1932

Abstract

The rhythmicity of breath is vital for normal physiology. Even so, breathing is enriched with multifunctionality. External signals constantly change breathing, stopping it when under water or deepening it during exertion. Internal cues utilize breath to express emotions such as sighs of frustration and yawns of boredom. Breathing harmonizes with other actions that use our mouth and throat, including speech, chewing, and swallowing. In addition, our perception of breathing intensity can dictate how we feel, such as during the slow breathing of calming meditation and anxiety-inducing hyperventilation. Heartbeat originates from a peripheral pacemaker in the heart, but the automation of breathing arises from neural clusters within the brainstem, enabling interaction with other brain areas and thus multifunctionality. Here, we document how the recent transformation of cellular and molecular tools has contributed to our appreciation of the diversity of neuronal types in the breathing control circuit and how they confer the multifunctionality of breathing.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-021522-094142
2023-02-10
2024-06-18
Loading full text...

Full text loading...

/deliver/fulltext/physiol/85/1/annurev-physiol-021522-094142.html?itemId=/content/journals/10.1146/annurev-physiol-021522-094142&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Smith JC, Abdala APL, Borgmann A, Rybak IA, Paton JFR. 2013. Brainstem respiratory networks: building blocks and microcircuits. Trends Neurosci. 36:3152–62
    [Google Scholar]
  2. 2.
    Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL. 1991. Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254:5032726–29
    [Google Scholar]
  3. 3.
    Chamberlin N, Saper C. 1994. Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat. J. Neurosci. 14:116500–10
    [Google Scholar]
  4. 4.
    Anderson TM, Garcia AJ, Baertsch NA, Pollak J, Bloom JC et al. 2016. A novel excitatory network for the control of breathing. Nature 536:761476–80
    [Google Scholar]
  5. 5.
    Pagliardini S, Janczewski WA, Tan W, Dickson CT, Deisseroth K, Feldman JL. 2011. Active expiration induced by excitation of ventral medulla in adult anesthetized rats. J. Neurosci. 31:82895–2905
    [Google Scholar]
  6. 6.
    Marder E, Bucher D. 2001. Central pattern generators and the control of rhythmic movements. Curr. Biol. 11:23R986–96
    [Google Scholar]
  7. 7.
    Marder E, Calabrese RL. 1996. Principles of rhythmic motor pattern generation. Physiol. Rev. 76:3687–717
    [Google Scholar]
  8. 8.
    Zoccal DB, Furuya WI, Bassi M, Colombari DSA, Colombari E. 2014. The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities. Front. Physiol. 5:238
    [Google Scholar]
  9. 9.
    Guyenet PG, Bayliss DA. 2015. Neural control of breathing and CO2 homeostasis. Neuron 87:5946–61
    [Google Scholar]
  10. 10.
    Guyenet PG, Stornetta RL, Bayliss DA. 2010. Central respiratory chemoreception. J. Comp. Neurol. 518:193883–3906
    [Google Scholar]
  11. 11.
    Okaty BW, Commons KG, Dymecki SM. 2019. Embracing diversity in the 5-HT neuronal system. Nat. Rev. Neurosci. 20:7397–424
    [Google Scholar]
  12. 12.
    Feldman JL, Del Negro CA, Gray PA. 2013. Understanding the rhythm of breathing: so near, yet so far. Annu. Rev. Physiol. 75:423–52
    [Google Scholar]
  13. 13.
    Del Negro CA, Funk GD, Feldman JL. 2018. Breathing matters. Nat. Rev. Neurosci. 19:351–67
    [Google Scholar]
  14. 14.
    Ramirez J-M, Baertsch NA. 2018. The dynamic basis of respiratory rhythm generation: one breath at a time. Annu. Rev. Neurosci. 41:475–99
    [Google Scholar]
  15. 15.
    Feldman JL, Del Negro CA. 2006. Looking for inspiration: new perspectives on respiratory rhythm. Nat. Rev. Neurosci. 7:3232–41
    [Google Scholar]
  16. 16.
    Feldman JL, Mitchell GS, Nattie EE. 2003. Breathing: rhythmicity, plasticity, chemosensitivity. Annu. Rev. Neurosci. 26:239–66
    [Google Scholar]
  17. 17.
