Development of the brainstem respiratory circuit

Focus Article

Meike E. Heijden, Huda Y. Zoghbi

Published Online: Dec 09 2019

DOI: 10.1002/wdev.366

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Abstract The respiratory circuit is comprised of over a dozen functionally and anatomically segregated brainstem nuclei that work together to control respiratory rhythms. These respiratory rhythms emerge prenatally but only acquire vital importance at birth, which is the first time the respiratory circuit faces the sole responsibility for O2/CO2 homeostasis. Hence, the respiratory circuit has little room for trial‐and‐error‐dependent fine tuning and relies on a detailed genetic blueprint for development. This blueprint is provided by transcription factors that have specific spatiotemporal expression patterns along the rostral‐caudal or dorsal‐ventral axis of the developing brainstem, in proliferating precursor cells and postmitotic neurons. Studying these transcription factors in mice has provided key insights into the functional segregation of respiratory control and the vital importance of specific respiratory nuclei. Many studies converge on just two respiratory nuclei that each have rhythmogenic properties during the prenatal period: the preBötzinger complex (preBötC) and retrotrapezoid nucleus/parafacial nucleus (RTN/pF). Here, we discuss the transcriptional regulation that guides the development of these nuclei. We also summarize evidence showing that normal preBötC development is necessary for neonatal survival, and that neither the preBötC nor the RTN/pF alone is sufficient to sustain normal postnatal respiratory rhythms. Last, we highlight several studies that use intersectional genetics to assess the necessity of transcription factors only in subregions of their expression domain. These studies independently demonstrate that lack of RTN/pF neurons weakens the respiratory circuit, yet these neurons are not necessary for neonatal survival because developmentally related populations can compensate for abnormal RTN/pF function at birth. This article is categorized under: Nervous System Development > Vertebrates: Regional Development

Dorsal‐ventral patterning genes in the developing brainstem. Note: Transcription factors indicated with “^†” are essential for neonatal survival. Genes before brackets are expressed in proliferating progenitor cells whereas transcription factors between brackets “()” are expressed in postmitotic neurons. Genes in bold are discussed in the text. Note, not all transcription factors mentioned in this figure are present in all rhombomeres. Specifically, Atoh1* is not expressed in all dB2 neurons but only in a subset of neurons in r2 and r5 domains

[ Normal View | Magnified View ]

Rhombomeric expression of rostral‐caudal patterning genes. Note: Transcription factors indicated with “^†” are essential for neonatal survival. Abbreviations: vi, fourth ventricle; r1–r7, rhombomere 1–7

[ Normal View | Magnified View ]

Schematic of the brainstem respiratory circuit. Note: All outlined areas are brainstem nuclei that contribute to respiratory control. Dotted nuclei have intrinsic rhythmogenic properties. Red outline nuclei are either intrinsic chemosensitive properties or are key relay nuclei for chemosensitive signals. Orange nuclei are motor nuclei of cranial nerves that control airflow through the upper airways. Purple nuclei are predominantly active during the inspiratory phase. Green nuclei are predominantly active during the expiratory phase. The role of all other nuclei is described in more depth in Section 2. Abbreviations: BötC, Bötzinger complex; cVRG, caudal ventral respiratory group; ITR, intertrigeminal region; KF, Kölliker Fuse; mV, trigeminal motor nucleus; mVII, facial motor nucleus; mXII, hypoglossal motor nucleus; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; PBN, parabrachial nuclei; PiCo, postinspiratory complex; preBötC, preBötzinger complex; RTN/pF, retrotrapezoid nucleus/parafacial nucleus; rVRG = rostral ventral respiratory group

[ Normal View | Magnified View ]

