex in rats. J. Neurophysiol. 108, 882–890 (2012).

    PubMed  Article  Google Scholar 

  82. 82.

    Marina, N. et al. Essential role of Phox2b-expressing ventrolateral brainstem neurons in the chemosensory control of inspiration and expiration. J. Neurosci. 30, 12466–12473 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Pagliardini, S. et al. Active expiration induced by excitation of ventral medulla in adult anesthetized rats. J. Neurosci. 31, 2895–2905 (2011). This report demonstrates active expiratory functions of the pF L .

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Shi, Y. et al. Neuromedin B expression defines the mouse retrotrapezoid nucleus. J. Neurosci. 37, 11744–11757 (2017).

    PubMed  Article  PubMed Central  CAS  Google Scholar 

  85. 85.

    Janczewski, W. A., Onimaru, H., Homma, I. & Feldman, J. L. Opioid-resistant respiratory pathway from the preinspiratory neurones to abdominal muscles: in vivo and in vitro study in the newborn rat. J. Physiol. 545, 1017–1026 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Silva, J. N., Tanabe, F. M., Moreira, T. S. & Takakura, A. C. Neuroanatomical and physiological evidence that the retrotrapezoid nucleus/parafacial region regulates expiration in adult rats. Respir. Physiol. Neurobiol. 227, 9–22 (2016).

    PubMed  Article  Google Scholar 

  87. 87.

    Takeda, S. et al. Opioid action on respiratory neuron activity of the isolated respiratory network in newborn rats. Anesthesiology 95, 740–749 (2001).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Sears, T. A., Berger, A. J. & Phillipson, E. A. Reciprocal tonic activation of inspiratory and expiratory motoneurones by chemical drives. Nature 299, 728–730 (1982).

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Tuck, S. A., Dort, J. C. & Remmers, J. E. Braking of expiratory airflow in obese pigs during wakefulness and sleep. Respir. Physiol. 128, 241–245 (2001).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Dutschmann, M., Jones, S. E., Subramanian, H. H., Stanic, D. & Bautista, T. G. The physiological significance of postinspiration in respiratory control. Prog. Brain Res. 212, 113–130 (2014).

    PubMed  Article  Google Scholar 

  91. 91.

    Pitts, T. et al. Coordination of cough and swallow: a meta-behavioral response to aspiration. Respir. Physiol. Neurobiol. 189, 543–551 (2013).

    PubMed  Article  Google Scholar 

  92. 92.

    Shannon, R. et al. Production of reflex cough by brainstem respiratory networks. Pulm. Pharmacol. Ther. 17, 369–376 (2004).

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Smith Hammond, C. A. et al. Predicting aspiration in patients with ischemic stroke: comparison of clinical signs and aerodynamic measures of voluntary cough. Chest 135, 769–777 (2009).

    PubMed  Article  Google Scholar 

  94. 94.

    Bautista, T. G., Sun, Q.-J. & Pilowsky, P. M. The generation of pharyngeal phase of swallow and its coordination with breathing: interaction between the swallow and respiratory central pattern generators. Prog. Brain Res. 212, 253–275 (2014).

    PubMed  Article  Google Scholar 

  95. 95.

    Wheeler Hegland, K., Huber, J. E., Pitts, T., Davenport, P. W. & Sapienza, C. M. Lung volume measured during sequential swallowing in healthy young adults. J. Speech Lang. Hear. Res. 54, 777–786 (2011).

    PubMed  Article  Google Scholar 

  96. 96.

    Jean, A. Brain stem control of swallowing: neuronal network and cellular mechanisms. Physiol. Rev. 81, 929–969 (2001).

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Pitts, T. et al. Impact of expiratory muscle strength training on voluntary cough and swallow function in Parkinson disease. Chest 135, 1301–1308 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Hernandez-Miranda, L. R. et al. Genetic identification of a hindbrain nucleus essential for innate vocalization. Proc. Natl Acad. Sci. USA 114, 8095–8100 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. 99.

    Richter, D. W. & Spyer, K. M. Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends Neurosci. 24, 464–472 (2001).

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Smith, J. C., Abdala, A. P. L., Borgmann, A., Rybak, I. A. & Paton, J. F. R. Brainstem respiratory networks: building blocks and microcircuits. Trends Neurosci. 36, 152–162 (2013).

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    Smith, J. C., Abdala, A. P. L., Koizumi, H., Rybak, I. A. & Paton, J. F. R. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J. Neurophysiol. 98, 3370–3387 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Richter, D. in Comprehensive Human Physiology: from Cellular Mechanisms to Integration (eds Greger, R. & Windhorst, U.) 2079–2095 (Springer, 1996).