    Baertsch NA, Bush NE, Burgraff NJ, Ramirez J-M. 2021. Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network. eLife 10:e67523
    [Google Scholar]
  18. 18.
    Bachmutsky I, Wei XP, Kish E, Yackle K. 2020. Opioids depress breathing through two small brainstem sites. eLife 9:e52694
    [Google Scholar]
  19. 19.
    Gray PA, Rekling JC, Bocchiaro CM, Feldman JL. 1999. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex. Science 286:54441566–68
    [Google Scholar]
  20. 20.
    Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M et al. 2003. 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301:5630226–29
    [Google Scholar]
  21. 21.
    Baertsch NA, Severs LJ, Anderson TM, Ramirez J-M. 2019. A spatially dynamic network underlies the generation of inspiratory behaviors. PNAS 116:7493–7502
    [Google Scholar]
  22. 22.
    Stornetta RL, Moreira TS, Takakura AC, Kang BJ, Chang DA et al. 2006. Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. J. Neurosci. 26:4010305–14
    [Google Scholar]
  23. 23.
    Rose MF, Ren J, Ahmad KA, Chao H-T, Klisch TJ et al. 2009. Math1 is essential for the development of hindbrain neurons critical for perinatal breathing. Neuron 64:3341–54
    [Google Scholar]
  24. 24.
    Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S et al. 2016. The peptidergic control circuit for sighing. Nature 530:7590293–97
    [Google Scholar]
  25. 25.
    Shi Y, Stornetta RL, Stornetta DS, Onengut-Gumuscu S, Farber EA et al. 2017. Neuromedin B expression defines the mouse retrotrapezoid nucleus. J. Neurosci. 37:4811744–57
    [Google Scholar]
  26. 26.
    Thoby-Brisson M, Karlén M, Wu N, Charnay P, Champagnat J, Fortin G. 2009. Genetic identification of an embryonic parafacial oscillator coupling to the preBötzinger complex. Nat. Neurosci. 12:81028–35
    [Google Scholar]
  27. 27.
    Takakura AC, Barna BF, Cruz JC, Colombari E, Moreira TS. 2014. Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats. Exp. Physiol. 99:3571–85
    [Google Scholar]
  28. 28.
    Kumar NN, Velic A, Soliz J, Shi Y, Li K et al. 2015. Regulation of breathing by CO2 requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 348:62401255–60
    [Google Scholar]
  29. 29.
    Wang S, Shi Y, Shu S, Guyenet PG, Bayliss DA. 2013. Phox2b-expressing retrotrapezoid neurons are intrinsically responsive to H+ and CO2. J. Neurosci. 33:187756–61
    [Google Scholar]
  30. 30.
    Guyenet PG, Bayliss DA, Stornetta RL, Ludwig M, Kumar NN et al. 2016. Proton detection and breathing regulation by the retrotrapezoid nucleus. J. Physiol. 594:61529–51
    [Google Scholar]
  31. 31.
    Nasirova N, Quina LA, Marlin IMA, Ramirez J-M, Lambe EK, Turner EE. 2019. Dual recombinase fate mapping reveals a transient cholinergic phenotype in multiple populations of developing glutamatergic neurons. J. Comp. Neurol. 528:2283–307
    [Google Scholar]
  32. 32.
    Bouvier J, Thoby-Brisson M, Renier N, Dubreuil V, Ericson J et al. 2010. Hindbrain interneurons and axon guidance signaling critical for breathing. Nat. Neurosci. 13:91066–74
    [Google Scholar]
  33. 33.
    Gray PA, Hayes JA, Ling GY, Llona I, Tupal S et al. 2010. Developmental origin of preBötzinger complex respiratory neurons. J. Neurosci. 30:4414883–95
    [Google Scholar]
  34. 34.
    Wu J, Capelli P, Bouvier J, Goulding M, Arber S, Fortin G. 2017. A V0 core neuronal circuit for inspiration. Nat. Commun. 8:1544
    [Google Scholar]
  35. 35.
    Pagliardini S, Ren J, Gray PA, VanDunk C, Gross M et al. 2008. Central respiratory rhythmogenesis is abnormal in Lbx1-deficient mice. J. Neurosci. 28:4311030–41
    [Google Scholar]
  36. 36.
    Wei XP, Collie M, Dempsey B, Fortin G, Yackle K 2022. A novel reticular node in the brainstem synchronizes neonatal mouse crying with breathing. Neuron 110:4644–57.e6
    [Google Scholar]
  37. 37.