References

Abdala,, A., Rybak,, I., Smith,, J., & Paton,, J. (2009). Abdominal expiratory activity in the rat brainstem–spinal cord in situ: Patterns, origins and implications for respiratory rhythm generation. The Journal of Physiology, 587(14), 3539–3559. https://doi.org/10.1113/jphysiol.2008.167502
Abu‐Shaweesh,, J. M. (2004). Maturation of respiratory reflex responses in the fetus and neonate. Seminars in Neonatology, 9(3), 169–180. https://doi.org/10.1016/j.siny.2003.09.003
Abu‐Shaweesh,, J. M., & Martin,, R. J. (2008). Neonatal apnea: What`s new? Pediatric Pulmonology, 43(10), 937–944. https://doi.org/10.1002/ppul.20832
Achard,, P., Zanella,, S., Rodriguez,, R., & Hilaire,, G. (2005). Perinatal maturation of the respiratory rhythm generator in mammals: From experimental results to computational simulation. Respiratory Physiology %26 Neurobiology, 149(1–3), 17–27. https://doi.org/10.1016/j.resp.2005.01.015
Anrep,, G. V., & Samaan,, Adli. (1932). Doublevagotomy in relation to respiration. The Journal of Physiology, 77. https://doi.org/10.1113/jphysiol.1932.sp002946.
Alheid,, G. F., & McCrimmon,, D. R. (2008). The chemical neuroanatomy of breathing. Respiratory Physiology %26 Neurobiology, 164(1–2), 3–11. https://doi.org/10.1016/j.resp.2008.07.014
Alheid,, G. F., Milsom,, W. K., & McCrimmon,, D. R. (2004). Pontine influences on breathing: An overview. Respiratory Physiology %26 Neurobiology, 143(2–3), 105–114. https://doi.org/10.1016/j.resp.2004.06.016
Amiel,, J., Laudier,, B., Attié‐Bitach,, T., Trang,, H., de Pontual,, L., Gener,, B., … Lyonnet,, S. (2003). Polyalanine expansion and frameshift mutations of the paired‐like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature Genetics, 33(4), 459–461. https://doi.org/10.1038/ng1130
Anderson,, T. M., Garcia,, A. J., Baertsch,, N. A., Pollak,, J., Bloom,, J. C., Wei,, A. D., … Ramirez,, J.‐M. M. (2016). A novel excitatory network for the control of breathing. Nature, 536(7614), 76–80. https://doi.org/10.1038/nature18944
Baertsch,, N. A., Baertsch,, H. C. & Ramirez,, J. M. (2018). The interdependence of excitation and inhibition for the control of dynamic breathing rhythms. Nature Communication, 9, 843. https://doi:10.1038/s41467-018-03223-x
Ben‐Arie,, N., Hassan,, B. N., Malicki,, D., Armstrong,, D., Matzuk,, M., … Zoghbi,, H. (2000). Functional conservation of atonal and Math1 in the CNS and PNS. Development, 127(5), 1039–1048.
Blanchi,, B., Kelly,, L. M., Viemari,, J.‐C., Lafon,, I., Burnet,, H., Bévengut,, M., … Sieweke,, M. H. (2003). MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth. Nature Neuroscience, 6(10), 1091–1100. https://doi.org/10.1038/nn1129
Bouvier,, J., Thoby‐Brisson,, M., Renier,, N., Dubreuil,, V., Ericson,, J., Champagnat,, J., … Fortin,, G. (2010). Hindbrain interneurons and axon guidance signaling critical for breathing. Nature Neuroscience, 13(9), 1066–1074. https://doi.org/10.1038/nn.2622
Brunet,, J.‐F., & Pattyn,, A. (2002). Phox2 genes — From patterning to connectivity. Current Opinion in Genetics %26 Development, 12(4), 435–440. https://doi.org/10.1016/s0959-437x(02)00322-2
Brust,, R. D., Corcoran,, A. E., Richerson,, G. B., Nattie,, E., & Dymecki,, S. M. (2014). Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. Cell Reports, 9(6), 2152–2165. https://doi.org/10.1016/j.celrep.2014.11.027
Bissonnette,, J. M., & Knopp,, S. J. (2001). Developmental changes in the hypoxic ventilatory response in C57BL/6 mice. RespirationPhysiology, 128(2), 179–186.
