Understanding the rhythm of breathing: So near, yet so far

Annual Review of Physiology

Volumn 75, Issue , 2013, Pages 423-452

  Feldman, Jack L ^a   Del Negro, Christopher A ^b   Gray, Paul A ^c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b The College of William and Mary   (United States)

^c WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Brain stem; Central pattern generation; Parafacial respiratory group; PreB tzinger Complex; Retrotrapezoid nucleus

Indexed keywords

FENTANYL; NARCOTIC ANALGESIC AGENT; OPIATE; SEROTONIN;

ASTROCYTE; BRAIN STEM; BREATHING; BREATHING RATE; CONGENITAL CENTRAL HYPOVENTILATION SYNDROME; DENDRITE; FETUS DEVELOPMENT; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LUNG FUNCTION; MORBIDITY; MORTALITY; NERVOUS SYSTEM FUNCTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SLEEP DISORDER; SUDDEN INFANT DEATH SYNDROME;

ANIMALS; EXHALATION; HUMANS; INHALATION; MEDULLA OBLONGATA; PERIODICITY; RESPIRATION; RESPIRATORY MECHANICS; RESPIRATORY PHYSIOLOGICAL PHENOMENA; RESPIRATORY SYSTEM;

EID: 84873621305     PISSN: 00664278     EISSN: 15451585     Source Type: Book Series    
DOI: 10.1146/annurev-physiol-040510-130049     Document Type: Review

References (218)

1. Pattinson KT, Mitsis GD, Harvey AK, Jbabdi S, Dirckx S, et al. 2009. Determination of the human brainstem respiratory control network and its cortical connections in vivo using functional and structural imaging. Neuroimage 44:295-305
2. 2+ dependence of inspiratory-related rhythm in novel "calibrated" mouse brainstem slices. Respir. Physiol. Neurobiol. 175:37-48
3. Ruangkittisakul A, Schwarzacher SW, Secchia L, Ma Y, Bobocea N, et al. 2008. Generation of eupnea and sighs by a spatiochemically organized inspiratory network. J. Neurosci. 28:2447-58
4. + antagonism of inspiratory centre rhythms in slices and en bloc preparations of newborn rat brainstem. J. Physiol. 584:489-508
5. 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 254:726-29
6. Del Negro CA, Kam K, Hayes JA, Feldman JL. 2009. Asymmetric control of inspiratory and expiratory phases by excitability in the respiratory network of neonatal mice in vitro. J. Physiol. 587:1217-31
7. Rekling JC, Champagnat J, Denavit-Saubie M. 1996. 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
8. Feldman JL. 1986. Neurophysiology of breathing in mammals. In Handbook of Physiology, Section I: The Nervous System, Volume IV: Intrinsic Regulatory Systems of the Brain, ed. FE Bloom, pp. 463-524. Bethesda, MD: Am. Physiol. Soc.
9. Paton JF. 1996. A working heart-brainstem preparation of the mouse. J. Neurosci. Methods 65:63-68
10. Lieske SP, Thoby-Brisson M, Telgkamp P, Ramirez JM. 2000. Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps. Nat. Neurosci. 3:600-7
11. Paton JF, Abdala AP, Koizumi H, Smith JC, St-John WM. 2006. Respiratory rhythm generation during gasping depends on persistent sodium current. Nat. Neurosci. 9:311-13
12. Viemari JC, Garcia AJ 3rd, Doi A, Ramirez JM. 2011. Activation of alpha-2 noradrenergic receptors is critical for the generation of fictive eupnea and fictive gasping inspiratory activities in mammals in vitro. Eur. J. Neurosci. 33:2228-37
13. Suzue T. 1984. Respiratory rhythm generation in the in vitro brain stem-spinal cord preparation of the neonatal rat. J. Physiol. 354:173-83
14. Feldman JL, Connelly CA, Ellenberger HH, Smith JC. 1990. The cardiorespiratory system within the brainstem. Eur. J. Neurosci. Suppl. 3:171
15. Feldman JL, Mitchell GS, Nattie EE. 2003. Breathing: rhythmicity, plasticity, chemosensitivity. Annu. Rev. Neurosci. 26:239-66
16. Rekling JC, Feldman JL. 1998. PreBötzinger Complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu. Rev. Physiol. 60:385-405
17. Feldman JL, Del Negro CA. 2006. Looking for inspiration: new perspectives on respiratory rhythm. Nat. Rev. Neurosci. 7:232-42
18. Janczewski WA, Feldman JL. 2006. Distinct rhythm generators for inspiration and expiration in the juvenile rat. J. Physiol. 570:407-20
19. Smith JC, Abdala AP, Koizumi H, Rybak IA, Paton JF. 2007. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J. Neurophysiol. 98:3370-87
20. Gray PA, Janczewski WA, Mellen N, McCrimmon DR, Feldman JL. 2001. Normal breathing requires preBötzinger Complex neurokinin-1 receptor-expressing neurons. Nat. Neurosci. 4:927-30
21. McKay LC, Janczewski WA, Feldman JL. 2005. Sleep-disordered breathing after targeted ablation of preBötzinger Complex neurons. Nat. Neurosci. 8:1142-44