    Moore JD, Deschênes M, Furuta T, Huber D, Smear MC et al. 2013. Hierarchy of orofacial rhythms revealed through whisking and breathing. Nature 497:7448205–10
    [Google Scholar]
  38. 38.
    Dempsey B, Sungeelee S, Bokiniec P, Chettouh Z, Diem S et al. 2021. A medullary centre for lapping in mice. Nat. Commun. 12:16307
    [Google Scholar]
  39. 39.
    Schwarzacher SW, Smith JC, Richter DW. 1995. pre-Bötzinger complex in the cat. J. Neurophysiol. 73:41452–61
    [Google Scholar]
  40. 40.
    Carroll MS, Viemari J-C, Ramirez J-M. 2013. Patterns of inspiratory phase-dependent activity in the in vitro respiratory network. J. Neurophysiol. 109:2285–95
    [Google Scholar]
  41. 41.
    Alheid GF, McCrimmon DR. 2008. The chemical neuroanatomy of breathing. Respir. Physiol. Neurobiol. 164:1–23–11
    [Google Scholar]
  42. 42.
    Ezure K, Manabe M, Yamada H. 1988. Distribution of medullary respiratory neurons in the rat. Brain Res. 455:2262–70
    [Google Scholar]
  43. 43.
    Sun Q-J, Goodchild AK, Chalmers JP, Pilowsky PM. 1998. The pre-Bötzinger complex and phase-spanning neurons in the adult rat. Brain Res. 809:2204–13
    [Google Scholar]
  44. 44.
    Kobayashi S, Onimaru H, Inoue M, Inoue T, Sasa R. 2005. Localization and properties of respiratory neurons in the rostral pons of the newborn rat. Neuroscience 134:1317–25
    [Google Scholar]
  45. 45.
    Ezure K, Tanaka I. 2006. Distribution and medullary projection of respiratory neurons in the dorsolateral pons of the rat. Neuroscience 141:21011–23
    [Google Scholar]
  46. 46.
    Ezure K, Tanaka I, Saito Y. 2003. Brainstem and spinal projections of augmenting expiratory neurons in the rat. Neurosci. Res. 45:141–51
    [Google Scholar]
  47. 47.
    Schreihofer AM, Stornetta RL, Guyenet PG. 1999. Evidence for glycinergic respiratory neurons: Bötzinger neurons express mRNA for glycinergic transporter 2. J. Comp. Neurol. 407:4583–97
    [Google Scholar]
  48. 48.
    Schwarzacher SW, Rub U, Deller T. 2010. Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases. Brain 134:124–35
    [Google Scholar]
  49. 49.
    Stornetta RL, Rosin DL, Wang H, Sevigny CP, Weston MC, Guyenet PG. 2002. 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. 455:4499–512
    [Google Scholar]
  50. 50.
    Cui Y, Kam K, Sherman D, Janczewski WA, Zheng Y, Feldman JL. 2016. Defining preBötzinger complex rhythm- and pattern-generating neural microcircuits in vivo. Neuron 91:3602–14
    [Google Scholar]
  51. 51.
    Abreu RPS, Bondarenko E, Feldman JL. 2021. Phase- and state-dependent modulation of breathing pattern by preBötzinger complex somatostatin expressing neurons. J. Physiol. 600:1143–65
    [Google Scholar]
  52. 52.
    Vann NC, Pham FD, Dorst KE, Negro CAD. 2018. Dbx1 pre-Bötzinger complex interneurons comprise the core inspiratory oscillator for breathing in unanesthetized adult mice. eNeuro 5:3ENEURO.0130–18.2018
    [Google Scholar]
  53. 53.
    Guyenet PG, Sevigny CP, Weston MC, Stornetta RL. 2002. Neurokinin-1 receptor-expressing cells of the ventral respiratory group are functionally heterogeneous and predominantly glutamatergic. J. Neurosci. 22:93806–16
    [Google Scholar]
  54. 54.
    Yang CF, Feldman JL. 2018. Efferent projections of excitatory and inhibitory preBötzinger Complex neurons. J. Comp. Neurol. 526:81389–1402
    [Google Scholar]
  55. 55.