Carroll,, J. L., & Agarwal,, A. (2010). Development of ventilatory control in infants. Paediatric Respiratory Reviews, 11(4), 199–207.
Cassidy,, S. B., Schwartz,, S., Miller,, J. L., & Driscoll,, D. J. (2011). Prader‐Willi syndrome. Genetics in Medicine, 14(1), 10–26. https://doi.org/10.1038/gim.0b013e31822bead0
Champagnat,, J., Morin‐Surun,, M., Fortin,, G., & Thoby‐Brisson,, M. (2009). Developmental basis of the rostro‐caudal organization of the brainstem respiratory rhythm generator. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 364(1529), 2469–2476. https://doi.org/10.1098/rstb.2009.0090
Chang,, A. J., Ortega,, F. E., Riegler,, J., Madison,, D. V., & Krasnow,, M. A. (2015). Oxygen regulation of breathing through an olfactory receptor activated by lactate. Nature, 527(7577), 240–244. https://doi.org/10.1038/nature15721
Chatonnet,, F., Thoby‐Brisson,, M., Abadie,, V., del Toro,, E., Champagnat,, J., & Fortin,, G. (2002). Early development of respiratory rhythm generation in mouse and chick. Respiratory Physiology %26 Neurobiology, 131(1–2), 5–13. https://doi.org/10.1016/S1569-9048(02)00033-2
Chatonnet,, F., Wrobel,, L. J., Mézières,, V., Pasqualetti,, M., Ducret,, S., Taillebourg,, E., … Champagnat,, J. (2007). Distinct roles of Hoxa2 and Krox20in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening. Neural Development, 2(1), 19. https://doi.org/10.1186/1749-8104-2-19
Corcoran,, A., Hodges,, M., Wu,, Y., Wang,, W., Wylie,, C., Deneris,, E., & Richerson,, G. (2009). Medullary serotonin neurons and central CO2 chemoreception. Respiratory Physiology %26 Neurobiology, 168(1–2), 49–58. https://doi.org/10.1016/j.resp.2009.04.014
Dauger,, S., Pattyn,, A., Lofaso,, F., Gaultier,, C., Goridis,, C., Gallego,, J., & Brunet,, J.‐F. (2003). Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways. Development, 130(26), 6635–6642. https://doi.org/10.1242/dev.00866
Del Negro,, C. A., Funk,, G. D., & Feldman,, J. L. (2018). Breathing matters. Nature Reviews. Neuroscience, 19(6), 351–367. https://doi.org/10.1038/s41583-018-0003-6 [Correction added on 20 January 2020, after first online publication: the surname of the first author has been updated to “Del Negro.”]
Dubreuil,, V., Barhanin,, J., Goridis,, C., & Brunet,, J.‐F. (2009). Breathing with Phox2b. Philosophical Transactions of the Royal Society of London B: Biological Sciences, 364(1529), 2477–2483. https://doi.org/10.1098/rstb.2009.0085
Dubreuil,, V., Ramanantsoa,, N., Trochet,, D., Vaubourg,, V., Amiel,, J., Gallego,, J., … Goridis,, C. (2008). A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proceedings of the National Academy of Sciences, 105(3), 1067–1072. https://doi.org/10.1073/pnas.0709115105
Dubreuil,, V., Thoby‐Brisson,, M., Rallu,, M., Persson,, K., Pattyn,, A., Birchmeier,, C., … Goridis,, C. (2009). Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting Retrotrapezoid nucleus neurons. The Journal of Neuroscience, 29(47), 14836–14846. https://doi.org/10.1523/JNEUROSCI.2623-09.2009
Eugenín,, J., von Bernhardi,, R., Muller,, K., & Llona,, I. (2006). Development and pH sensitivity of the respiratory rhythm of fetal mice in vitro. Neuroscience, 141(1), 223–231. https://doi.org/10.1016/j.neuroscience.2006.03.046
Fortin,, G., & Thoby‐Brisson,, M. (2009). Embryonic emergence of the respiratory rhythm generator. Respiratory Physiology %26 Neurobiology, 168(1–2), 86–91. https://doi.org/10.1016/j.resp.2009.06.013