22. Stornetta RL, Rosin DL, Wang H, Sevigny CP, Weston MC, Guyenet PG. 2003. A group of gluta-matergic 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
23. Llona I, Ampuero E, Eugenin JL. 2004. Somatostatin inhibition of fictive respiration is modulated by pH. Brain Res. 1026:136-42
24. Tan W, Janczewski WA, Yang P, Shao XM, Callaway EM, Feldman JL. 2008. Silencing preBötzinger Complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat. Neurosci. 11:538-40
25. Grillner S, Jessell TM. 2009. Measured motion: searching for simplicity in spinal locomotor networks. Curr. Opin. Neurobiol. 19:572-86
26. Gossard JP, Dubuc R, Kolta A. 2011. Preface. Breathe, walk and chew: the neural challenge: part II. Prog. Brain Res. 188:ix
27. Tan W, Pagliardini S, Yang P, Janczewski WA, Feldman JL. 2010. Projections of preBötzinger Complex neurons in adult rats. J. Comp. Neurol. 518:1862-78
28. Bianchi AL, Denavit-Saubie M, Champagnat J. 1995. Central controlof breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol. Rev. 75:1-45
29. von Euler C. 1986. Brain stem mechanisms for generation and control of breathing pattern. In Handbook of Physiology, Section 3: The Respiratory System, Volume II: Control of Breathing, ed. A Fishman, N Cherniak, J Widdicombe, pp. 1-67. Bethesda: Am. Physiol. Soc.
30. Richter DW. 1982. Generation and maintenance of the respiratory rhythm. J. Exp. Biol. 100:93-107
31. Funk GD, Smith JC, Feldman JL. 1993. Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids. J. Neurophysiol. 70:1497-515
32. Wallen-Mackenzie A, Gezelius H, Thoby-Brisson M, Nygard A, Enjin A, et al. 2006. Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation. J. Neurosci. 26:12294-307
33. Gossard JP, Dubuc R, Kolta A, eds. 2010. Breathe, Walk and Chew: The Neural Challenge: Part I (Prog. Brain Res. 187:2-230). New York: Elsevier
34. Tazerart S, Vinay L, Brocard F. 2008. The persistent sodium current generates pacemaker activities in the central pattern generator for locomotion and regulates the locomotor rhythm. J. Neurosci. 28:8577-89
35. Brocard F, Verdier D, Arsenault I, Lund JP, Kolta A. 2006. Emergence of intrinsic bursting in trigeminal sensory neurons parallels the acquisition of mastication in weanling rats. J. Neurophysiol. 96:2410-24
36. Best J, Borisyuk A, Rubin J, Terman D, Wechselberger M. 2005. The dynamic range of bursting in a model respiratory pacemaker network. SIAM J. App. Dyn. Sys. 4:1107-39
37. Purvis LK, Smith JC, Koizumi H, Butera RJ. 2007. Intrinsic bursters increase the robustness of rhythm generation in an excitatory network. J. Neurophysiol. 97:1515-26
38. +-dominated leak currents contribute to respiratory rhythm generation in the pre-Bötzinger Complex in vitro. J. Neurosci. 28:1773-85
39. Ramirez JM, Koch H, Garcia AJ3rd, Doi A, Zanella S. 2011. The role of spiking and bursting pacemakers in the neuronal control of breathing. J. Biol. Phys. 37:241-61
40. CAN-dependent pacemaker activity. Eur. J. Neurosci. 31:1219-32
41. Tryba AK, Peña F, Lieske SP, Viemari JC, Thoby-Brisson M, Ramirez JM. 2008. Differential modulation of neural network and pacemaker activity underlying eupnea and sigh-breathing activities. J. Neurophysiol. 99:2114-25
42. Peña F, Parkis MA, Tryba AK, Ramirez JM. 2004. Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron 43:105-17
43. Wittmeier S, Song G, Duffin J, Poon CS. 2008. Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis. Proc. Natl. Acad. Sci. USA 105:18000-5
44. Peña F, Ramirez JM. 2004. Substance P-mediated modulationofpacemaker properties inthe mammalian respiratory network. J. Neurosci. 24:7549-56
45. Brockhaus J, Ballanyi K. 1998. Synaptic inhibition in the isolated respiratory network of neonatal rats. Eur. J. Neurosci. 10:3823-39
46. Feldman JL, Smith JC. 1989. Cellular mechanisms underlying modulation of breathing pattern in mammals. Ann. NY Acad. Sci. 563:114-30
47. Ren J, Greer JJ. 2006. Modulation of respiratory rhythmogenesis by chloride-mediated conductances during the perinatal period. J. Neurosci. 26:3721-30
48. Shao XM, Feldman JL. 1997. Respiratory rhythm generation and synaptic inhibition of expiratory neurons in pre-Bötzinger Complex: differential roles of glycinergic and GABAergic neural transmission. J. Neurophysiol. 77:1853-60
49. Del Negro CA, Morgado-Valle C, Hayes JA, Mackay DD, Pace RW, et al. 2005. Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation. J. Neurosci. 25:446-53