    Li P, Li S-B, Wang X, Phillips CD, Schwarz LA et al. 2020. Brain circuit of claustrophobia-like behavior in mice identified by upstream tracing of sighing. Cell Rep. 31:11107779
    [Google Scholar]
  56. 56.
    Yackle K, Schwarz LA, Kam K, Sorokin JM, Huguenard JR et al. 2017. Breathing control center neurons that promote arousal in mice. Science 355:63321411–15
    [Google Scholar]
  57. 57.
    Varga AG, Reid BT, Kieffer BL, Levitt ES. 2019. Differential impact of two critical respiratory centers in opioid-induced respiratory depression in awake mice. J. Physiol. 598:1189–205
    [Google Scholar]
  58. 58.
    Sun X, Pérez CT, Halemani ND, Shao XM, Greenwood M et al. 2019. Opioids modulate an emergent rhythmogenic process to depress breathing. eLife 8:e50613
    [Google Scholar]
  59. 59.
    Kaur S, Wang JL, Ferrari L, Thankachan S, Kroeger D et al. 2017. A genetically defined circuit for arousal from sleep during hypercapnia. Neuron 96:51153–67
    [Google Scholar]
  60. 60.
    Dutschmann M, Herbert H. 2006. 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. 24:41071–84
    [Google Scholar]
  61. 61.
    Levitt ES, Abdala AP, Paton JFR, Bissonnette JM, Williams JT. 2015. μ Opioid receptor activation hyperpolarizes respiratory-controlling Kölliker-Fuse neurons and suppresses post-inspiratory drive. J. Physiol. 593:194453–69
    [Google Scholar]
  62. 62.
    Liu S, Kim D-I, Oh TG, Pao GM, Kim J-H et al. 2021. Neural basis of opioid-induced respiratory depression and its rescue. PNAS 118:23e2022134118
    [Google Scholar]
  63. 63.
    Liu S, Ye M, Pao GM, Song SM, Jhang J et al. 2022. Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions. Neuron 110:5857–73.e9
    [Google Scholar]
  64. 64.
    Ramirez JM, Schwarzacher SW, Pierrefiche O, Olivera BM, Richter DW. 1998. Selective lesioning of the cat pre-Bötzinger complex in vivo eliminates breathing but not gasping. J. Physiol. 507:3895–907
    [Google Scholar]
  65. 65.
    Wang H, Stornetta RL, Rosin DL, Guyenet PG. 2001. Neurokinin-1 receptor-immunoreactive neurons of the ventral respiratory group in the rat. J. Comp. Neurol. 434:2128–46
    [Google Scholar]
  66. 66.
    Gray PA, Janczewski WA, Mellen N, McCrimmon DR, Feldman JL. 2001. Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons. Nat. Neurosci. 4:9927–30
    [Google Scholar]
  67. 67.
    Guyenet PG, Wang H. 2001. Pre-Bötzinger neurons with preinspiratory discharges “in vivo” express NK1 receptors in the rat. J. Neurophysiol. 86:1438–46
    [Google Scholar]
  68. 68.
    Fong AY, Potts JT. 2006. Neurokinin-1 receptor activation in Bötzinger complex evokes bradypnoea. J. Physiol. 575:3869–85
    [Google Scholar]
  69. 69.
    Blanchi B, Kelly LM, Viemari J-C, Lafon I, Burnet H et al. 2003. MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth. Nat. Neurosci. 6:101091–1100
    [Google Scholar]
  70. 70.
    Monteau R, Morin D, Hennequin S, Hilaire G. 1990. Differential effects of serotonin on respiratory activity of hypoglossal and cervical motoneurons: an in vitro study on the newborn rat. Neurosci. Lett. 111:1–2127–32
    [Google Scholar]
  71. 71.
    Morin D, Hennequin S, Monteau R, Hilaire G. 1990. Depressant effect of raphe stimulation on inspiratory activity of the hypoglossal nerve: in vitro study in the newborn rat. Neurosci. Lett. 116:3299–303
    [Google Scholar]
  72. 72.
    Morin D, Hennequin S, Monteau R, Hilaire G. 1990. Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat. Brain Res. 535:2281–87
    [Google Scholar]
  73. 73.
    Pasquale ED, Monteau R, Hilaire G. 1994. Endogenous serotonin modulates the fetal respiratory rhythm: an in vitro study in the rat. Dev. Brain Res. 80:1–2222–32
    [Google Scholar]
  74. 74.