Goldstein,, R. D., Trachtenberg,, F. L., Sens,, M., Harty,, B. J., & Kinney,, H. C. (2016). Overall postneonatal mortality and rates of SIDS. Pediatrics, 137(1), e20152298. https://doi.org/10.1542/peds.2015-2298
Gray,, P. A. (2008). Transcription factors and the genetic organization of brain stem respiratory neurons. Journal of Applied Physiology, 104(5), 1513–1521. https://doi.org/10.1152/japplphysiol.01383.2007
Gray,, P. A. (2013). Transcription factors define the neuroanatomical organization of the medullary reticular formation. Frontiers in Neuroanatomy, 7, 7. https://doi.org/10.3389/fnana.2013.00007
Gray,, P. A., Hayes,, J. A., Ling,, G. Y., Llona,, I., nivasan,, T., Picardo,, M. D., … Del Negro,, C. A. (2010). Developmental origin of preBötzinger complex respiratory neurons. The Journal of Neuroscience, 30(44), 14883–14895. https://doi.org/10.1523/JNEUROSCI.4031-10.2010
Guyenet,, P. G., & Bayliss,, D. A. (2015). Neural control of breathing and CO2 homeostasis. Neuron, 87(5), 946–961. https://doi.org/10.1016/j.neuron.2015.08.001
Haddad,, G. G., & Mellins,, R. B. (1984). Hypoxia and respiratory control in early life. Annual Review of Physiology, 46, 629–643.
Haldane,, J. S., & Priestley,, J. G. (1905). The regulation of the lung‐ventilation. The Journal of physiology, 32(3‐4), 225–266. https://doi.org/10.1113/jphysiol.1905.sp001081
Haynes,, R. L., Frelinger,, A. L., Giles,, E. K., Goldstein,, R. D., Tran,, H., Kozakewich,, H. P., … Michelson,, A. D. (2017). High serum serotonin in sudden infant death syndrome. Proceedings of the National Academy of Sciences of the United States of America, 114(29), 7695–7700. https://doi.org/10.1073/pnas.1617374114
Hennessy,, M., Corcoran,, A., Brust,, R., Chang,, Y., Nattie,, E., & Dymecki,, S. (2017). Activity of tachykinin1‐expressing Pet1 raphe neurons modulates the respiratory chemoreflex. Journal of Neuroscience, 37(7), 1807–1819. https://doi.org/10.1523/JNEUROSCI.2316-16.2016
Hernandez‐Miranda,, L., Ibrahim,, D. M., Ruffault,, P.‐L., Larrosa,, M., Balueva,, K., Müller,, T., … Birchmeier,, C. (2018). Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice. Proceedings of the National Academy of Sciences, 115(51), 201813520–201813026. https://doi.org/10.1073/pnas.1813520115
Hodges,, M., & Richerson,, G. (2010). Medullary serotonin neurons and their roles in central respiratory chemoreception. Respiratory Physiology %26 Neurobiology, 173(3), 256–263. https://doi.org/10.1016/j.resp.2010.03.006
Hodges,, M., Wehner,, M., Aungst,, J., Smith,, J., & Richerson,, G. (2009). Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development. The Journal of Neuroscience, 29(33), 10341–10349. https://doi.org/10.1523/JNEUROSCI.1963-09.2009
Horan,, G., Wu,, K., Wolgemuth,, D., & Behringer,, R. (1994). Homeotic transformation of cervical vertebrae in Hoxa‐4 mutant mice. Proceedings of the National Academy of Sciences, 91(26), 12644–12648. https://doi.org/10.1073/pnas.91.26.12644
Huang,, W.‐H. H., Tupal,, n., Huang,, T.‐W. W., Ward,, C. S., Neul,, J. L., Klisch,, T. J., … Zoghbi,, H. Y. (2012). Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood. Neuron, 75(5), 799–809. https://doi.org/10.1016/j.neuron.2012.06.027
Huckstepp,, R. T., Cardoza,, K. P., Henderson,, L. E., & Feldman,, J. L. (2018). Distinct parafacial regions in control of breathing in adult rats. PLoS One, 13(8), e0201485. https://doi.org/10.1371/journal.pone.0201485