50. Thoby-Brisson M, Ramirez JM. 2001. Identification of two types of inspiratory pacemaker neurons in the isolated respiratory neural network of mice. J. Neurophysiol. 86:104-12
51. Del Negro CA, Koshiya N, Butera RJ Jr, Smith JC. 2002. Persistent sodium current, membrane properties and bursting behavior of pre-Bötzinger Complex inspiratory neurons in vitro. J. Neurophysiol. 88:2242-50
52. Del Negro CA, Hayes JA, Pace RW, Brush BR, Teruyama R, Feldman JL. 2010. Synaptically activated burst-generating conductances underlie a group-pacemaker mechanism for respiratory rhythm generation in mammal. See Ref. 33, pp. 111-36
53. Butera RJ Jr, Rinzel J, Smith JC. 1999. Models of respiratory rhythm generation in the pre-Bö tzinger Complex. I. Bursting pacemaker neurons. J. Neurophysiol. 82:382-97
54. Koizumi H, Wilson CG, Wong S, Yamanishi T, Koshiya N, Smith JC. 2008. Functional imaging, spatial reconstruction, and biophysical analysis of a respiratory motor circuit isolated in vitro. J. Neurosci. 28:2353-65
55. Johnson SM, Smith JC, Funk GD, Feldman JL. 1994. Pacemaker behavior of respiratory neurons in medullary slices from neonatal rat. J. Neurophysiol. 72:2598-608
56. Ramirez JM, Tryba AK, Peña F. 2004. Pacemaker neurons and neuronal networks: an integrative view. Curr. Opin. Neurobiol. 14:665-74
57. Viemari JC, Ramirez JM. 2006. Norepinephrine differentially modulates different types of respiratory pacemaker and nonpacemaker neurons. J. Neurophysiol. 95:2070-82
58. Pagliardini S, Adachi T, Ren J, Funk GD, Greer JJ. 2005. Fluorescent tagging of rhythmically active respiratory neurons within the pre-Bötzinger Complex of rat medullary slice preparations. J. Neurosci. 25:2591-96
59. Morgado-Valle C, Baca SM, Feldman JL. 2010. Glycinergic pacemaker neurons in preBötzinger Complex of neonatal mouse. J. Neurosci. 30:3634-39
60. Winter SM, Fresemann J, Schnell C, Oku Y, Hirrlinger J, Hulsmann S. 2009. Glycinergic interneurons are functionally integrated into the inspiratory network of mouse medullary slices. Pflüg. Arch. 458:459-69
61. Del Negro CA, Morgado-Valle C, Feldman JL. 2002. Respiratory rhythm: an emergent network property? Neuron 34:821-30
62. Pace RW, Mackay DD, Feldman JL, Del Negro CA. 2007. Role of persistent sodium current in mouse preBötzinger Complex neurons and respiratory rhythm generation. J. Physiol. 580:485-96
63. St-John WM, Waki H, Dutschmann M, Paton JF. 2007. Maintenance of eupnea of in situ and in vivo rats following riluzole: a blocker of persistent sodium channels. Respir. Physiol. Neurobiol. 155:97-100
64. Ptak K, Zummo GG, Alheid GF, Tkatch T, Surmeier DJ, McCrimmon DR. 2005. Sodium currents in medullary neurons isolated from the pre-Bötzinger Complex region. J. Neurosci. 25:5159-70
65. Ptak K, Yamanishi T, Aungst J, Milescu LS, Zhang R, et al. 2009. Raphe neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P. J. Neurosci. 29:3720-37
66. Brocard F, Tazerart S, Vinay L. 2010. Do pacemakers drive the central pattern generator for locomotion in mammals? Neuroscientist 16:139-55
67. Rubin JE, Hayes JA, Mendenhall JL, Del Negro CA. 2009. Calcium-activated nonspecific cation current and synaptic depression promote network-dependent burst oscillations. Proc. Natl. Acad. Sci. USA 106:2939-44
68. Mironov SL. 2008. Metabotropic glutamate receptors activate dendritic calcium waves and TRPM channels which drive rhythmic respiratory patterns in mice. J. Physiol. 586:2277-91
69. Rekling JC, Shao XM, Feldman JL. 2000. Electrical coupling and excitatory synaptic transmission between rhythmogenic respiratory neurons in the preBötzinger Complex. J. Neurosci. 20:RC113
70. Krey RA, Goodreau AM, Arnold TB, Del Negro CA. 2010. Outward currents contributing to inspiratory burst termination in preBö tzinger Complex neurons of neonatal mice studied in vitro. Front. Neural Circuits 4:124
71. ATP channels in rhythmically active neurons. J. Physiol. 537:69-81
72. Mironov SL, Langohr K, Haller M, Richter DW. 1998. Hypoxia activates ATP-dependent potassium channels in inspiratory neurones of neonatal mice. J. Physiol. 509(Pt. 3):755-66
73. Mironov SL, Skorova EY. 2011. Stimulation of bursting in pre-Bötzinger neurons by Epac through calcium release and modulation of TRPM4 and K-ATP channels. J. Neurochem. 117:295-308
74. Rall W, Burke RE, Smith TG, Nelson PG, Frank K. 1967. Dendritic location of synapses and possible mechanisms for the monosynaptic EPSP in motoneurons. J. Neurophysiol. 30:1169-93