    Al-Zubaidy ZA, Erickson RL, Greer JJ. 1996. Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats. Pflügers Archiv. 431:Suppl. 6942–49
    [Google Scholar]
  75. 75.
    Johnson SM, Smith JC, Feldman JL. 1996. Modulation of respiratory rhythm in vitro: role of Gi/o protein-mediated mechanisms. J. Appl. Physiol. 80:62120–33
    [Google Scholar]
  76. 76.
    Hennessy ML, Corcoran AE, Brust RD, Chang Y, Nattie EE, Dymecki SM. 2017. Activity of tachykinin1-expressing Pet1 raphe neurons modulates the respiratory chemoreflex. J. Neurosci. 37:71807–19
    [Google Scholar]
  77. 77.
    Ptak K, Yamanishi T, Aungst J, Milescu LS, Zhang R et al. 2009. Raphé neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P. J. Neurosci. 29:123720–37
    [Google Scholar]
  78. 78.
    Lu B, Su Y, Das S, Liu J, Xia J, Ren D. 2007. The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129:2371–83
    [Google Scholar]
  79. 79.
    Yeh S-Y, Huang W-H, Wang W, Ward CS, Chao ES et al. 2017. Respiratory network stability and modulatory response to substance P require Nalcn. Neuron 94:2294–303
    [Google Scholar]
  80. 80.
    Doi A, Ramirez JM. 2010. State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing. J. Neurosci. 30:248251–62
    [Google Scholar]
  81. 81.
    Schwarzacher SW, Pestean A, Günther S, Ballanyi K. 2002. Serotonergic modulation of respiratory motoneurons and interneurons in brainstem slices of perinatal rats. Neuroscience 115:41247–59
    [Google Scholar]
  82. 82.
    DePuy SD, Kanbar R, Coates MB, Stornetta RL, Guyenet PG. 2011. Control of breathing by raphe obscurus serotonergic neurons in mice. J. Neurosci. 31:61981–90
    [Google Scholar]
  83. 83.
    Peña F, Ramirez J-M. 2002. Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro. J. Neurosci. 22:2411055–64
    [Google Scholar]
  84. 84.
    Hodges MR, Wehner M, Aungst J, Smith JC, Richerson GB. 2009. Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development. J. Neurosci. 29:3310341–49
    [Google Scholar]
  85. 85.
    Erickson JT, Shafer G, Rossetti MD, Wilson CG, Deneris ES. 2007. Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges. Respir. Physiol. Neurobiol. 159:185–101
    [Google Scholar]
  86. 86.
    Chen J, Magnusson J, Karsenty G, Cummings KJ. 2013. Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice. J. Appl. Physiol. 114:121668–76
    [Google Scholar]
  87. 87.
    Kaplan K, Echert AE, Massat B, Puissant MM, Palygin O et al. 2016. Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats. J. Appl. Physiol. 120:91070–81
    [Google Scholar]
  88. 88.
    Young JO, Geurts A, Hodges MR, Cummings KJ. 2017. Active sleep unmasks apnea and delayed arousal in infant rat pups lacking central serotonin. J. Appl. Physiol. 123:4825–34
    [Google Scholar]
  89. 89.
    Cummings KJ, Commons KG, Hewitt JC, Daubenspeck JA, Li A et al. 2011. Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS. J. Appl. Physiol. 111:3825–33
    [Google Scholar]
  90. 90.
    Dosumu-Johnson RT, Cocoran AE, Chang Y, Nattie E, Dymecki SM. 2018. Acute perturbation of Pet1-neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery. eLife 7:e37857
    [Google Scholar]
  91. 91.
    Erickson JT, Sposato BC. 2009. Autoresuscitation responses to hypoxia-induced apnea are delayed in newborn 5-HT-deficient Pet-1 homozygous mice. J. Appl. Physiol. 106:61785–92
    [Google Scholar]
  92. 92.
    Knowlton GC, Larrabee MG. 1946. A unitary analysis of pulmonary volume receptors. Am. J. Physiol. 147:100–14
    [Google Scholar]
  93. 93.
    Mazzone SB, Undem BJ. 2016. Vagal afferent innervation of the airways in health and disease. Physiol. Rev. 96:3975–1024
    [Google Scholar]
  94. 94.
    Jerry Y. 2020. A historical perspective of pulmonary rapidly adapting receptors. Respir. Physiol. Neurobiol. 287:103595
    [Google Scholar]
  95. 95.
    Canning BJ, Spina D. 2009. Sensory nerves and airway irritability. In Sensory Nerves. Handbook of Experimental Pharmacology, Vol. 194, ed. B Canning, D Spina139–83 Berlin/Heidelberg: Springer
    [Google Scholar]
  96. 96.
    Lieu T, Kollarik M, Myers AC, Undem BJ. 2011. Neurotrophin and GDNF family ligand receptor expression in vagal sensory nerve subtypes innervating the adult guinea pig respiratory tract. Am. J. Physiol. Lung Cell. Mol. Physiol. 300:5L790–98
    [Google Scholar]
  97. 97.
    Undem BJ, Chuaychoo B, Lee M-G, Weinreich D, Myers AC, Kollarik M. 2004. Subtypes of vagal afferent C-fibres in guinea-pig lungs. J. Physiol. 556:3905–17
    [Google Scholar]
  98. 98.
    Agostoni E, Chinnock JE, Daly MDB, Murray JG. 1957. Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat. J. Physiol. 135:1182–205
    [Google Scholar]
  99. 99.
    Coleridge HM, Coleridge JCG. 1994. Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu. Rev. Physiol. 56:69–91
    [Google Scholar]
  100. 100.
    Clark FJ, von Euler C. 1972. On the regulation of depth and rate of breathing. J. Physiol. 222:2267–95
    [Google Scholar]
  101. 101.
    Umans BD, Liberles SD. 2018. Neural sensing of organ volume. Trends Neurosci. 41:12911–24
    [Google Scholar]
  102. 102.
    Schelegle ES, Green JF. 2001. An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors. Respir. Physiol. 125:1–217–31
    [Google Scholar]
  103. 103.
    Kollarik M, Dinh QT, Fischer A, Undem BJ. 2003. Capsaicin-sensitive and -insensitive vagal bronchopulmonary C-fibres in the mouse. J. Physiol. 551:3869–79
    [Google Scholar]
  104. 104.
    Widdicombe J. 2006. Reflexes from the lungs and airways: historical perspective. J. Appl. Physiol. 101:2628–34
    [Google Scholar]
  105. 105.
    Kubin L, Alheid GF, Zuperku EJ, McCrimmon DR. 2006. Central pathways of pulmonary and lower airway vagal afferents. J. Appl. Physiol. 101:2618–27
    [Google Scholar]
  106. 106.
    Lee L-Y, Yu J 2014. Sensory nerves in lung and airways. Compr. Physiol. 4:1287–324
    [Google Scholar]
  107. 107.
    Carr MJ, Undem BJ. 2003. Bronchopulmonary afferent nerves. Respirology 8:3291–301
    [Google Scholar]
  108. 108.
    Prescott SL, Liberles SD. 2022. Internal senses of the vagus nerve. Neuron 110:4579–99
    [Google Scholar]
  109. 109.
    Chou Y-L, Scarupa MD, Mori N, Canning BJ. 2008. Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs. Am. J. Physiol. 295:5R1572–84
    [Google Scholar]
  110. 110.
    Driessen AK, Farrell MJ, Mazzone SB, McGovern AE. 2016. Multiple neural circuits mediating airway sensations: recent advances in the neurobiology of the urge-to-cough. Respir. Physiol. Neurobiol. 226:115–20
    [Google Scholar]
  111. 111.
    McGovern AE, Davis-Poynter N, Yang S-K, Simmons DG, Farrell MJ, Mazzone SB 2015. Evidence for multiple sensory circuits in the brain arising from the respiratory system: an anterograde viral tract tracing study in rodents. Brain Struct. Funct. 220:63683–99
    [Google Scholar]
  112. 112.
    Kupari J, Häring M, Agirre E, Castelo-Branco G, Ernfors P. 2019. An atlas of vagal sensory neurons and their molecular specialization. Cell Rep. 27:82508–23.e4
    [Google Scholar]
  113. 113.
    Prescott SL, Umans BD, Williams EK, Brust RD, Liberles SD. 2020. An airway protection program revealed by sweeping genetic control of vagal afferents. Cell 181:3574–89
    [Google Scholar]
  114. 114.
    Nassenstein C, Taylor-Clark TE, Myers AC, Ru F, Nandigama R et al. 2010. Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs. J. Physiol. 588:234769–83
    [Google Scholar]
  115. 115.
    Mazzone SB, Tian L, Moe AAK, Trewella MW, Ritchie ME, McGovern AE. 2020. Transcriptional profiling of individual airway projecting vagal sensory neurons. Mol. Neurobiol. 57:2949–63
    [Google Scholar]
  116. 116.
    D'Autréaux F, Coppola E, Hirsch M-R, Birchmeier C, Brunet J-F. 2011. Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways. PNAS 108:5020018–23
    [Google Scholar]
  117. 117.
    Berthoud H-R, Neuhuber WL. 2000. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 85:1–31–17
    [Google Scholar]
  118. 118.
    Zhao Q, Yu CD, Wang R, Xu QJ, Dai Pra R, Zhang L, Chang RB 2022. A multidimensional coding architecture of the vagal interoceptive system. Nature 603:7903878–84
    [Google Scholar]
  119. 119.
    Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD. 2015. Vagal sensory neuron subtypes that differentially control breathing. Cell 161:3622–33
    [Google Scholar]
  120. 120.
    Kim S-H, Hadley SH, Maddison M, Patil M, Cha B et al. 2020. Mapping of sensory nerve subsets within the vagal ganglia and the brainstem using reporter mice for Pirt, TRPV1, 5-HT3, and Tac1 expression. eNeuro 7:2ENEURO.0494–19.2020
    [Google Scholar]
  121. 121.
    Alheid GF, Jiao W, McCrimmon DR. 2011. Caudal nuclei of the rat nucleus of the solitary tract differentially innervate respiratory compartments within the ventrolateral medulla. Neuroscience 109:207–27
    [Google Scholar]
  122. 122.
    Bonham AC, McCrimmon DR. 1990. Neurones in a discrete region of the nucleus tractus solitarius are required for the Breuer-Hering reflex in rat. J. Physiol. 427:1261–80
    [Google Scholar]
  123. 123.
    Green JF, Schmidt ND, Schultz HD, Roberts AM, Coleridge HM, Coleridge JC. 1984. Pulmonary C-fibers evoke both apnea and tachypnea of pulmonary chemoreflex. J. Appl. Physiol. 57:2562–67
    [Google Scholar]
  124. 124.
    Chuaychoo B, Lee M-G, Kollarik M, Undem BJ. 2005. Effect of 5-hydroxytryptamine on vagal C-fiber subtypes in guinea pig lungs. Pulm. Pharmacol. Ther. 18:4269–76
    [Google Scholar]
  125. 125.
    Moreira TS, Takakura AC, Colombari E, Guyenet PG. 2007. Activation of 5-hydroxytryptamine type 3 receptor-expressing C-fiber vagal afferents inhibits retrotrapezoid nucleus chemoreceptors in rats. J. Neurophysiol. 98:63627–37
    [Google Scholar]
  126. 126.
    Bonham AC, Joad JP. 1991. Neurones in commissural nucleus tractus solitarii required for full expression of the pulmonary C fibre reflex in rat. J. Physiol. 441:195–112
    [Google Scholar]
  127. 127.
    Gourine AV, Dale N, Korsak A, Llaudet E, Tian F et al. 2008. Release of ATP and glutamate in the nucleus tractus solitarii mediate pulmonary stretch receptor (Breuer-Hering) reflex pathway. J. Physiol. 586:Part 163963–78
    [Google Scholar]
  128. 128.
    Bonham AC, Coles SK, McCrimmon DR. 1993. Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats. J. Physiol. 464:Part 2725–45
    [Google Scholar]
  129. 129.
    Miyazaki M, Tanaka I, Ezure K. 1999. Excitatory and inhibitory synaptic inputs shape the discharge pattern of pump neurons of the nucleus tractus solitarii in the rat. Exp. Brain Res. 129:2191–200
    [Google Scholar]
  130. 130.
    Ezure K, Tanaka I. 1996. Pump neurons of the nucleus of the solitary tract project widely to the medulla. Neurosci. Lett. 215:2123–26
    [Google Scholar]
  131. 131.
    Ezure K, Tanaka I, Miyazaki M. 1998. Pontine projections of pulmonary slowly adapting receptor relay neurons in the cat. Neuroreport 9:3411–14
    [Google Scholar]
  132. 132.