Huckstepp,, R. T., Henderson,, L. E., Cardoza,, K. P., & Feldman,, J. L. (2016). Interactions between respiratory oscillators in adult rats. eLife, 5, e14203. https://doi.org/10.7554/eLife.14203
Jacquin,, T., Borday,, V., Schneider‐Maunoury,, S., Topilko,, P., Ghilini,, G., Kato,, F., … Champagnat,, J. (1996). Reorganization of pontine rhythmogenic neuronal networks in Krox‐20 knockout mice. Neuron, 17(4), 747–758. https://doi.org/10.1016/S0896-6273(00)80206-8
Janczewski,, W. A., & Feldman,, J. L. (2006). Distinct rhythm generators for inspiration and expiration in the juvenile rat. The Journal of Physiology, 570(2), 407–420. https://doi.org/10.1113/jphysiol.2005.098848
Janczewski,, W. A., Onimaru,, H., Homma,, I., & Feldman,, J. L. (2002). Opioid‐resistant respiratory pathway from the preinspiratory neurones to abdominal muscles: in vivo and in vitro study in the newborn rat. The Journal of Physiology, 545(3), 1017–1026. https://doi.org/10.1113/jphysiol.2002.023408
Kinney,, H. C., Richerson,, G. B., Dymecki,, S. M., Darnall,, R. A., & Nattie,, E. E. (2009). The brainstem and serotonin in the sudden infant death syndrome. Annual Review of Pathology, 4, 517–550. https://doi.org/10.1146/annurev.pathol.4.110807.092322
Korsak,, A., Sheikhbahaei,, S., Machhada,, A., Gourine,, A. V., & Huckstepp,, R. T. (2018). The role of parafacial neurons in the control of breathing during exercise. Scientific Reports, 8(1), 400. https://doi.org/10.1038/s41598-017-17412-z
Krüger,, M., Schäfer,, K., & Braun,, T. (2002). The homeobox containing gene Lbx1 is required for correct dorsal–ventral patterning of the neural tube. Journal of Neurochemistry, 82(4), 774–782. https://doi.org/10.1046/j.1471-4159.2002.01078.x
Krumlauf,, R. (1994). Hox genes in vertebrate development. Cell, 78(2), 191–201. https://doi.org/10.1016/0092-8674(94)90290-9
Lufkin,, T., Dierich,, A., LeMeur,, M., Mark,, M., & Chambon,, P. (1991). Disruption of the Hox‐1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell, 66(6), 1105–1119.
Maricich,, S. M., Xia,, A., Mathes,, E. L., Wang,, V. Y., Oghalai,, J. S., Fritzsch,, B., & Zoghbi,, H. Y. (2009). Atoh1‐lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei. The Journal of Neuroscience, 29(36), 11123–11133. https://doi.org/10.1523/JNEUROSCI.2232-09.2009
Matarazzo,, V., Caccialupi,, L., Schaller,, F., Shvarev,, Y., Kourdougli,, N., Bertoni,, A., … Muscatelli,, F. (2017). Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader‐Willi syndrome. eLife, 6. https://doi.org/10.7554/elife.32640
Mayer,, C., Wilson,, C., & MacFarlane,, P. (2015). Changes in carotid body and nTS neuronal excitability following neonatal sustained and chronic intermittent hypoxia exposure. Respiratory Physiology %26 Neurobiology, 205, 28–36. https://doi.org/10.1016/j.resp.2014.09.015
Mellen,, N. M., & Thoby‐Brisson,, M. (2012). Respiratory circuits: Development, function and models. Current Opinion in Neurobiology, 22(4), 676–685. https://doi.org/10.1016/j.conb.2012.01.001
Mizuno,, K., & Ueda,, A. (2003). The maturation and coordination of sucking, swallowing, and respiration in preterm infants. The Journal of Pediatrics, 142(1), 36–40. https://doi.org/10.1067/mpd.2003.mpd0312
Moon,, R. Y., Horne,, R. S., & Hauck,, F. R. (2007). Sudden infant death syndrome. Lancet, 370(9598), 1578–1587. https://doi.org/10.1016/S0140-6736(07)61662-6