75. Branco T, Hausser M. 2010. The single dendritic branch as a fundamental functional unit in the nervous system. Curr. Opin. Neurobiol. 20:494-502
76. Pace RW, Del Negro CA. 2008. AMPA and metabotropic glutamate receptors cooperatively generate inspiratory-like depolarization in mouse respiratory neurons in vitro. Eur. J. Neurosci. 28:2434-42
77. Pace RW, Mackay DD, Feldman JL, Del Negro CA. 2007. Inspiratory bursts in the preBötzinger Complex depend on a calcium-activated nonspecific cationic current linked to glutamate receptors. J. Physiol. 582:113-25
78. 2+ transients do not contribute to inspiratory drive in preBötzinger Complex neurons. J. Physiol. 586:4531-40
79. Crowder EA, Saha MS, Pace RW, Zhang H, Prestwich GD, Del Negro CA. 2007. Phosphatidylinositol 4, 5-bisphosphate regulates inspiratory burst activity in the neonatal mouse preBötzinger Complex. J. Physiol. 582:1047-58
80. London M, Hausser M. 2005. Dendritic computation. Annu. Rev. Neurosci. 28:503-32
81. Del Negro CA, Hayes JA, Rekling JC. 2011. Dendritic calcium activity precedes inspiratory bursts in preBötzinger Complex neurons. J. Neurosci. 31:1017-22
82. Orlovsky GN, Deliagina TG, Grillner S. 1999. Neuronal Control of Locomotion: From Mollusc to Man. New York: Oxford Univ. Press. 322 pp.
83. Brown TG. 1914. 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
84. Sherrington CS. 1906. The Integrative Action of the Nervous System. New York: Yale Univ. Press. 411 pp.
85. Kiehn O. 2006. Locomotor circuits in the mammalian spinal cord. Annu. Rev. Neurosci. 29:279-306
86. Goulding M. 2009. Circuits controlling vertebrate locomotion: moving in a new direction. Nat. Rev. Neurosci. 10:507-18
87. Büsselberg D, Bischoff AM, Paton JF, Richter DW. 2001. Reorganisation of respiratory network activity after loss of glycinergic inhibition. Pflüg. Arch. 441:444-49
88. Büsselberg D, Bischoff AM, Richter DW. 2003. A combined blockade of glycine and calcium-dependent potassium channels abolishes the respiratory rhythm. Neuroscience 122:831-41
89. Richter DW, Spyer KM. 2001. Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends Neurosci. 24:464-72
90. Molkov YI, Abdala AP, Bacak BJ, Smith JC, Paton JF, Rybak IA. 2010. Late-expiratory activity: emergence and interactions with the respiratory CPG. J. Neurophysiol. 104:2713-29
91. Janczewski WA, Tashima A, Hsu P, Cui Y, Feldman JL. 2013. Role of inhibition in respiratory pattern generation. J. Neurosci. In press
92. Gray PA, Rekling JC, Bocchiaro CM, Feldman JL. 1999. Modulation of respiratory frequency by pep-tidergic input to rhythmogenic neurons in the preBötzinger Complex. Science 286:1566-68
93. Montandon G, Qin W, Liu H, Ren J, Greer JJ, Horner RL. 2011. PreBötzinger Complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression. J. Neurosci. 31:1292-301
94. 4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301:226-29
95. Bell SC, Saunders MJ, Elborn JS, Shale DJ. 1996. Resting energy expenditure and oxygen cost of breathing in patients with cystic fibrosis. Thorax 51:126-31
96. Gardner WN. 1980. The pattern of breathing following step changes of alveolar partial pressures of carbon dioxide and oxygen in man. J. Physiol. 300:55-73
97. Aliverti A, Cala SJ, Duranti R, Ferrigno G, Kenyon CM, et al. 1997. Human respiratory muscle actions and control during exercise. J. Appl. Physiol. 83:1256-69
98. Mellen NM, Janczewski WA, Bocchiaro CM, Feldman JL. 2003. Opioid-induced quantal slowing reveals dual networks for respiratory rhythm generation. Neuron 37:821-26
99. Onimaru H, Homma I. 2003. A novel functional neuron group for respiratory rhythm generation in the ventral medulla. J. Neurosci. 23:1478-86
100. 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. 26:10305-14
101. Guyenet PG, Bayliss DA, Stornetta RL, Fortuna MG, Abbott SB, DePuy SD. 2009. Retrotrapezoid nucleus, respiratory chemosensitivity and breathing automaticity. Respir. Physiol. Neurobiol. 168:59-68
102. Smith JC, Morrison DE, Ellenberger HH, Otto MR, Feldman JL. 1989. Brainstem projections to the major respiratory neuron populations in the medulla of the cat. J. Comp. Neurol. 281:69-96
103. Onimaru H, Homma I, Feldman JL, Janczewski WA. 2006. The parafacial respiratory group (pFRG)/pre-Bötzinger Complex (preBötC) is the primary site of respiratory rhythm generation in the mammal. J. Appl. Physiol. 100:2094-98
104. Onimaru H, Homma I. 2008. Two modes of respiratory rhythm generation in the newborn rat brainstem-spinal cord preparation. Adv. Exp. Med. Biol. 605:104-8
105. Fortuna MG, West GH, Stornetta RL, Guyenet PG. 2008. Bötzinger expiratory-augmenting neurons and the parafacial respiratory group. J. Neurosci. 28:2506-15
106. Mulkey DK, Talley EM, Stornetta RL, Siegel AR, West GH, et al. 2007. TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity. J. Neurosci. 27:14049-58
107. 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. 31:2895-905
108. Eldridge FL, Millhorn DE, Kiley JP, Waldrop TG. 1985. Stimulation by central command of locomotion, respiration and circulation during exercise. Respir. Physiol. 59:313-37
109. de Almeida AT, Al-Izki S, Denton ME, Kirkwood PA. 2010. Patterns of expiratory and inspiratory activation for thoracic motoneurones in the anaesthetized and the decerebrate rat. J. Physiol. 588:2707-29
110. de Almeida AT, Kirkwood PA. 2010. Multiple phases of excitation and inhibition in central respiratory drive potentials of thoracic motoneurones in the rat. J. Physiol. 588: 2731-44
111. Iizuka M. 2009. Abdominal expiratory muscle activity in anesthetized vagotomized neonatal rats. J. Physiol. Sci. 59:157-63
112. Abdala AP, Rybak IA, Smith JC, Paton JF. 2009. Abdominal expiratory activity in the rat brainstem-spinal cord in situ: patterns, origins and implications for respiratory rhythm generation. J. Physiol. 587:3539-59
113. Iizuka M. 2004 Rostrocaudal distribution of spinal respiratory motor activity in an in vitro neonatal rat preparation. Neurosci. Res. 50:263-69
114. Taccola G, Secchia L, Ballanyi K. 2007. Anoxic persistence of lumbar respiratory bursts and block of lumbar locomotion in newborn rat brainstem spinal cords. J. Physiol. 585:507-24
115. Cohen MI, Feldman JL. 1978. Central mechanisms controlling expiratory duration. Adv. Exp. Med. Biol. 99:369-82
116. Hayes JA, Del Negro CA. 2007. Neurokinin receptor-expressing pre-Bötzinger Complex neurons in neonatal mice studied in vitro. J. Neurophysiol. 97:4215-24
117. Bogaard A, Parent J, Zochowski M, Booth V. 2009. Interaction of cellular and network mechanisms in spatiotemporal pattern formation in neuronal networks. J. Neurosci. 29:1677-87
118. Barabási A-L. 2003. Linked: How Everything Is Connected to Everything Else and What It Means for Business, Science, and Everyday Life. New York: Plume. 294 pp.
119. Hayes JA, Wang X, Del Negro CA. 2012. Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro. Proc. Natl. Acad. Sci. USA 109:8286-91
120. Alheid GF, Milsom WK, McCrimmon DR. 2004. Pontine influences on breathing: an overview. Respir. Physiol. Neurobiol. 143:105-14
121. Bochorishvili G, Stornetta RL, Coates MB, Guyenet PG. 2012. Pre-Bötzinger Complex receives glu-tamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J. Comp. Neurol. 520:1047-61
122. Ma LH, Gilland E, Bass AH, Baker R. 2010. Ancestry of motor innervation to pectoral fin and forelimb. Nat. Commun. 1:49
123. Straka H, Baker R, Gilland E. 2006. Preservation of segmental hindbrain organization in adult frogs. J. Comp. Neurol. 494:228-45
124. Gray PA. 2008. Transcription factors and the genetic organization of brain stem respiratory neurons. J. Appl. Physiol. 104:1513-21
125. Gray PA, Fu H, Luo P, Zhao Q, Yu J, et al. 2004. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306:2255-57
126. Briscoe J, Pierani A, Jessell TM, Ericson J. 2000. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101:435-45
127. Lumsden A. 1990. The cellular basis of segmentation in the developing hindbrain. Trends Neurosci. 13:329-35
128. Sieber MA, Storm R, Martinez-de-la-Torre M, Muller T, Wende H, et al. 2007. Lbx1 acts as a selector gene in the fate determination of somatosensory and viscerosensory relay neurons in the hindbrain. J. Neurosci. 27:4902-9
129. 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. 22:3806-16
130. Guyenet PG, Wang H. 2001. Pre-Bötzinger neurons with preinspiratory discharges "in vivo" express NK1 receptors in the rat. J. Neurophysiol. 86:438-46
131. 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. 434:128-46
132. Tan W, Sherman D, Turesson J, Shao XM, Janczewski WA, Feldman JL. 2012. Reelin demarks a subset of pre-Bötzinger Complex neurons in adult rat. J. Comp. Neurol. 520:606-19
133. Gray PA, Hayes JA, Ling GY, Llona I, Tupal S, et al. 2010. Developmental origin of preBötzinger Complex respiratory neurons. J. Neurosci. 30:14883-95
134. -/-). Adv. Exp. Med. Biol. 669:129-32