    Ezure K, Tanaka I, Saito Y, Otake K. 2002. Axonal projections of pulmonary slowly adapting receptor relay neurons in the rat. J. Comp. Neurol. 446:181–94
    [Google Scholar]
  133. 133.
    Cohen MI, Feldman JL. 1984. Discharge properties of dorsal medullary inspiratory neurons: relation to pulmonary afferent and phrenic efferent discharge. J. Neurophysiol. 51:4753–76
    [Google Scholar]
  134. 134.
    Lipski J, Kubin L, Jodkowski J. 1983. Synaptic action of Rβ neurons on phrenic motoneurons studied with spike-triggered averaging. Brain Res. 288:1–2105–18
    [Google Scholar]
  135. 135.
    Davies RO, Kubin L. 1986. Projection of pulmonary rapidly adapting receptors to the medulla of the cat: an antidromic mapping study. J. Physiol. 373:163–86
    [Google Scholar]
  136. 136.
    Kalia M, Richter D. 1988. Rapidly adapting pulmonary receptor afferents: I. Arborization in the nucleus of the tractus solitarius. J. Comp. Neurol. 274:4560–73
    [Google Scholar]
  137. 137.
    Lipski J, Ezure K, She RBW. 1991. Identification of neurons receiving input from pulmonary rapidly adapting receptors in the cat. J. Physiol. 443:155–77
    [Google Scholar]
  138. 138.
    Ezure K, Otake K, Lipski J, She RBW. 1991. Efferent projections of pulmonary rapidly adapting receptor relay neurons in the cat. Brain Res. 564:2268–78
    [Google Scholar]
  139. 139.
    McCrimmon DR, Speck DF, Feldman JL. 1987. Role of the ventrolateral region of the nucleus of the tractus solitarius in processing respiratory afferent input from vagus and superior laryngeal nerves. Exp. Brain Res. 67:3449–59
    [Google Scholar]
  140. 140.
    Otake K, Nakamura Y, Tanaka I, Ezure K. 2001. Morphology of pulmonary rapidly adapting receptor relay neurons in the rat. J. Comp. Neurol. 430:4458–70
    [Google Scholar]
  141. 141.
    Ezure K, Tanaka I. 2000. Identification of deflation-sensitive inspiratory neurons in the dorsal respiratory group of the rat. Brain Res. 883:122–30
    [Google Scholar]
  142. 142.
    Kubin L, Kimura H, Davies RO. 1991. The medullary projections of afferent bronchopulmonary C fibres in the cat as shown by antidromic mapping. J. Physiol. 435:1207–28
    [Google Scholar]
  143. 143.
    Nonomura K, Woo S-H, Chang RB, Gillich A, Qiu Z et al. 2016. Piezo2 senses airway stretch and mediates lung inflation-induced apnoea. Nature 541:7636176–81
    [Google Scholar]
  144. 144.
    Ezure K, Tanaka I. 2004. 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 127:2409–17
    [Google Scholar]
  145. 145.
    Hayashi F, Coles SK, McCrimmon DR. 1996. Respiratory neurons mediating the Breuer-Hering reflex prolongation of expiration in rat. J. Neurosci. 16:206526–36
    [Google Scholar]
  146. 146.
    Sherman D, Worrell JW, Cui Y, Feldman JL. 2015. Optogenetic perturbation of preBötzinger complex inhibitory neurons modulates respiratory pattern. Nat. Neurosci. 18:3408–14
    [Google Scholar]
  147. 147.
    Janczewski WA, Tashima A, Hsu P, Cui Y, Feldman JL. 2013. Role of inhibition in respiratory pattern generation. J. Neurosci. 33:135454–65
    [Google Scholar]
  148. 148.
    Zuperku EJ, Hopp FA, Stuth EAE, Stucke AG. 2021. Interaction between the pulmonary stretch receptor and pontine control of expiratory duration. Respir. Physiol. Neurobiol. 293:103715
    [Google Scholar]
  149. 149.
    Motekaitis AM, Solomon IC, Kaufman MP. 1995. Role of the parabrachial nuclei in the airway dilation evoked by the Hering-Breuer reflex. Brain Res. 671:2314–16
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-021522-094142
Loading
/content/journals/10.1146/annurev-physiol-021522-094142
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error