Pattyn,, A., Morin,, X., Cremer,, H., Goridis,, C., & Brunet,, J.‐F. (1999). The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature, 399(6734), 20700.
Nixon,, G. M., & Brouillette,, R. T. (2002). Sleep and breathing in Prader‐Willi syndrome. Pediatric Pulmonology, 34(3), 209–217. https://doi.org/10.1002/ppul.10152
Oku,, Y., Masumiya,, H., & Okada,, Y. (2007). Postnatal developmental changes in activation profiles of the respiratory neuronal network in the rat ventral medulla. The Journal of Physiology, 585(1), 175–186. https://doi.org/10.1113/jphysiol.2007.138180
Onimaru,, H., & Homma,, I. (2003). A novel functional neuron group for respiratory rhythm generation in the ventral medulla. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(4), 1478–1486.
Pagliardini,, S., Ren,, J., Gray,, P. A., VanDunk,, C., Gross,, M., Goulding,, M., & Greer,, J. J. (2008). Central respiratory rhythmogenesis is abnormal in Lbx1‐ deficient mice. The Journal of Neuroscience, 28(43), 11030–11041. https://doi.org/10.1523/JNEUROSCI.1648-08.2008
Pattyn,, A., Hirsch,, M., Goridis,, C., & Brunet,, J. (2000). Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b. Development, 127(7), 1349–1358. (Original work published).
Philippidou,, P., & Dasen,, J. S. (2013). Hox genes: Choreographers in neural development, architects of circuit organization. Neuron, 80(1), 12–34. https://doi.org/10.1016/j.neuron.2013.09.020
Pierani,, A., Moran‐Rivard,, L., Sunshine,, M., Littman,, D., Goulding,, M., & Jessell,, T. (2001). Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron, 29(2), 367–384. https://doi.org/10.1016/s0896-6273(01)00212-4
Pisanski,, A., & Pagliardini,, S. (2018). The parafacial respiratory group and the control of active expiration. Respiratory Physiology %26 Neurobiology, 265, 153–160. https://doi.org/10.1016/j.resp.2018.06.010
Poets,, C. F. (2010). Apnea of prematurity: What can observational studies tell us about pathophysiology? Sleep Medicine, 11(7), 701–707. https://doi.org/10.1016/j.sleep.2009.11.016
Radulovacki,, M., Pavlovic,, S., Saponjic,, J., & Carley,, D. W. (2003). Intertrigeminal region attenuates reflex apnea and stabilizes respiratory pattern in rats. Brain Research, 975(1–2), 66–72. https://doi.org/10.1016/S0006-8993(03)02587-3
Radulovacki,, M., Pavlovic,, S., Saponjic,, J., & Carley,, D. W. (2004). Modulation of reflex and sleep related apnea by pedunculopontine tegmental and intertrigeminal neurons. Respiratory Physiology %26 Neurobiology, 143(2–3), 293–306. https://doi.org/10.1016/j.resp.2004.02.012
Ramanantsoa,, N., Hirsch,, M.‐R., Thoby‐Brisson,, M., Dubreuil,, V., Bouvier,, J., Ruffault,, P.‐L., … Goridis,, C. (2011). Breathing without CO(2) chemosensitivity in conditional Phox2b mutants. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(36), 12880–12888. https://doi.org/10.1523/jneurosci.1721-11.2011
Ramirez,, J.‐M., & Baertsch,, N. (2018). Defining the rhythmogenic elements of mammalian breathing. Physiology, 33(5), 302–316. https://doi.org/10.1152/physiol.00025.2018
Ray,, R., Corcoran,, A., Brust,, R., Kim,, J., Richerson,, G., Nattie,, E., & Dymecki,, S. (2011). Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science, 333(6042), 637–642. https://doi.org/10.1126/science.1205295
Roman,, C. W., Derkach,, V. A., & Palmiter,, R. D. (2016). Genetically and functionally defined NTS to PBN brain circuits mediating anorexia. Nature Communications, 7, 11905. https://doi.org/10.1038/ncomms11905