  103. 103.

    Dutschmann, M. & Herbert, H. The Kölliker-Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off-switch and upper airway resistance in rat. Eur. J. Neurosci. 24, 1071–1084 (2006).

    PubMed  Article  Google Scholar 

  104. 104.

    Dutschmann, M. & Dick, T. E. Pontine mechanisms of respiratory control. Compr. Physiol. 2, 2443–2469 (2012).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Poon, C.-S. & Song, G. Bidirectional plasticity of pontine pneumotaxic postinspiratory drive: implication for a pontomedullary respiratory central pattern generator. Prog. Brain Res 209, 235–254 (2014).

    PubMed  Article  Google Scholar 

  106. 106.

    Anderson, T. M. et al. A novel excitatory network for the control of breathing. Nature 536, 76–80 (2016). This paper proposes that an autonomous postinspiratory oscillator circuit in the rostral medulla ordinarily couples with the preBötC during breathing to aid in inspiratory–expiratory phase transition.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Ezure, K. & Tanaka, I. GABA, in some cases together with glycine, is used as the inhibitory transmitter by pump cells in the Hering-Breuer reflex pathway of the rat. Neuroscience 127, 409–417 (2004).

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    Ezure, K., Tanaka, I. & Kondo, M. Glycine is used as a transmitter by decrementing expiratory neurons of the ventrolateral medulla in the rat. J. Neurosci. 23, 8941–8948 (2003).

    PubMed  Article  CAS  Google Scholar 

  109. 109.

    Tian, G. F., Peever, J. H. & Duffin, J. Mutual inhibition between Bötzinger-complex bulbospinal expiratory neurons detected with cross-correlation in the decerebrate rat. Exp. Brain Res. 125, 440–446 (1999).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Tian, G. F., Peever, J. H. & Duffin, J. Bötzinger-complex, bulbospinal expiratory neurones monosynaptically inhibit ventral-group respiratory neurones in the decerebrate rat. Exp. Brain Res. 124, 173–180 (1999).

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Kam, K., Worrell, J. W., Janczewski, W. A., Cui, Y. & Feldman, J. L. Distinct inspiratory rhythm and pattern generating mechanisms in the preBötzinger complex. J. Neurosci. 33, 9235–9245 (2013). This paper presents the idea that burstlets, which are subthreshold for motor output, are nonetheless rhythmogenic in the preBötC.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Stuart, D. G. & Hultborn, H. Thomas Graham Brown (1882–1965), Anders Lundberg (1920-), and the neural control of stepping. Brain Res. Rev. 59, 74–95 (2008).

    PubMed  Article  Google Scholar 

  113. 113.

    Brown, T. G. On the nature of the fundamental activity of the nervous centres; together with an analysis of the conditioning of rhythmic activity in progression, and a theory of the evolution of function in the nervous system. J. Physiol. 48, 18–46 (1914).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    von Euler, C. On the central pattern generator for the basic breathing rhythmicity. J. Appl. Physiol. 55, 1647–1659 (1983).

    Article  Google Scholar 

  115. 115.

    Feldman, J. L. in Handbook of Physiology 463–524 (American Physiology Society, 1986).

  116. 116.

    Feldman, J. L. & Smith, J. C. Cellular mechanisms underlying modulation of breathing pattern in mammals. Ann. NY Acad. Sci. 563, 114–130 (1989).

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    Zhang, W., Barnbrock, A., Gajic, S., Pfeiffer, A. & Ritter, B. Differential ontogeny of GABAB-receptor-mediated pre- and postsynaptic modulation of GABA and glycine transmission in respiratory rhythm-generating network in mouse. J. Physiol. 540, 435–446 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

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

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Funk, G. D. & Greer, J. J. The rhythmic, transverse medullary slice preparation in respiratory neurobiology: contributions and caveats. Respir. Physiol. Neurobiol. 186, 236–253 (2013).

    PubMed  Article  Google Scholar 

  120. 120.

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

    PubMed  CAS  Google Scholar 

  121. 121.

    Richter, D. W. & Smith, J. C. Respiratory rhythm generation in vivo. Physiology 29, 58–71 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Dutschmann, M. & Paton, J. F. R. Glycinergic inhibition is essential for co-ordinating cranial and spinal respiratory motor outputs in the neonatal rat. J. Physiol. 543, 643–653 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123.

    Marchenko, V. et al. Perturbations of respiratory rhythm and pattern by disrupting synaptic inhibition within pre-Bötzinger and Bötzinger complexes. eNeuro https://doi.org/10.1523/eneuro.0011-16.2016 (2016).

  124. 124.

    Cregg, J. M., Chu, K. A., Dick, T. E., Landmesser, L. T. & Silver, J. Phasic inhibition as a mechanism for generation of rapid respiratory rhythms. Proc. Natl Acad. Sci. USA 114, 12815–12820 (2017).

    PubMed  Article  PubMed Central  CAS  Google Scholar 

  125. 125.

    Baertsch, N. A., Baertsch, H. C. & Ramirez, J. M. The interdependence of excitation and inhibition for the control of dynamic breathing rhythms. Nat. Commun. 9, 843 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

    Janczewski, W. A., Tashima, A., Hsu, P., Cui, Y. & Feldman, J. L. Role of inhibition in respiratory pattern generation. J. Neurosci. 33, 5454–5465 (2013). This paper demonstrates that blockade of inhibition in the preBötC and other sites in the medulla does not stop respiratory rhythm and breathing.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Sherman, D., Worrell, J. W., Cui, Y. & Feldman, J. L. Optogenetic perturbation of preBötzinger complex inhibitory neurons modulates respiratory pattern. Nat. Neurosci. 18, 408–414 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Del Negro, C. A., Koshiya, N., Butera, R. J. Jr & Smith, J. C. Persistent sodium current, membrane properties and bursting behavior of pre-Bötzinger complex inspiratory neurons in vitro. J. Neurophysiol. 88, 2242–2250 (2002).

    PubMed  Article  Google Scholar 

  129. 129.

    Del Negro, C. A. et al. Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation. J. Neurosci. 25, 446–453 (2005).

    PubMed  Article  CAS  Google Scholar 

  130. 130.

    Thoby-Brisson, M. & Ramirez, J. M. Identification of two types of inspiratory pacemaker neurons in the isolated respiratory neural network of mice. J. Neurophysiol. 86, 104–112 (2001).

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Peña, F., Parkis, M. A., Tryba, A. K. & Ramirez, J.-M. Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron 43, 105–117 (2004).

    PubMed  Article  Google Scholar 

  132. 132.

    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).

    PubMed  Article  CAS  Google Scholar 

  133. 133.

    Butera, R. J., 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).

    PubMed  Article  Google Scholar 

  134. 134.

    Butera, R. J., Rinzel, J. & Smith, J. C. Models of respiratory rhythm generation in the pre-Bötzinger complex. II. Populations of coupled pacemaker neurons. J. Neurophysiol. 82, 398–415 (1999).

    PubMed  Article  Google Scholar 

  135. 135.

    Del Negro, C. A., Johnson, S. M., Butera, R. J. & Smith, J. C. Models of respiratory rhythm generation in the pre-Bötzinger complex. III. Experimental tests of model predictions. J. Neurophysiol. 86, 59–74 (2001).

    PubMed  Article  Google Scholar 

  136. 136.

    Koizumi, H. et al. Structural-functional properties of identified excitatory and inhibitory interneurons within pre-Bötzinger complex respiratory microcircuits. J. Neurosci. 33, 2994–3009 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Morgado-Valle, C., Baca, S. M. & Feldman, J. L. Glycinergic pacemaker neurons in preBötzinger Complex of neonatal mouse. J. Neurosci. 30, 3634–3639 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    Doble, A. The pharmacology and mechanism of action of riluzole. Neurology 47, S233–241 (1996).

    PubMed  Article  CAS  Google Scholar 

  139. 139.

    Guinamard, R., Simard, C. & Del Negro, C. Flufenamic acid as an ion channel modulator. Pharmacol. Ther. 138, 272–284 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Pace, R. W., Mackay, D. D., Feldman, J. L. & Del Negro, C. A. Role of persistent sodium current in mouse preBötzinger Complex neurons and respiratory rhythm generation. J. Physiol. 580, 485–496 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. 141.

    Paton, J. F. R., Abdala, A. P. L., Koizumi, H., Smith, J. C. & St-John, W. M. Respiratory rhythm generation during gasping depends on persistent sodium current. Nat. Neurosci. 9, 311–313 (2006).

    PubMed  Article  CAS  Google Scholar 

  142. 142.

    Koizumi, H. & Smith, J. C. Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Bötzinger complex in vitro. J. Neurosci. 28, 1773–1785 (2008).

    PubMed  Article  CAS  Google Scholar 

  143. 143.

    Chevalier, M., Toporikova, N., Simmers, J. & Thoby-Brisson, M. Development of pacemaker properties and rhythmogenic mechanisms in the mouse embryonic respiratory network. eLife 5, e16125 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Ramirez, J.-M., Tryba, A. K. & Peña, F. Pacemaker neurons and neuronal networks: an integrative view. Curr. Opin. Neurobiol. 14, 665–674 (2004).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    Grillner, S. Biological pattern generation: the cellular and computational logic of networks in motion. Neuron 52, 751–766 (2006).

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Grillner, S. The motor infrastructure: from ion channels to neuronal networks. Nat. Rev. Neurosci. 4, 573–586 (2003).

    PubMed  Article  CAS  Google Scholar 

  147. 147.

    Carroll, M. S. & Ramirez, J.-M. Cycle-by-cycle assembly of respiratory network activity is dynamic and stochastic. J. Neurophysiol. 109, 296–305 (2013).

    PubMed  Article  Google Scholar 

  148. 148.

    Kam, K., Worrell, J. W., Ventalon, C., Emiliani, V. & Feldman, J. L. Emergence of population bursts from simultaneous activation of small subsets of preBötzinger Complex inspiratory neurons. J. Neurosci. 33, 3332–3338 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    Feldman, J. L. & Del Negro, C. A. Looking for inspiration: new perspectives on respiratory rhythm. Nat. Rev. Neurosci. 7, 232–242 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. 150.

    Feldman, J. L., Del Negro, C. A. & Gray, P. A. Understanding the rhythm of breathing: so near, yet so far. Annu. Rev. Physiol. 75, 423–452 (2013).

    PubMed  Article  CAS  Google Scholar 

  151. 151.

    Feldman, J. L. & Kam, K. Facing the challenge of mammalian neural microcircuits: taking a few breaths may help. J. Physiol. 593, 3–23 (2015).

    PubMed  Article  CAS  Google Scholar 

  152. 152.

    Kam, K. & Feldman, J. L. in Handbook of Brain Microcircuits 2nd edn 624 (Oxford Univ. Press, 2018).

  153. 153.

    Rekling, J. C., Champagnat, J. & Denavit-Saubié, M. Electroresponsive properties and membrane potential trajectories of three types of inspiratory neurons in the newborn mouse brain stem in vitro. J. Neurophysiol. 75, 795–810 (1996).

    PubMed  Article  CAS  Google Scholar 

  154. 154.

    Rubin, J. E., Hayes, J. A., Mendenhall, J. L. & Del Negro, C. A. Calcium-activated nonspecific cation current and synaptic depression promote network-dependent burst oscillations. Proc. Natl Acad. Sci. USA 106, 2939–2944 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Krey, R. A., Goodreau, A. M., Arnold, T. B. & Del Negro, C. A. Outward currents contributing to inspiratory burst termination in preBötzinger Complex neurons of neonatal mice studied in vitro. Front. Neural Circuits 4, 124 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. 156.

    Kottick, A. & Del Negro, C. A. Synaptic depression influences inspiratory-expiratory phase transition in Dbx1 interneurons of the preBötzinger complex in neonatal mice. J. Neurosci. 35, 11606–11611 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    Mironov, S. L. Metabotropic glutamate receptors activate dendritic calcium waves and TRPM channels which drive rhythmic respiratory patterns in mice. J. Physiol. 586, 2277–2291 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  158. 158.

    Del Negro, C. A., Kam, K., Hayes, J. A. & Feldman, J. L. Asymmetric control of inspiratory and expiratory phases by excitability in the respiratory network of neonatal mice in vitro. J. Physiol. 587, 1217–1231 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  159. 159.

    Orlovskiı˘, G. N. Neuronal Control of Locomotion: from Mollusc to Man. (Oxford Univ. Press, 1999).

  160. 160.

    Lu, B. et al. The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129, 371–383 (2007).

    PubMed  Article  CAS  Google Scholar 

  161. 161.

    Lu, B. et al. Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 68, 488–499 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. 162.

    Lu, B. et al. Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457, 741–744 (2009).

    PubMed  Article  Google Scholar 

  163. 163.

    Yeh, S.-Y. et al. Respiratory network stability and modulatory response to substance P require Nalcn. Neuron 94, 294–303.e4 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164.

    Ono, T., Ishiwata, Y., Inaba, N., Kuroda, T. & Nakamura, Y. Hypoglossal premotor neurons with rhythmical inspiratory-related activity in the cat: localization and projection to the phrenic nucleus. Exp. Brain Res. 98, 1–12 (1994).

    PubMed  Article  CAS  Google Scholar 

  165. 165.

    Dobbins, E. G. & Feldman, J. L. Differential innervation of protruder and retractor muscles of the tongue in rat. J. Comp. Neurol. 357, 376–394 (1995).

    PubMed  Article  CAS  Google Scholar 

  166. 166.

    Ellenberger, H. H. & Feldman, J. L. Brainstem connections of the rostral ventral respiratory group of the rat. Brain Res. 513, 35–42 (1990).