135. Doi A, Ramirez JM. 2008. Neuromodulation and the orchestration of the respiratory rhythm. Respir. Physiol. Neurobiol. 164:96-104
136. Berner J, Shvarev Y, Lagercrantz H, Bilkei-Gorzo A, Hokfelt T, Wickstrom R. 2007. Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene. J. Appl. Physiol. 103:552-59
137. Hilaire G, Burnet H, Ptak K, Sieweke M, Blanchi B, et al. 2003. Deletion of tachykinin NK1 receptor gene in mice does not alter respiratory network maturation but alters respiratory responses to hypoxia. Adv. Exp. Med. Biol. 536:497-504
138. Schreihofer AM, Stornetta RL, Guyenet PG. 1999. Evidence for glycinergic respiratory neurons: Bötzinger neurons express mRNA for glycinergic transporter 2. J. Comp. Neurol. 407:583-97
139. Winter SM, Fresemann J, Schnell C, Oku Y, Hirrlinger J, Hulsmann S. 2010. Glycinergic interneurons in the respiratory network of the rhythmic slice preparation. Adv. Exp. Med. Biol. 669:97-100
140. Greer JJ, Smith JC, Feldman JL. 1991. Role of excitatory amino acids in the generation and transmission of respiratory drive in neonatal rat. J. Physiol. 437:727-49
141. Blanchi B, Sieweke MH. 2005. Mutations of brainstem transcription factors and central respiratory disorders. Trends Mol. Med. 11:23-30
142. Rose MF, Ren J, Ahmad KA, Chao HT, Klisch TJ, et al. 2009. Math1 is essential for the development of hindbrain neurons critical for perinatal breathing. Neuron 64:341-54
143. Blanchi B, Kelly LM, Viemari JC, Lafon I, Burnet H, et al. 2003. MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth. Nat. Neurosci. 6:1091-100
144. - deficient mice. J. Neurosci. 28:11030-41
145. Borday C, Chatonnet F, Thoby-Brisson M, Champagnat J, Fortin G. 2005. Neural tube patterning by Krox20 and emergence of a respiratory control. Respir. Physiol. Neurobiol. 149:63-72
146. Thoby-Brisson M, Karlen M, Wu N, Charnay P, Champagnat J, Fortin G. 2009. Genetic identification of an embryonic parafacial oscillator coupling to the preBötzinger Complex. Nat. Neurosci. 12:1028-35
147. Nsegbe E, Wallen-Mackenzie A, Dauger S, Roux JC, Shvarev Y, et al. 2004. Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice. J. Physiol. 556:43-59
148. 2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proc. Natl. Acad. Sci. USA 105:1067-72
149. Pattyn A, Goridis C, Brunet JF. 2000. Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Mol. Cell. Neurosci. 15:235-43
150. Caubit X, Thoby-Brisson M, Voituron N, Filippi P, Bevengut M, et al. 2010. Teashirt 3 regulates development of neurons involved in both respiratory rhythm and airflow control. J. Neurosci. 30:9465-76
151. Glasgow SM, Henke RM, Macdonald RJ, Wright CV, Johnson JE. 2005. Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development 132:5461-69
152. Goridis C, Dubreuil V, Thoby-Brisson M, Fortin G, Brunet JF. 2010. Phox2b, congenital central hy-poventilation syndrome and the control of respiration. Semin. Cell Dev. Biol. 21:814-22
153. Cheng L, Arata A, Mizuguchi R, Qian Y, Karunaratne A, et al. 2004. Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat. Neurosci. 7:510-17
154. Rose MF, Ahmad KA, Thaller C, Zoghbi HY. 2009. Excitatory neurons of the proprioceptive, intero-ceptive, and arousal hindbrain networks share a developmental requirement for Math1. Proc. Natl. Acad. Sci. USA 106:22462-67
155. Pierani A, Moran-Rivard L, Sunshine MJ, Littman DR, Goulding M, Jessell TM. 2001. Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1. Neuron 29:367-84
156. Lanuza GM, Gosgnach S, Pierani A, Jessell TM, Goulding M. 2004. Genetic identification of spinal interneurons that coordinate left-right locomotor activity necessary for walking movements. Neuron 42:375-86
157. 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. 13:1066-74
158. Gosgnach S. 2011. The role of genetically-defined interneurons in generating the mammalian locomotor rhythm. Integ. Comp. Biol. 51:903-12
159. Champagnat J, Morin-Surun MP, Fortin G, Thoby-Brisson M. 2009. Developmental basis of the rostro-caudal organization of the brainstem respiratory rhythm generator. Philos. Trans. R. Soc. Lond. B 364:2469-76
160. Neumueller S, Hodges MR, Krause K, Marshall B, Bonis J, et al. 2011. Anatomic changes in multiple brainstem nuclei after incremental, near-complete neurotoxic destruction of the pre-Bötzinger Complex in adult goats. Respir. Physiol. Neurobiol. 175:1-11
161. Krause KL, Forster HV, Kiner T, Davis SE, Bonis JM, et al. 2009. Normal breathing pattern and arterial blood gases in awake and sleeping goats after near total destruction of the presumed pre-Bötzinger Complex and the surrounding region. J. Appl. Physiol. 106:605-19
162. Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, et al. 2004. Large lesions in the pre-Bötzinger Complex area eliminate eupneic respiratory rhythm in awake goats. J. Appl. Physiol. 97:1629-36
163. Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, et al. 2004. Small reduction of neurokinin-1 receptor-expressing neurons in the pre-Bötzinger Complex area induces abnormal breathing periods in awake goats. J. Appl. Physiol. 97:1620-28
164. Wang H, Weston MC, McQuiston TJ, Stornetta RL, Guyenet PG. 2003. Neurokinin-1 receptor-expressing cells regulate depressor region of rat ventrolateral medulla. Am. J. Physiol. Heart Circ. Physiol. 285:H2757-69
165. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H. 2010. An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am. J. Respir. Crit. Care Med. 181:626-44
166. Takakura AC, Moreira TS, Stornetta RL, West GH, Gwilt JM, Guyenet PG. 2008. Selective lesion of retrotrapezoid Phox2b-expressing neurons raises the apnoeic threshold in rats. J. Physiol. 586:2975-91
167. Abbott SB, Stornetta RL, Fortuna MG, Depuy SD, West GH, et al. 2009. Photostimulation of retro-trapezoid nucleus Phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats. J. Neurosci. 29:5806-19
168. Abbott SB, Stornetta RL, Coates MB, Guyenet PG. 2011. Phox2b-expressing neurons of the parafacial region regulate breathing rate, inspiration, and expiration in conscious rats. J. Neurosci. 31:16410-22
169. Guyenet PG, Mulkey DK, Stornetta RL, Bayliss DA. 2005. Regulation of ventral surface chemoreceptors by the central respiratory pattern generator. J. Neurosci. 25:8938-47
170. Mulkey DK, Stornetta RL, Weston MC, Simmons JR, Parker A, et al. 2004. Respiratory control by ventral surface chemoreceptor neurons in rats. Nat. Neurosci. 7:1360-69
171. Kang BJ, Chang DA, Mackay DD, West GH, Moreira TS, et al. 2007. Central nervous system distribution of the transcription factor Phox2b in the adult rat. J. Comp. Neurol. 503:627-41
172. Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. 1997. Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development 124:4065-75
173. Jacquin TD, Borday V, Schneider-Maunoury S, Topilko P, Ghilini G, et al. 1996. Reorganization of pontine rhythmogenic neuronal networks in Krox-20 knockout mice. Neuron 17:747-58
174. 2 chemosensitivity in conditional Phox2b mutants. J. Neurosci. 31:12880-88
175. Huang WH, Tupal S, Huang TW, Ward CS, Neul JL, et al. 2012. Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood. Neuron 75:799-809
176. Thoby-Brisson M, Trinh JB, Champagnat J, Fortin G. 2005. Emergence of the pre-Bötzinger respiratory rhythm generator in the mouse embryo. J. Neurosci. 25:4307-18
177. 2-sensitive preinspiratory neurons of the parafacial respiratory group express Phox2b in the neonatal rat. J. Neurosci. 28:12845-50
178. 2 responses in parafacial respiratory neurons of newborn rats. J. Physiol. 590:1615-24
179. Vasilakos K, Wilson RJ, Kimura N, Remmers JE. 2005. Ancient gill and lung oscillators may generate the respiratory rhythm of frogs and rats. J. Neurobiol. 62:369-85
180. Hodges MR, Richerson GB. 2010. Medullary serotonin neurons and their roles in central respiratory chemoreception. Respir. Physiol. Neurobiol. 173:256-63
181. Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, et al. 2003. Pet-1 ETS gene plays a critical role in 5-HT neuron development and isrequired for normal anxiety-like and aggressive behavior. Neuron 37:233-47
182. Hodges MR, Tattersall GJ, Harris MB, McEvoy SD, Richerson DN, et al. 2008. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. J. Neurosci. 28:2495-505
183. Hodges MR, Best S, Richerson GB. 2011. Altered ventilatory and thermoregulatory control in male and female adult Pet-1 null mice. Respir. Physiol. Neurobiol. 177:133-40
184. 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. 29:10341-49
185. Ray RS, Corcoran AE, Brust RD, Kim JC, Richerson GB, et al. 2011. Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 333:637-42
186. 2 chemosensitivity-towards a better understanding of mechanism. J. Physiol. 589:5561-79
187. Richter DW, Manzke T, Wilken B, Ponimaskin E. 2003. Serotonin receptors: guardians of stable breathing. Trends Mol. Med. 9:542-48
188. Doi A, Ramirez JM. 2010. State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing. J. Neurosci. 30:8251-62
189. Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, et al. 2006. Multiple sero-tonergic brainstem abnormalities in sudden infant death syndrome. JAMA 296:2124-32
190. Peña F, Ramirez JM. 2002. Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro. J. Neurosci. 22:11055-64
191. 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 129:371-83
192. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, et al. 2010. Astrocytes control breathing through pH-dependent release of ATP. Science 329:571-75
193. Nattie EE, Li A. 1996. Central chemoreception in the region of the ventral respiratory group in the rat. J. Appl. Physiol. 81:1987-95
194. Schlafke ME, Pokorski M, See WR, Prill RK, Loeschcke HH. 1975. Chemosensitive neurons on the ventral medullary surface. Bull. Physiopathol. Respir. 11:277-84
195. Gourine AV, Llaudet E, Dale N, Spyer KM. 2005. ATP is a mediator of chemosensory transduction in the central nervous system. Nature 436:108-11
196. 2-dependent opening of connexin 26 and related beta connexins. J. Physiol. 588:3921-31
197. 2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosen-sitivity. J. Physiol. 588:3901-20
198. +-sensitive neurons by purinergic signaling. J. Physiol. 590(Pt. 9):2137-50
199. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Rand CM. 2008. Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disordersof autonomic regulation. Respir. Physiol. Neurobiol. 164:38-48
200. Weese-Mayer DE, Lieske SP, Boothby CM, Kenny AS, Bennett HL, et al. 2006. Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatr. Res. 60:443-49
201. Ben-Shachar S, Chahrour M, Thaller C, Shaw CA, Zoghbi HY. 2009. Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum. Mol. Genet. 18:2431-42
202. Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, et al. 2006. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat. Genet. 38:623-25
203. Valente EM, Brancati F, Silhavy JL, Castori M, Marsh SE, et al. 2006. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann. Neurol. 59:527-34
204. Weese-Mayer DE, Lieske SP, Boothby CM, Kenny AS, Bennett HL, Ramirez JM. 2008. Autonomic dysregulation in young girls with Rett syndrome during nighttime in-home recordings. Pediatr. Pulmonol. 43:1045-60
205. Dunn HG, MacLeod PM. 2001. Rett syndrome: review of biological abnormalities. Can. J. Neurol. Sci. 28:16-29
206. Voituron N, Zanella S, Menuet C, Lajard AM, Dutschmann M, Hilaire G. 2010. Early abnormalities of post-sigh breathing in a mouse model of Rett syndrome. Respir. Physiol. Neurobiol. 170:173-82
207. Viemari JC, Roux JC, Tryba AK, Saywell V, Burnet H, et al. 2005. Mecp2 deficiency disrupts nor-epinephrine and respiratory systems in mice. J. Neurosci. 25:11521-30
208. Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, et al. 2011. A role for glia in the progression of Rett's syndrome. Nature 475:497-500
209. Robinson L, Guy J, McKay L, Brockett E, Spike RC, et al. 2012. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain 135:2699-710
210. Benarroch EE. 2003. Brainstem in multiple system atrophy: clinicopathological correlations. Cell. Mol. Neurobiol. 23:519-26
211. Benarroch EE. 2007. Brainstem respiratory control: substrates of respiratory failure of multiple system atrophy. Mov. Disord. 22:155-61
212. Benarroch EE, Schmeichel AM, Low PA, Parisi JE. 2003. Depletion of ventromedullary NK-1 receptor-immunoreactive neurons in multiple system atrophy. Brain 126:2183-90
213. Schwarzacher SW, Rüb U, Deller T. 2011. Neuroanatomical characteristics of the human pre-Bö tzinger Complex and its involvement in neurodegenerative brainstem diseases. Brain 134(Pt. 1):24-35
214. Rand CM, Patwari PP, Rodikova EA, Zhou L, Berry-Kravis EM, et al. 2011. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: analysis of hypothalamic and autonomic candidate genes. Pediatr. Res. 70:375-78
215. Ize-Ludlow D, Gray JA, Sperling MA, Berry-Kravis EM, Milunsky JM, et al. 2007. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics 120:e179-88
216. Weese-Mayer DE. 2008. Sudden infant death syndrome: the genetic segue? Acta Paediatr. 97:846-47
217. Paterson DS, Hilaire G, Weese-Mayer DE. 2009. Medullary serotonin defects and respiratory dysfunction in sudden infant death syndrome. Respir. Physiol. Neurobiol. 168:133-43
218. Tsuboi Y, Dickson DW, Nabeshima K, Schmeichel AM, Wszolek ZK, et al. 2008. Neurodegeneration involving putative respiratory neurons in Perry syndrome. Acta Neuropathol. 115:263-68