Rose,, M. F., Ahmad,, K. A., Thaller,, C., & Zoghbi,, H. Y. (2009). Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1. Proceedings of the National Academy of Sciences of the United States of America, 106(52), 22462–22467. https://doi.org/10.1073/pnas.0911579106
Rose,, M. F., Ren,, J., Ahmad,, K. A., Chao,, H.‐T., Klisch,, T. J., Flora,, A., … Zoghbi,, H. Y. (2009). Math1 is essential for the development of hindbrain neurons critical for perinatal breathing. Neuron, 64(3), 341–354. https://doi.org/10.1016/j.neuron.2009.10.023
Rubin,, J. E., Shevtsova,, N. A., Ermentrout,, B. G., Smith,, J. C., & Rybak,, I. A. (2009). Multiple rhythmic states in a model of the respiratory central pattern generator. Journal of Neurophysiology, 101(4), 2146–2165. https://doi.org/10.1152/jn.90958.2008
Ruffault,, P.‐L., D`Autréaux,, F., Hayes,, J. A., Nomaksteinsky,, M., Autran,, S., Fujiyama,, T., … Goridis,, C. (2015). The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO₂. eLife, 4. https://doi.org/10.7554/elife.07051
Sieber,, M., Storm,, R., Martinez‐de‐la‐Torre,, M., Müller,, T., Vasyutina,, E., Dutschmann,, M., … Birchmeier,, C. (2006). The homeodomain factor Lbx1 controls the differentiation of sensory relay neurons in the hindbrain. International Journal of Developmental Neuroscience, 24(8), 590. https://doi.org/10.1016/j.ijdevneu.2006.09.279
Smith,, J., Ellenberger,, H., Ballanyi,, K., Richter,, D., & Feldman,, J. (1991). Pre‐Bötzinger complex: A brainstem region that may generate respiratory rhythm in mammals. Science, 254(5032), 726–729.
Smith,, J., Abdala,, A., Koizumi,, H., Rybak,, I., & Paton,, J. (2007). Spatial and functional architecture of the mammalian brain stem respiratory network: A hierarchy of three oscillatory mechanisms. Journal of Neurophysiology, 98(6), 3370–3387. https://doi.org/10.1152/jn.00985.2007
Smith,, J. C., Abdala,, A., Borgmann,, A., Rybak,, I. A., & Paton,, J. (2013). Brainstem respiratory networks: Building blocks and microcircuits. Trends in Neurosciences, 36(3), 152–162. https://doi.org/10.1016/j.tins.2012.11.004
Song,, G., Xu,, H., Wang,, H., MacDonald,, S. M., & Poon,, C.‐S. (2011). Hypoxia‐excited neurons in NTS send axonal projections to Kölliker‐Fuse/parabrachial complex in dorsolateral pons. Neuroscience, 175, 145–153. https://doi.org/10.1016/j.neuroscience.2010.11.065
Souza,, G. M., Kanbar,, R., Stornetta,, D. S., Abbott,, S. B., Stornetta,, R. L., & Guyenet,, P. G. (2018). Breathing regulation and blood gas homeostasis after near complete lesions of the retrotrapezoid nucleus in adult rats. The Journal of Physiology, 596(13), 2521–2545. https://doi.org/10.1113/JP275866
Stornetta,, R. L., Moreira,, T. S., Takakura,, A. C., Kang,, B., Chang,, D. A., West,, G. H., … Guyenet,, P. G. (2006). Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26(40), 10305–10314. https://doi.org/10.1523/JNEUROSCI.2917-06.2006
SYNDROME,, T. O. (2016). SIDS and other sleep‐related infant deaths: Updated 2016 recommendations for a safe infant sleeping environment. Pediatrics, 138(5), e20162938. https://doi.org/10.1542/peds.2016-2938
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. Nature Neuroscience, 12(8), 1028–1035. https://doi.org/10.1038/nn.2354
Vaage,, S. (1969). The segmentation of the primitive neural tube in chick embryos (Gallus domesticus), a morphological, histochemical and autoradiographical investigation. Ergeb Anat Entwicklungsgesch, 41(3), 3–87. https://doi.org/10.1007/978-3-662-29669-1_7