    PubMed  Article  CAS  Google Scholar 

  167. 167.

    Koizumi, H. et al. Functional imaging, spatial reconstruction, and biophysical analysis of a respiratory motor circuit isolated in vitro. J. Neurosci. 28, 2353–2365 (2008).

    PubMed  Article  CAS  Google Scholar 

  168. 168.

    Stanek, E. 4th, Cheng, S., Takatoh, J., Han, B.-X. & Wang, F. Monosynaptic premotor circuit tracing reveals neural substrates for oro-motor coordination. eLife 3, e02511 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Revill, A. L. et al. Dbx1 precursor cells are a source of inspiratory XII premotoneurons. eLife 4, e12301 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Song, H. et al. Functional interactions between mammalian respiratory rhythmogenic and premotor circuitry. J. Neurosci. 36, 7223–7233 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171.

    Rekling, J. C., Shao, X. M. & Feldman, J. L. Electrical coupling and excitatory synaptic transmission between rhythmogenic respiratory neurons in the preBötzinger complex. J. Neurosci. 20, RC113 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. 172.

    Guerrier, C., Hayes, J. A., Fortin, G. & Holcman, D. Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics. Proc. Natl Acad. Sci. USA 112, 9728–9733 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. 173.

    Hayes, J. A., Wang, X. & Del Negro, C. A. Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro. Proc. Natl Acad. Sci. USA 109, 8286–8291 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Pace, R. W., Mackay, D. D., Feldman, J. L. & Del Negro, C. A. Inspiratory bursts in the preBötzinger complex depend on a calcium-activated non-specific cation current linked to glutamate receptors in neonatal mice. J. Physiol. 582, 113–125 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. 175.

    Crowder, E. A. et al. Phosphatidylinositol 4,5-bisphosphate regulates inspiratory burst activity in the neonatal mouse preBötzinger complex. J. Physiol. 582, 1047–1058 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. 176.

    Morquette, P. et al. An astrocyte-dependent mechanism for neuronal rhythmogenesis. Nat. Neurosci. 18, 844–854 (2015).

    PubMed  Article  CAS  Google Scholar 

  177. 177.

    Hülsmann, S., Oku, Y., Zhang, W. & Richter, D. W. Metabolic coupling between glia and neurons is necessary for maintaining respiratory activity in transverse medullary slices of neonatal mouse. Eur. J. Neurosci. 12, 856–862 (2000).

    PubMed  Article  Google Scholar 

  178. 178.

    Huxtable, A. G. et al. Glia contribute to the purinergic modulation of inspiratory rhythm-generating networks. J. Neurosci. 30, 3947–3958 (2010).

    PubMed  Article  CAS  Google Scholar 

  179. 179.

    Okada, Y. et al. Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes. J. Physiol. 590, 4933–4944 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. 180.

    Angelova, P. R. et al. Functional oxygen sensitivity of astrocytes. J. Neurosci. 35, 10460–10473 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  181. 181.

    Rajani, V. et al. Release of ATP by pre-Bötzinger complex astrocytes contributes to the hypoxic ventilatory response via a Ca2+ -dependent P2Y1 receptor mechanism. J. Physiol. 589, 4583–4600 (2017).

  182. 182.

    Travers, J. B., DiNardo, L. A. & Karimnamazi, H. Medullary reticular formation activity during ingestion and rejection in the awake rat. Exp. Brain Res. 130, 78–92 (2000).

    PubMed  Article  CAS  Google Scholar 

  183. 183.

    Welzl, H. & Bures, J. Lick-synchronized breathing in rats. Physiol. Behav. 18, 751–753 (1977).

    PubMed  Article  CAS  Google Scholar 

  184. 184.

    Kleinfeld, D., Deschênes, M., Wang, F. & Moore, J. D. More than a rhythm of life: breathing as a binder of orofacial sensation. Nat. Neurosci. 17, 647–651 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. 185.

    Kurnikova, A., Moore, J. D., Liao, S.-M., Deschênes, M. & Kleinfeld, D. Coordination of orofacial motor actions into exploratory behavior by rat. Curr. Biol. 27, 688–696 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  186. 186.

    Nguyen Chi, V. et al. Hippocampal respiration-driven rhythm distinct from theta oscillations in awake mice. J. Neurosci. 36, 162–177 (2016).

    PubMed  Article  CAS  Google Scholar 

  187. 187.

    Grion, N., Akrami, A., Zuo, Y., Stella, F. & Diamond, M. E. Coherence between rat sensorimotor system and hippocampus is enhanced during tactile discrimination. PLoS Biol. 14, e1002384 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  188. 188.

    Zelano, C. et al. Nasal respiration entrains human limbic oscillations and modulates cognitive function. J. Neurosci. 36, 12448–12467 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. 189.

    Li, P. et al. The peptidergic control circuit for sighing. Nature 530, 293–297 (2016). This report demonstrates that pF peptidergic neurons project to the preBötC to influence physiological sighing behaviour.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  190. 190.

    Stornetta, R. L. Identification of neurotransmitters and co-localization of transmitters in brainstem respiratory neurons. Respir. Physiol. Neurobiol. 164, 18–27 (2008).

    PubMed  Article  CAS  Google Scholar 

  191. 191.

    Dubreuil, V. et al. A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proc. Natl Acad. Sci. USA 105, 1067–1072 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    Li, P. & Yackle, K. Sighing. Curr. Biol. 27, R88–R89 (2017).

    PubMed  Article  CAS  Google Scholar 

  193. 193.

    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).

    PubMed  Article  CAS  Google Scholar 

  194. 194.

    Ruangkittisakul, A. et al. Generation of eupnea and sighs by a spatiochemically organized inspiratory network. J. Neurosci. 28, 2447–2458 (2008).

    PubMed  Article  CAS  Google Scholar 

  195. 195.

    Boiten, F. A., Frijda, N. H. & Wientjes, C. J. Emotions and respiratory patterns: review and critical analysis. Int. J. Psychophysiol. 17, 103–128 (1994).

    PubMed  Article  CAS  Google Scholar 

  196. 196.

    Arch, J. J. & Craske, M. G. Mechanisms of mindfulness: emotion regulation following a focused breathing induction. Behav. Res. Ther. 44, 1849–1858 (2006).

    PubMed  Article  Google Scholar 

  197. 197.

    Brown, R. P. & Gerbarg, P. L. Sudarshan Kriya Yogic breathing in the treatment of stress, anxiety, and depression. Part II — clinical applications and guidelines. J. Altern. Complement. Med. 11, 711–717 (2005).

    PubMed  Article  Google Scholar 

  198. 198.

    Brown, R. P., Gerbarg, P. L. & Muench, F. Breathing practices for treatment of psychiatric and stress-related medical conditions. Psychiatr. Clin. North Am. 36, 121–140 (2013).

    PubMed  Article  Google Scholar 

  199. 199.

    Descilo, T. et al. Effects of a yoga breath intervention alone and in combination with an exposure therapy for post-traumatic stress disorder and depression in survivors of the 2004 South-East Asia tsunami. Acta Psychiatr. Scand. 121, 289–300 (2010).

    PubMed  Article  CAS  Google Scholar 

  200. 200.

    Jella, S. A. & Shannahoff-Khalsa, D. S. The effects of unilateral forced nostril breathing on cognitive performance. Int. J. Neurosci. 73, 61–68 (1993).

    PubMed  Article  CAS  Google Scholar 

  201. 201.

    Katzman, M. A. et al. A multicomponent yoga-based, breath intervention program as an adjunctive treatment in patients suffering from generalized anxiety disorder with or without comorbidities. Int. J. Yoga 5, 57–65 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Paul, N. A., Stanton, S. J., Greeson, J. M., Smoski, M. J. & Wang, L. Psychological and neural mechanisms of trait mindfulness in reducing depression vulnerability. Soc. Cogn. Affect. Neurosci. 8, 56–64 (2013).

    PubMed  Article  Google Scholar 

  203. 203.

    Zeidan, F., Johnson, S. K., Diamond, B. J., David, Z. & Goolkasian, P. Mindfulness meditation improves cognition: evidence of brief mental training. Conscious Cogn. 19, 597–605 (2010).

    PubMed  Article  Google Scholar 

  204. 204.

    Carreno, F. R. & Frazer, A. Vagal nerve stimulation for treatment-resistant depression. Neurotherapeutics 14, 716–727 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Masaoka, Y., Izumizaki, M. & Homma, I. Where is the rhythm generator for emotional breathing? Prog. Brain Res. 209, 367–377 (2014).

    PubMed  Article  Google Scholar 

  206. 206.

    Dayan, P. & Abbott, L. F. Theoretical Neuroscience: Computational and Mathematical Modeling of Neural Systems. (Massachusetts Institute of Technology Press, 2001).

  207. 207.

    Pathmanathan, P. & Gray, R. A. Verification of computational models of cardiac electro-physiology. Int. J. Num Method. Biomed. Eng. 30, 525–544 (2013).

    Article  Google Scholar 

  208. 208.

    Carroll, M. S., Viemari, J.-C. & Ramirez, J.-M. Patterns of inspiratory phase-dependent activity in the in vitro respiratory network. J. Neurophysiol. 109, 285–295 (2013).

    PubMed  Article  Google Scholar 

  209. 209.

    Prinz, A. A., Bucher, D. & Marder, E. Similar network activity from disparate circuit parameters. Nat. Neurosci. 7, 1345–1352 (2004).

    PubMed  Article  CAS  Google Scholar 

  210. 210.

    Alsahafi, Z., Dickson, C. T. & Pagliardini, S. Optogenetic excitation of preBötzinger complex neurons potently drives inspiratory activity in vivo. J. Physiol. 593, 3673–3692 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  211. 211.

    Del Negro, C. A., Morgado-Valle, C. & Feldman, J. L. Respiratory rhythm: an emergent network property? Neuron 34, 821–830 (2002).

    PubMed  Article  Google Scholar 

  212. 212.

    Purvis, L. K., Smith, J. C., Koizumi, H. & Butera, R. J. Intrinsic bursters increase the robustness of rhythm generation in an excitatory network. J. Neurophysiol. 97, 1515–1526 (2007).

    PubMed  Article  CAS  Google Scholar 

  213. 213.

    Smith, J. C. et al. Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker-network model. Respir. Physiol. 122, 131–147 (2000).

    PubMed  Article  CAS  Google Scholar 

  214. 214.

    Song, H., Hayes, J. A., Vann, N. C., Drew LaMar, M. & Del Negro, C. A. Mechanisms leading to rhythm cessation in the respiratory preBötzinger complex due to piecewise cumulative neuronal deletions. eNeuro https://doi.org/10.1523/eneuro.0031-15.2015 (2015).

  215. 215.

    Schwab, D. J., Bruinsma, R. F., Feldman, J. L. & Levine, A. J. Rhythmogenic neuronal networks, emergent leaders, and k-cores. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 82, 051911 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  216. 216.

    Webb, P. W. Synchrony of locomotion and ventilation in Cymatogaster aggregata. Can. J. Zool. 53, 904–907 (1975).

    Article  Google Scholar 

  217. 217.

    Wegner, N. C., Sepulveda, C. A., Aalbers, S. A. & Graham, J. B. Structural adaptations for ram ventilation: gill fusions in scombrids and billfishes. J. Morphol. 274, 108–120 (2013).

    PubMed  Article  Google Scholar 

  218. 218.

    Wang, T., Carrier, D. R. & Hicks, J. W. Ventilation and gas exchange in lizards during treadmill exercise. J. Exp. Biol. 200, 2629–2639 (1997).

    PubMed  CAS  Google Scholar 

  219. 219.

    Bramble, D. M. & Carrier, D. R. Running and breathing in mammals. Science 219, 251–256 (1983).

    PubMed  Article  CAS  Google Scholar 

  220. 220.

    Funk, G. D., Steeves, J. D. & Milsom, W. K. Coordination of wingbeat and respiration in birds. II. ‘Fictive’ flight. J. Appl. Physiol. 73, 1025–1033 (1992).

    PubMed  Article  CAS  Google Scholar 

  221. 221.

    Perségol, L., Jordan, M., Viala, D. & Fernandez, C. Evidence for central entrainment of the medullary respiratory pattern by the locomotor pattern in the rabbit. Exp. Brain Res. 71, 153–162 (1988).

    PubMed  Article  Google Scholar 

  222. 222.

    Funk, G. D., Milsom, W. K. & Steeves, J. D. Coordination of wingbeat and respiration in the Canada goose. I. Passive wing flapping. J. Appl. Physiol. 73, 1014–1024 (1992).

    PubMed  Article  CAS  Google Scholar 

  223. 223.

    Funk, G. D., Valenzuela, I. I. & Milsom, W. K. Energetic consequences of coordinating wingbeat and respiratory rhythms in birds. J. Exp. Biol. 200, 915–920 (1997).

    PubMed  CAS  Google Scholar 

  224. 224.

    Potts, J. T., Rybak, I. A. & Paton, J. F. R. Respiratory rhythm entrainment by somatic afferent stimulation. J. Neurosci. 25, 1965–1978 (2005).

    PubMed  Article  CAS  Google Scholar 

  225. 225.

    Lancaster, W. C., Henson, O. W. & Keating, A. W. Respiratory muscle activity in relation to vocalization in flying bats. J. Exp. Biol. 198, 175–191 (1995).

    PubMed  CAS  Google Scholar 

  226. 226.

    Speakman, J. R. & Racey, P. A. No cost of echolocation for bats in flight. Nature 350, 421–423 (1991).

    PubMed  Article  CAS  Google Scholar 

  227. 227.

    Feldman, J. L. & McCrimmon, D. R. Fundamental Neuroscience 3rd edn (eds Squire, L. R. et al.) 855–872 (Academic Press, 2008).

  228. 228.

    Hayashi, F. & McCrimmon, D. R. Respiratory motor responses to cranial nerve afferent stimulation in rats. Am. J. Physiol. 271, R1054–R1062 (1996).

    PubMed  CAS  Google Scholar 

  229. 229.

    Jenkin, S. E. M., Milsom, W. K. & Zoccal, D. B. The Kölliker-Fuse nucleus acts as a timekeeper for late-expiratory abdominal activity. Neuroscience 348, 63–72 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  230. 230.

    Pagliardini, S., Ren, J. & Greer, J. J. Ontogeny of the pre-Bötzinger complex in perinatal rats. J. Neurosci. 23, 9575–9584 (2003).

    PubMed  Article  CAS  Google Scholar 

  231. 231.

    Thoby-Brisson, M., Trinh, J.-B., Champagnat, J. & Fortin, G. Emergence of the pre-Bötzinger respiratory rhythm generator in the mouse embryo. J. Neurosci. 25, 4307–4318 (2005).

    PubMed  Article  CAS  Google Scholar 

  232. 232.

    Wallén-Mackenzie, A. et al. Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation. J. Neurosci. 26, 12294–12307 (2006).

    PubMed  Article  CAS  Google Scholar 

  233. 233.

    Gray, P. A. Transcription factors define the neuroanatomical organization of the medullary reticular formation. Front. Neuroanat. https://doi.org/10.3389/fnana.2013.00007 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank W. K. Milsom, T. G. Pitts and numerous colleagues for helpful comments in review and J. Milstein for anatomical drawings that were the basis of Figure 1.

Author information

Affiliations

Authors

Contributions

All authors researched data for the article, made substantial contributions to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jack L. Feldman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related Links

Model DB: https://senselab.med.yale.edu/modeldb/

BioModels Database: https://www.ebi.ac.uk/biomodels-main/

Electronic supplementary material

Glossary

Central pattern generator

(CPG). A network that generates the rhythm and basic motor pattern for behaviours such as locomotion, swimming, chewing and breathing in vertebrate and invertebrate animals.

Eupnoea

Breathing typical at rest and in normal air (~21% O2 and trace amounts of CO2).

Breuer-Hering reflexes

Any of several reflexes mediated by mechanical sensory feedback from the lungs that control inflation and deflation of the lungs.

Phrenic premotor neurons

Neurons that project directly to the diaphragmatic motor neurons of the phrenic cervical motor nuclei, some of which receive input from the preBötzinger Complex.

Bursts

Suprathreshold neuronal depolarizations that drive high-frequency (20–120 Hz) spiking.

Valsalva manoeuvres

Co-contractions of expiratory and inspiratory muscles with a closed glottis, which elevates intra-abdominal pressure.

Laminar

Smooth, non-turbulent.

Tidal breathing

Periodic inhalation and exhalation of gas in and out of the gas-exchange structure (lungs) along a common pathway (the trachea).

VII nucleus

The facial motor nucleus, the constituent motor neurons of which innervate facial muscles via the seventh cranial nerve.

Phase-sequencing synaptic inhibition

Transitions between phases of a network rhythm that are governed by synaptic inhibition.

Vagotomized

Cutting the vagus nerve (cranial nerve X), which removes pulmonary sensory feedback (primarily mechanoreceptive) from the breathing CPG.

Network oscillator

A group of interconnected neurons from which rhythms emerge as a result of synaptic interactions.

Photolytic glutamate uncaging

A technique whereby molecules that chelate glutamate can be cleaved by light at a focal point to locally release the neuromessenger.

Cichlid fish

A large diverse group of ovoid, laterally compressed fish.

Opercula

Plural of operculum; the hard flap covering the gill slits in fishes.

Hypoxia

O2 deficiency.

Aspiration pneumonia

A lung infection that results from the ‘inhalation’ into the lungs of material from the stomach or mouth.

Crural diaphragm

The portion of the diaphragm (the main inspiratory muscle) that surrounds the oesophagus and that, when contracted, prevents gastro-oesophageal reflux.

Atelectasis

Complete or partial collapse of a region of the lung that develops when alveoli (the tiny air sacs within the lung) become deflated.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Del Negro, C.A., Funk, G.D. & Feldman, J.L. Breathing matters. Nat Rev Neurosci 19, 351–367 (2018). https://doi.org/10.1038/s41583-018-0003-6

Download citation

Further reading

Search

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