Valarché,, I., Tissier‐Seta,, J., Hirsch,, M., Martinez,, S., Goridis,, C., & Brunet,, J. (1993). The mouse homeodomain protein Phox2 regulates Ncam promoter activity in concert with Cux/CDP and is a putative determinant of neurotransmitter phenotype. Development (Cambridge, England), 119(3), 881–896.
van der Heijden,, M. E., & Zoghbi,, H. Y. (2018). Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice. eLife, 7, e38455. https://doi.org/10.7554/elife.38455 (Original work published).
Vann,, N. C., Pham,, F. D., Dorst,, K. E., & Del Negro,, C. A. (2018). Dbx1 pre‐Bötzinger complex interneurons comprise the Core inspiratory oscillator for breathing in Unanesthetized adult mice. ENeuro, 5(3). https://doi.org/10.1523/eneuro.0130-18.2018
Vann,, N. C., Pham,, F. D., Hayes,, J. A., Kottick,, A., & Del Negro,, C. A. (2016). Transient suppression of Dbx1 PreBötzinger interneurons disrupts breathing in adult mice. PLoS One, 11(9), e0162418. https://doi.org/10.1371/journal.pone.0162418
Wang,, V. Y., Rose,, M. F., & Zoghbi,, H. Y. (2005). Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron, 48(1), 31–43. https://doi.org/10.1016/j.neuron.2005.08.024
Wang,, X., Hayes,, J. A., Revill,, A. L., Song,, H., Kottick,, A., Vann,, N. C., … Del Negro,, C. A. (2014). Laser ablation of Dbx1 neurons in the pre‐Bötzinger complex stops inspiratory rhythm and impairs output in neonatal mice. eLife, 3, e03427. https://doi.org/10.7554/eLife.03427
Waters,, K. A., & Gozal,, D. (2003). Responses to hypoxia during early development. Respiratory Physiology %26 Neurobiology, 136(2–3), 115–129.
Wu,, J., Capelli,, P., Bouvier,, J., Goulding,, M., Arber,, S., & Fortin,, G. (2017). A V0 core neuronal circuit for inspiration. Nature Communications, 8(1), 544. https://doi.org/10.1038/s41467-017-00589-2
Wurst,, W., erbach,, A., & Joyner,, A. (1994). Multiple developmental defects in Engrailed‐1 mutant mice: an early mid‐hindbrain deletion and patterning defects in forelimbs and sternum. Development, 120(7), 2065–2075.
Yackle,, K., Schwarz,, L., Kam,, K., Sorokin,, J., Huguenard,, J., Feldman,, J., … Krasnow,, M. (2017). Breathing control center neurons that promote arousal in mice. Science, 355(6332), 1411–1415. https://doi.org/10.1126/science.aai7984
Zhao,, J., Gonzalez,, F., & Mu,, D. (2011). Apnea of prematurity: From cause to treatment. European Journal of Pediatrics, 170(9), 1097–1105. https://doi.org/10.1007/s00431-011-1409-6
Zoccal,, D. B., Furuya,, W. I., Bassi,, M., Colombari,, D. S., & Colombari,, E. (2014). The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities. Frontiers in Physiology, 5, 238. https://doi.org/10.3389/fphys.2014.00238
Zoccal,, D. B., Silva,, J. N., Barnett,, W. H., Lemes,, E. V., Falquetto,, B., Colombari,, E., … Takakura,, A. C. (2018). Interaction between the retrotrapezoid nucleus and the parafacial respiratory group to regulate active expiration and sympathetic activity in rats. American Journal of Physiology. Lung Cellular and Molecular Physiology, 315, L891–L909. https://doi.org/10.1152/ajplung.00011.2018

Society Partners

	Free online access to WIREs Developmental Biology is a member benefit. Learn More
	SDB Collaborative Resources
	Society for Developmental Biology Homepage

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Development of the brainstem respiratory circuit

Browse by Topic

Society Partners

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox