1932

Abstract

Breathing is a vital rhythmic motor behavior with a surprisingly broad influence on the brain and body. The apparent simplicity of breathing belies a complex neural control system, the breathing central pattern generator (bCPG), that exhibits diverse operational modes to regulate gas exchange and coordinate breathing with an array of behaviors. In this review, we focus on selected advances in our understanding of the bCPG. At the core of the bCPG is the preBötzinger complex (preBötC), which drives inspiratory rhythm via an unexpectedly sophisticated emergent mechanism. Synchronization dynamics underlying preBötC rhythmogenesis imbue the system with robustness and lability. These dynamics are modulated by inputs from throughout the brain and generate rhythmic, patterned activity that is widely distributed. The connectivity and an emerging literature support a link between breathing, emotion, and cognition that is becoming experimentally tractable. These advances bring great potential for elucidating function and dysfunction in breathing and other mammalian neural circuits.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-neuro-090121-014424
2022-07-08
2024-12-04
Loading full text...

Full text loading...

/deliver/fulltext/neuro/45/1/annurev-neuro-090121-014424.html?itemId=/content/journals/10.1146/annurev-neuro-090121-014424&mimeType=html&fmt=ahah

Literature Cited

  1. Alheid GF, McCrimmon DR. 2008.. The chemical neuroanatomy of breathing. . Respir. Physiol. Neurobiol. 164::311
    [Google Scholar]
  2. Anderson TM, Garcia AJ, Baertsch NA, Pollak J, Bloom JC, et al. 2016.. A novel excitatory network for the control of breathing. . Nature 536::7680
    [Google Scholar]
  3. Ashhad S, Feldman JL. 2020.. Emergent elements of inspiratory rhythmogenesis: network synchronization and synchrony propagation. . Neuron 106::48297.e4
    [Google Scholar]
  4. Ausborn J, Koizumi H, Barnett WH, John TT, Zhang R, et al. 2018.. Organization of the core respiratory network: insights from optogenetic and modeling studies. . PLOS Comput. Biol. 14::e1006148
    [Google Scholar]
  5. Bacak BJ, Kim T, Smith JC, Rubin JE, Rybak IA. 2016.. Mixed-mode oscillations and population bursting in the pre-Bötzinger complex. . eLife 5::e13403
    [Google Scholar]
  6. Bachmutsky I, Wei XP, Durand A, Yackle K. 2021.. β-Arrestin 2 germline knockout does not attenuate opioid respiratory depression. . eLife 10::e62552
    [Google Scholar]
  7. Bachmutsky I, Wei XP, Kish E, Yackle K. 2020.. Opioids depress breathing through two small brainstem sites. . eLife 9::e52694
    [Google Scholar]
  8. Baertsch NA, Baertsch HC, Ramirez JM. 2018.. The interdependence of excitation and inhibition for the control of dynamic breathing rhythms. . Nat. Commun. 9::843
    [Google Scholar]
  9. 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]
  10. Bagur S, Lefort JM, Lacroix MM, de Lavilléon G, Herry C, et al. 2021.. Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation. . Nat. Commun. 12::2605
    [Google Scholar]
  11. Banzett R, Lansing R, Binks A. 2021.. Air hunger: a primal sensation and a primary element of dyspnea. . Compr. Physiol. 11:(2):144983
    [Google Scholar]
  12. Barnett WH, Jenkin SEM, Milsom WK, Paton JFR, Abdala AP, et al. 2018.. The Kölliker-Fuse nucleus orchestrates the timing of expiratory abdominal nerve bursting. . J. Neurophysiol. 119::40112
    [Google Scholar]
  13. Bautista TG, Dutschmann M. 2014.. Ponto-medullary nuclei involved in the generation of sequential pharyngeal swallowing and concomitant protective laryngeal adduction in situ. . J. Physiol. 592::260523
    [Google Scholar]
  14. Bautista TG, Sun Q-J, Pilowsky PM. 2014.. The generation of pharyngeal phase of swallow and its coordination with breathing: interaction between the swallow and respiratory central pattern generators. . Prog. Brain Res. 212::25375
    [Google Scholar]
  15. Benedetto L, Rodriguez-Servetti Z, Lagos P, D'Almeida V, Monti JM, Torterolo P. 2013.. Microinjection of melanin concentrating hormone into the lateral preoptic area promotes non-REM sleep in the rat. . Peptides 39::1115
    [Google Scholar]
  16. Bhattarai JP, Etyemez S, Jaaro-Peled H, Janke E, Leon Tolosa UD, et al. 2021.. Olfactory modulation of the medial prefrontal cortex circuitry: implications for social cognition. . Semin. Cell Dev. Biol. In press
    [Google Scholar]
  17. Bonvallet M, Gary Bobo E. 1972.. Changes in phrenic activity and heart rate elicited by localized stimulation of amygdala and adjacent structures. . Electroencephalogr. Clin. Neurophysiol. 32::116
    [Google Scholar]
  18. Borgdorff P. 1975.. Respiratory fluctuations in pupil size. . Am. J. Physiol. 228::1094102
    [Google Scholar]
  19. Boutin RCT, Alsahafi Z, Pagliardini S. 2017.. Cholinergic modulation of the parafacial respiratory group. . J. Physiol. 595::137792
    [Google Scholar]
  20. 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::106674
    [Google Scholar]
  21. Boyadzhieva A, Kayhan E. 2021.. Keeping the breath in mind: respiration, neural oscillations, and the free energy principle. . Front. Neurosci. 15::647579
    [Google Scholar]
  22. Brockhaus J, Ballanyi K. 1998.. Synaptic inhibition in the isolated respiratory network of neonatal rats. . Eur. J. Neurosci. 10::382339
    [Google Scholar]
  23. Broncel A, Bocian R, Kłos-Wojtczak P, Konopacki J. 2018.. Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation. . PLOS ONE 13::e0206532
    [Google Scholar]
  24. Brown RP, Gerbarg PL. 2005.. Sudarshan kriya yogic breathing in the treatment of stress, anxiety, and depression: part II—clinical applications and guidelines. . J. Altern. Complement. Med. 11::71117
    [Google Scholar]
  25. Bruce EN. 1988.. Correlated and uncorrelated high-frequency oscillations in phrenic and recurrent laryngeal neurograms. . J. Neurophysiol. 59::1188203
    [Google Scholar]
  26. Burgraff NJ, Bush NE, Ramirez JM, Baertsch NA. 2021.. Dynamic rhythmogenic network states drive differential opioid responses in the in vitro respiratory network. . J. Neurosci. 41::991931
    [Google Scholar]
  27. Büsselberg D, Bischoff AM, Becker K, Becker CM, Richter DW. 2001a.. The respiratory rhythm in mutant oscillator mice. . Neurosci. Lett. 316::99102
    [Google Scholar]
  28. Büsselberg D, Bischoff AM, Paton JF, Richter DW. 2001b.. Reorganisation of respiratory network activity after loss of glycinergic inhibition. . Pflüg. Arch. Eur. J. Physiol. 441::44449
    [Google Scholar]
  29. Butera RJ, Rinzel J, Smith JC. 1999.. Models of respiratory rhythm generation in the pre-Bötzinger complex. II. Populations of coupled pacemaker neurons. . J. Neurophysiol. 82::398415
    [Google Scholar]
  30. Buzsáki G. 2004.. Neuronal oscillations in cortical networks. . Science 304::192629
    [Google Scholar]
  31. Buzsáki G. 2006.. Rhythms of the Brain. Oxford, UK:: Oxford Univ. Press
    [Google Scholar]
  32. Buzsáki G, Mizuseki K. 2014.. The log-dynamic brain: how skewed distributions affect network operations. . Nat. Rev. Neurosci. 15::26478
    [Google Scholar]
  33. Carreno FR, Frazer A. 2017.. Vagal nerve stimulation for treatment-resistant depression. . Neurother. J. Am. Soc. Exp. Neurother. 14::71627
    [Google Scholar]
  34. Carroll MS, Ramirez J-M. 2013.. Cycle-by-cycle assembly of respiratory network activity is dynamic and stochastic. . J. Neurophysiol. 109::296305
    [Google Scholar]
  35. Chandla SS, Sood S, Dogra R, Das S, Shukla SK, Gupta S. 2013.. Effect of short-term practice of pranayamic breathing exercises on cognition, anxiety, general well being and heart rate variability. . J. Indian Med. Assoc. 111::66265
    [Google Scholar]
  36. Chritaakos CN, Cohen MI, See WR, Barnhardt R. 1988.. Fast rhythms in the discharges of medullary inspiratory neurons. . Brain Res. 463::36267
    [Google Scholar]
  37. Clark FJ, von Euler C. 1972.. On the regulation of depth and rate of breathing. . J. Physiol. 222::26795
    [Google Scholar]
  38. Cohen MI. 1973.. Synchronization of discharge, spontaneous and evoked, between inspiratory neurons. . Acta Neurobiol. Exp. 33::189218
    [Google Scholar]
  39. Cohen MI, Feldman JL. 1984.. Discharge properties of dorsal medullary inspiratory neurons: relation to pulmonary afferent and phrenic efferent discharge. . J. Neurophysiol. 51::75376
    [Google Scholar]
  40. Cohen MI, Piercey MF, Gootman PM, Wolotsky P. 1974.. Synaptic connections between medullary inspiratory neurons and phrenic motoneurons as revealed by cross-correlation. . Brain Res. 81::31924
    [Google Scholar]
  41. Cregg JM, Chu KA, Dick TE, Landmesser LT, Silver J. 2017.. Phasic inhibition as a mechanism for generation of rapid respiratory rhythms. . PNAS 114::1281520
    [Google Scholar]
  42. Crone SA, Viemari J-C, Droho S, Mrejeru A, Ramirez J-M, Sharma K. 2012.. Irregular breathing in mice following genetic ablation of V2a neurons. . J. Neurosci. 32::7895906
    [Google Scholar]
  43. 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::60214
    [Google Scholar]
  44. Dalgleish T. 2004.. The emotional brain. . Nat. Rev. Neurosci. 5::58389
    [Google Scholar]
  45. de Britto AA, Moraes DJA. 2017.. Non-chemosensitive parafacial neurons simultaneously regulate active expiration and airway patency under hypercapnia in rats: hypercapnia and active expiration. . J. Physiol. 595::204364
    [Google Scholar]
  46. Del Negro CA, Funk GD, Feldman JL. 2018.. Breathing matters. . Nat. Rev. Neurosci. 19::35167
    [Google Scholar]
  47. 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::121731
    [Google Scholar]
  48. 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::224250
    [Google Scholar]
  49. Deschênes M, Takatoh J, Kurnikova A, Moore JD, Demers M, et al. 2016.. Inhibition, not excitation, drives rhythmic whisking. . Neuron 90::37487
    [Google Scholar]
  50. Dhingra RR, Dick TE, Furuya WI, Galán RF, Dutschmann M. 2020.. Volumetric mapping of the functional neuroanatomy of the respiratory network in the perfused brainstem preparation of rats. . J. Physiol. 598::206179
    [Google Scholar]
  51. Diesmann M, Gewaltig M-O, Aertsen A. 1999.. Stable propagation of synchronous spiking in cortical neural networks. . Nature 402::52933
    [Google Scholar]
  52. Doi A, Ramirez J-M. 2010.. State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing. . J. Neurosci. 30::825162
    [Google Scholar]
  53. Donaldson GC. 1992.. The chaotic behaviour of resting human respiration. . Respir. Physiol. 88::31321
    [Google Scholar]
  54. Dougherty DD. 2018.. Deep brain stimulation. . Psychiatr. Clin. North Am. 41::38594
    [Google Scholar]
  55. Drobisz D, Damborská A. 2019.. Deep brain stimulation targets for treating depression. . Behav. Brain Res. 359::26673
    [Google Scholar]
  56. Durstewitz D, Seamans JK, Sejnowski TJ. 2000.. Neurocomputational models of working memory. . Nat. Neurosci. 3::118491
    [Google Scholar]
  57. Dutschmann M, Dick TE. 2012.. Pontine mechanisms of respiratory control. . Compr. Physiol. 2::244369
    [Google Scholar]
  58. 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::107184
    [Google Scholar]
  59. Dutschmann M, Paton JFR. 2002.. Glycinergic inhibition is essential for co-ordinating cranial and spinal respiratory motor outputs in the neonatal rat. . J. Physiol. 543::64353
    [Google Scholar]
  60. Ermentrout GB, Galán RF, Urban NN. 2008.. Reliability, synchrony and noise. . Trends Neurosci. 31::42834
    [Google Scholar]
  61. Ezure K, Tanaka I, Kondo M. 2003.. Glycine is used as a transmitter by decrementing expiratory neurons of the ventrolateral medulla in the rat. . J. Neurosci. 23::894148
    [Google Scholar]
  62. Fadok JP, Markovic M, Tovote P, Lüthi A. 2018.. New perspectives on central amygdala function. . Curr. Opin. Neurobiol. 49::14147
    [Google Scholar]
  63. Faisal AA, Selen LPJ, Wolpert DM. 2008.. Noise in the nervous system. . Nat. Rev. Neurosci. 9::292303
    [Google Scholar]
  64. Feldman J, Connelly C, Ellenberger H, Smith J. 1990.. The cardiorespiratory system within the brainstem. . Eur. J. Neurosci. 3:(Suppl.):171
    [Google Scholar]
  65. Feldman JL. 1986.. Neurophysiology of breathing in mammals. . In Handbook of Physiology: The Nervous System. Intrinsic Regulatory Systems in the Brain, ed. FE Bloom , pp. 463524. Washington, DC:: Am. Physiol. Soc
    [Google Scholar]
  66. Feldman JL, Del Negro CA. 2006.. Looking for inspiration: new perspectives on respiratory rhythm. . Nat. Rev. Neurosci. 7::23242
    [Google Scholar]
  67. Feldman JL, Del Negro CA, Gray PA. 2013.. Understanding the rhythm of breathing: so near, yet so far. . Annu. Rev. Physiol. 75::42352
    [Google Scholar]
  68. Feldman JL, Kam K. 2015.. Facing the challenge of mammalian neural microcircuits: taking a few breaths may help. . J. Physiol. 593::323
    [Google Scholar]
  69. Feldman JL, McCrimmon DR, Speck DF. 1984.. Effect of synchronous activation of medullary inspiratory bulbo-spinal neurones on phrenic nerve discharge in cat. . J. Physiol. 347::24154
    [Google Scholar]
  70. Feldman JL, Smith JC. 1989.. Cellular mechanisms underlying modulation of breathing pattern in mammals. . Ann. N. Y. Acad. Sci. 563::11430
    [Google Scholar]
  71. Fiamma M-N, Straus C, Thibault S, Wysocki M, Baconnier P, Similowski T. 2007.. Effects of hypercapnia and hypocapnia on ventilatory variability and the chaotic dynamics of ventilatory flow in humans. . Am. J. Physiol. 292::R198593
    [Google Scholar]
  72. Flor KC, Barnett WH, Karlen-Amarante M, Molkov YI, Zoccal DB. 2020.. Inhibitory control of active expiration by the Bötzinger complex in rats. . J. Physiol. 598::496994
    [Google Scholar]
  73. Fontes MAP, Xavier CH, de Menezes RCA, DiMicco JA. 2011.. The dorsomedial hypothalamus and the central pathways involved in the cardiovascular response to emotional stress. . Neuroscience 184::6474
    [Google Scholar]
  74. Funk GD, Parkis MA. 2002.. High frequency oscillations in respiratory networks: functionally significant or phenomenological?. Respir. Physiol. Neurobiol. 131::10120
    [Google Scholar]
  75. Funk GD, Smith JC, Feldman JL. 1993.. Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids. . J. Neurophysiol. 70::1497515
    [Google Scholar]
  76. Gillis A, Kliewer A, Kelly E, Henderson G, Christie MJ, et al. 2020.. Critical assessment of G protein-biased agonism at the μ-opioid receptor. . Trends Pharmacol. Sci. 41::94759
    [Google Scholar]
  77. Glass L. 2001.. Synchronization and rhythmic processes in physiology. . Nature 410::27784
    [Google Scholar]
  78. Goaillard J-M, Marder E. 2021.. Ion channel degeneracy, variability, and covariation in neuron and circuit resilience. . Annu. Rev. Neurosci. 44::33557
    [Google Scholar]
  79. Gómez CD, Rasmussen CM, Rekling JC. 2021.. GABAergic inhibition of presynaptic Ca2+ transients in respiratory preBötzinger neurons in organotypic slice cultures. . eNeuro 8::ENEURO.015421.2021
    [Google Scholar]
  80. Gray PA, Hayes JA, Ling GY, Llona I, Tupal S, et al. 2010.. Developmental origin of preBötzinger complex respiratory neurons. . J. Neurosci. 30::1488395
    [Google Scholar]
  81. 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::156668
    [Google Scholar]
  82. Gray R, Johnston D. 2021.. Sodium sensitivity of KNa channels in mouse CA1 neurons. . J. Neurophysiol. 125::169097
    [Google Scholar]
  83. Guerrier C, Hayes JA, Fortin G, Holcman D. 2015.. Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics. . PNAS 112::972833
    [Google Scholar]
  84. Guzman-Ruiz MA, Ramirez-Corona A, Guerrero-Vargas NN, Sabath E, Ramirez-Plascencia OD, et al. 2015.. Role of the suprachiasmatic and arcuate nuclei in diurnal temperature regulation in the rat. . J. Neurosci. 35::1541929
    [Google Scholar]
  85. Harris GC, Aston-Jones G. 2006.. Arousal and reward: a dichotomy in orexin function. . Trends Neurosci. 29::57177
    [Google Scholar]
  86. Hartelt N, Skorova E, Manzke T, Suhr M, Mironova L, Kügler S, Mironov SL. 2008.. Imaging of respiratory network topology in living brainstem slices. . Mol. Cell. Neurosci. 37::42531
    [Google Scholar]
  87. Hayes JA, Kottick A, Picardo MCD, Halleran AD, Smith RD, et al. 2017.. Transcriptome of neonatal preBötzinger complex neurones in Dbx1 reporter mice. . Sci. Rep. 7::8669
    [Google Scholar]
  88. Heck DH, Kozma R, Kay LM. 2019.. The rhythm of memory: how breathing shapes memory function. . J. Neurophysiol. 122::56371
    [Google Scholar]
  89. Hermida AP, Glass OM, Shafi H, McDonald WM. 2018.. Electroconvulsive therapy in depression. . Psychiatr. Clin. North Am. 41::34153
    [Google Scholar]
  90. Hernandez-Miranda LR, Ruffault P-L, Bouvier JC, Murray AJ, Morin-Surun M-P, et al. 2017.. Genetic identification of a hindbrain nucleus essential for innate vocalization. . PNAS 114::8095100
    [Google Scholar]
  91. Hess A, Yu L, Klein I, De Mazancourt M, Jebrak G, et al. 2013.. Neural mechanisms underlying breathing complexity. . PLOS ONE 8::e75740
    [Google Scholar]
  92. Huckstepp RTR, Cardoza KP, Henderson LE, Feldman JL. 2015.. Role of parafacial nuclei in control of breathing in adult rats. . J. Neurosci. 35::105267
    [Google Scholar]
  93. Huckstepp RTR, Llaudet E, Gourine AV. 2016.. CO2-induced ATP-dependent release of acetylcholine on the ventral surface of the medulla oblongata. . PLOS ONE 11::e0167861
    [Google Scholar]
  94. 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::74758
    [Google Scholar]
  95. Janczewski WA, Feldman JL. 2006.. Distinct rhythm generators for inspiration and expiration in the juvenile rat. . J. Physiol. 570::40720
    [Google Scholar]
  96. Janczewski WA, Tashima A, Hsu P, Cui Y, Feldman JL. 2013.. Role of inhibition in respiratory pattern generation. . J. Neurosci. 33::545465
    [Google Scholar]
  97. Jansen AH, Chernick V. 1983.. Development of respiratory control. . Physiol. Rev. 63::43783
    [Google Scholar]
  98. Jenkin SEM, Milsom WK, Zoccal DB. 2017.. The Kölliker-Fuse nucleus acts as a timekeeper for late-expiratory abdominal activity. . Neuroscience 348::6372
    [Google Scholar]
  99. Johnson SM, Smith JC, Feldman JL. 1996.. Modulation of respiratory rhythm in vitro: role of Gi/o protein-mediated mechanisms. . J Appl. Physiol. 80::212033
    [Google Scholar]
  100. Jubran A, Grant BJB, Tobin MJ. 1997.. Effect of hyperoxic hypercapnia on variational activity of breathing. . Am. J. Respir. Crit. Care Med. 156::112939
    [Google Scholar]
  101. Kabir MM, Beig MI, Baumert M, Trombini M, Mastorci F, et al. 2010.. Respiratory pattern in awake rats: effects of motor activity and of alerting stimuli. . Physiol. Behav. 101::2231
    [Google Scholar]
  102. Kallurkar PS, Grover C, Picardo MCD, Del Negro CA. 2020.. Evaluating the burstlet theory of inspiratory rhythm and pattern generation. . eNeuro 7::ENEURO.031419.2019
    [Google Scholar]
  103. Kam K, Worrell JW, Janczewski WA, Cui Y, Feldman JL. 2013a.. Distinct inspiratory rhythm and pattern generating mechanisms in the preBötzinger complex. . J. Neurosci. 33::923545
    [Google Scholar]
  104. Kam K, Worrell JW, Ventalon C, Emiliani V, Feldman JL. 2013b.. Emergence of population bursts from simultaneous activation of small subsets of preBötzinger complex inspiratory neurons. . J. Neurosci. 33::333238
    [Google Scholar]
  105. Kamalifard M, Shahnazi M, Sayyah Melli M, Allahverdizadeh S, Toraby S, Ghahvechi A. 2012.. The efficacy of massage therapy and breathing techniques on pain intensity and physiological responses to labor pain. . J. Caring Sci. 1::7378
    [Google Scholar]
  106. Karalis N, Sirota A. 2022.. Breathing coordinates cortico-hippocampal dynamics in mice during offline states. . Nat. Commun. 13::467
    [Google Scholar]
  107. 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::115367.e5
    [Google Scholar]
  108. Keay KA, Redgrave P, Dean P. 1988.. Cardiovascular and respiratory changes elicited by stimulation of rat superior colliculus. . Brain Res. Bull. 20::1326
    [Google Scholar]
  109. Kleinfeld D, Moore JD, Wang F, Deschênes M. 2014.. The brainstem oscillator for whisking and the case for breathing as the master clock for orofacial motor actions. . Cold Spring Harb. Symp. Quant. Biol. 79::2939
    [Google Scholar]
  110. Knierim JJ, Zhang K. 2012.. Attractor dynamics of spatially correlated neural activity in the limbic system. . Annu. Rev. Neurosci. 35::26785
    [Google Scholar]
  111. Kocsis B, Gyimesi-Pelczer K. 1997.. Power spectral analysis of inspiratory nerve activity in the anesthetized rat: uncorrelated fast oscillations in different inspiratory nerves. . Brain Res. 745::30912
    [Google Scholar]
  112. Koizumi H, Smith JC. 2008.. Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Bötzinger complex in vitro. . J. Neurosci. 28::177385
    [Google Scholar]
  113. Kottick A, Del Negro CA. 2015.. Synaptic depression influences inspiratory-expiratory phase transition in Dbx1 interneurons of the preBötzinger complex in neonatal mice. . J. Neurosci. 35::11606611
    [Google Scholar]
  114. Kremkow J, Aertsen A, Kumar A. 2010.. Gating of signal propagation in spiking neural networks by balanced and correlated excitation and inhibition. . J. Neurosci. 30::1576068
    [Google Scholar]
  115. Krey RA, Goodreau AM, Arnold TB, Del Negro CA. 2010.. Outward currents contributing to inspiratory burst termination in preBötzinger complex neurons of neonatal mice studied in vitro. . Front. Neural Circuits 4::124
    [Google Scholar]
  116. Kumar A, Rotter S, Aertsen A. 2010.. Spiking activity propagation in neuronal networks: reconciling different perspectives on neural coding. . Nat. Rev. Neurosci. 11::61527
    [Google Scholar]
  117. Kumar VM. 2004.. Body temperature and sleep: Are they controlled by the same mechanism?. Sleep Biol. Rhythms 2::10324
    [Google Scholar]
  118. Kuwana S, Tsunekawa N, Yanagawa Y, Okada Y, Kuribayashi J, Obata K. 2006.. Electrophysiological and morphological characteristics of GABAergic respiratory neurons in the mouse pre-Bötzinger complex. . Eur. J. Neurosci. 23::66774
    [Google Scholar]
  119. Lavretsky H, Feldman JL. 2021.. Precision medicine for breath-focused mind-body therapies for stress and anxiety: Are we ready yet?. Glob. Adv. Health Med. 10::2164956120986129
    [Google Scholar]
  120. LeDoux JE. 2000.. Emotion circuits in the brain. . Annu. Rev. Neurosci. 23::15584
    [Google Scholar]
  121. 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::445369
    [Google Scholar]
  122. Li F, Jiang H, Shen X, Yang W, Guo C, et al. 2021.. Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem. . Cell 184::376273.e10
    [Google Scholar]
  123. Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S, et al. 2016.. The peptidergic control circuit for sighing. . Nature 530::29397
    [Google Scholar]
  124. 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::107779
    [Google Scholar]
  125. Li Y, Dulac C. 2018.. Neural coding of sex-specific social information in the mouse brain. . Curr. Opin. Neurobiol. 53::12030
    [Google Scholar]
  126. Lima JD, Sobrinho CR, Falquetto B, Santos LK, Takakura AC, et al. 2019.. Cholinergic neurons in the pedunculopontine tegmental nucleus modulate breathing in rats by direct projections to the retrotrapezoid nucleus. . J. Physiol. 597::191934
    [Google Scholar]
  127. 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::e2022134118
    [Google Scholar]
  128. 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::85773.e9
    [Google Scholar]
  129. Magalhães KS, da Silva MP, Mecawi AS, Paton JFR, Machado BH, Moraes DJA. 2021.. Intrinsic and synaptic mechanisms controlling the expiratory activity of excitatory lateral parafacial neurones of rats. . J. Physiol. 599::492548
    [Google Scholar]
  130. Mainen Z, Sejnowski T. 1995.. Reliability of spike timing in neocortical neurons. . Science 268::15036
    [Google Scholar]
  131. Malheiros-Lima MR, Silva JN, Souza FC, Takakura AC, Moreira TS. 2020.. C1 neurons are part of the circuitry that recruits active expiration in response to the activation of peripheral chemoreceptors. . eLife 9::e52572
    [Google Scholar]
  132. Marchenko V, Koizumi H, Mosher B, Koshiya N, Tariq MF, et al. 2016.. Perturbations of respiratory rhythm and pattern by disrupting synaptic inhibition within pre-Bötzinger and Bötzinger complexes. . eNeuro 3::ENEURO.001116.2016
    [Google Scholar]
  133. Marder E. 2011.. Variability, compensation, and modulation in neurons and circuits. . PNAS 108:(Suppl. 3):1554248
    [Google Scholar]
  134. Marder E. 2012.. Neuromodulation of neuronal circuits: back to the future. . Neuron 76::111
    [Google Scholar]
  135. Maric V, Ramanathan D, Mishra J. 2020.. Respiratory regulation and interactions with neuro-cognitive circuitry. . Neurosci. Biobehav. Rev. 112::95106
    [Google Scholar]
  136. Martin-Harris B. 2006.. Coordination of respiration and swallowing. . GI Motil. Online. https://www.nature.com/gimo/contents/pt1/full/gimo10.html
    [Google Scholar]
  137. McCrimmon DR, Mitchell GS, Alheid GF. 2008.. Overview: the neurochemistry of respiratory control. . Respir. Physiol. Neurobiol. 164::12
    [Google Scholar]
  138. Medina JF, Repa JC, Mauk MD, LeDoux JE. 2002.. Parallels between cerebellum- and amygdala-dependent conditioning. . Nat. Rev. Neurosci. 3::12231
    [Google Scholar]
  139. Mellen NM, Janczewski WA, Bocchiaro CM, Feldman JL. 2003.. Opioid-induced quantal slowing reveals dual networks for respiratory rhythm generation. . Neuron 37::82126
    [Google Scholar]
  140. Melnychuk MC, Dockree PM, O'Connell RG, Murphy PR, Balsters JH, Robertson IH. 2018.. Coupling of respiration and attention via the locus coeruleus: effects of meditation and pranayama. . Psychophysiology 55::e13091
    [Google Scholar]
  141. Meuret AE, Ritz T. 2010.. Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies. . Int. J. Psychophysiol. 78::6879
    [Google Scholar]
  142. Meuret AE, Ritz T, Wilhelm FH, Roth WT, Rosenfield D. 2018.. Hypoventilation therapy alleviates panic by repeated induction of dyspnea. . Biol. Psychiatry Cogn. Neurosci. Neuroimaging 3::53945
    [Google Scholar]
  143. Meuret AE, Wilhelm FH, Ritz T, Roth WT. 2008.. Feedback of end-tidal pCO2 as a therapeutic approach for panic disorder. . J. Psychiatr. Res. 42::56068
    [Google Scholar]
  144. Moberly AH, Schreck M, Bhattarai JP, Zweifel LS, Luo W, Ma M. 2018.. Olfactory inputs modulate respiration-related rhythmic activity in the prefrontal cortex and freezing behavior. . Nat. Commun. 9::1528
    [Google Scholar]
  145. 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::1292301
    [Google Scholar]
  146. Montandon G, Ren J, Victoria NC, Liu H, Wickman K, et al. 2016.. G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids. . Anesthesiology 124::64150
    [Google Scholar]
  147. Morgado-Valle C, Baca SM, Feldman JL. 2010.. Glycinergic pacemaker neurons in preBötzinger complex of neonatal mouse. . J. Neurosci. 30::363439
    [Google Scholar]
  148. Nakamura NH, Fukunaga M, Oku Y. 2018.. Respiratory modulation of cognitive performance during the retrieval process. . PLOS ONE 13::e0204021
    [Google Scholar]
  149. Nasirova N, Quina LA, Agosto-Marlin IM, Ramirez J, Lambe EK, Turner EE. 2020.. Dual recombinase fate mapping reveals a transient cholinergic phenotype in multiple populations of developing glutamatergic neurons. . J. Comp. Neurol. 528::283307
    [Google Scholar]
  150. Nestor J. 2020.. Breath: The New Science of a Lost Art. New York:: Riverhead Books
    [Google Scholar]
  151. Niewoehner DE, Levine AS, Morley JE. 1983.. Central effects of neuropeptides on ventilation in the rat. . Peptides 4::27781
    [Google Scholar]
  152. Noble D, Hochman S. 2019.. Hypothesis: pulmonary afferent activity patterns during slow, deep breathing contribute to the neural induction of physiological relaxation. . Front. Physiol. 10::1176
    [Google Scholar]
  153. Orem J, Trotter RH. 1992.. Postinspiratory neuronal activities during behavioral control, sleep, and wakefulness. . J. Appl. Physiol. 72::236977
    [Google Scholar]
  154. Orr JE, Ayappa I, Eckert DJ, Feldman JL, Jackson CL, et al. 2021.. Research priorities for patients with heart failure and central sleep apnea. an official American Thoracic Society research statement. . Am. J. Respir. Crit. Care Med. 203::e1124
    [Google Scholar]
  155. Ozawa M, Davis P, Ni J, Maguire J, Papouin T, Reijmers L. 2020.. Experience-dependent resonance in amygdalo-cortical circuits supports fear memory retrieval following extinction. . Nat. Commun. 11::4358
    [Google Scholar]
  156. 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::2895905
    [Google Scholar]
  157. Palkovic B, Marchenko V, Zuperku EJ, Stuth EAE, Stucke AG. 2020.. Multi-level regulation of opioid-induced respiratory depression. . Physiology 35::391404
    [Google Scholar]
  158. Park H-D, Barnoud C, Trang H, Kannape OA, Schaller K, Blanke O. 2020.. Breathing is coupled with voluntary action and the cortical readiness potential. . Nat. Commun. 11::289
    [Google Scholar]
  159. Parkis MA, Feldman JL, Robinson DM, Funk GD. 2003.. Oscillations in endogenous inputs to neurons affect excitability and signal processing. . J. Neurosci. 23::815258
    [Google Scholar]
  160. Perl O, Ravia A, Rubinson M, Eisen A, Soroka T, et al. 2019.. Human non-olfactory cognition phase-locked with inhalation. . Nat. Hum. Behav. 3::50112
    [Google Scholar]
  161. Poon C-S, Song G. 2014.. Bidirectional plasticity of pontine pneumotaxic postinspiratory drive: implication for a pontomedullary respiratory central pattern generator. . Prog. Brain Res. 209::23554
    [Google Scholar]
  162. Raehal KM, Walker JKL, Bohn LM. 2005.. Morphine side effects in β-arrestin 2 knockout mice. . J. Pharmacol. Exp. Ther. 314::1195201
    [Google Scholar]
  163. Rathour RK, Narayanan R. 2019.. Degeneracy in hippocampal physiology and plasticity. . Hippocampus 29::9801022
    [Google Scholar]
  164. Ratté S, Hong S, De Schutter E, Prescott SA. 2013.. Impact of neuronal properties on network coding: roles of spike initiation dynamics and robust synchrony transfer. . Neuron 78::75872
    [Google Scholar]
  165. Ravel N, Pager J. 1990.. Respiratory patterning of the rat olfactory bulb unit activity: nasal versus tracheal breathing. . Neurosci. Lett. 115::21318
    [Google Scholar]
  166. Rea P. 2015.. Essential Clinical Anatomy of the Nervous System. Amsterdam:: Academic, 1st ed.
    [Google Scholar]
  167. Rekling JC, Champagnat J, Denavit-Saubié 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::795810
    [Google Scholar]
  168. 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
    [Google Scholar]
  169. Ressler KJ. 2010.. Amygdala activity, fear, and anxiety: modulation by stress. . Biol. Psychiatry 67::111719
    [Google Scholar]
  170. Revill AL, Katzell A, Del Negro CA, Milsom WK, Funk GD. 2021.. KCNQ current contributes to inspiratory burst termination in the pre-Bötzinger complex of neonatal rats in vitro. . Front. Physiol. 12::626470
    [Google Scholar]
  171. Rhone AE, Kovach CK, Harmata GIS, Sullivan AW, Tranel D, . 2020.. A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy. . JCI Insight 5::e134852
    [Google Scholar]
  172. Samara Z, Raux M, Fiamma M-N, Gharbi A, Gottfried SB, et al. 2009.. Effects of inspiratory loading on the chaotic dynamics of ventilatory flow in humans. . Respir. Physiol. Neurobiol. 165::8289
    [Google Scholar]
  173. Saunders SE, Levitt ES. 2020.. Kölliker-Fuse/Parabrachial complex mu opioid receptors contribute to fentanyl-induced apnea and respiratory rate depression. . Respir. Physiol. Neurobiol. 275::103388
    [Google Scholar]
  174. Schreihofer AM, Stornetta RL, Guyenet PG. 1999.. Evidence for glycinergic respiratory neurons: Bötzinger neurons express mRNA for glycinergic transporter 2. . J. Comp. Neurol. 407::58397
    [Google Scholar]
  175. Schulz A, Schilling TM, Vögele C, Larra MF, Schächinger H. 2016.. Respiratory modulation of startle eye blink: a new approach to assess afferent signals from the respiratory system. . Philos. Trans. R. Soc. Lond. B Biol. Sci. 371::20160019
    [Google Scholar]
  176. Schwarzacher SW, Rüb U, Deller T. 2011.. Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases. . Brain J. Neurol. 134::2435
    [Google Scholar]
  177. 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::185360
    [Google Scholar]
  178. Sherman D, Worrell JW, Cui Y, Feldman JL. 2015.. Optogenetic perturbation of preBötzinger complex inhibitory neurons modulates respiratory pattern. . Nat. Neurosci. 18::40814
    [Google Scholar]
  179. Shi Y, Stornetta DS, Reklow RJ, Sahu A, Wabara Y, et al. 2021.. A brainstem peptide system activated at birth protects postnatal breathing. . Nature 589::42630
    [Google Scholar]
  180. Slepukhin VM, Ashhad S, Feldman JL, Levine AJ. 2020.. Microcircuit synchronization and heavy tailed synaptic weight distribution in preBötzinger complex contribute to generation of breathing rhythm. . bioRxiv 2020.12.22.424079. https://doi.org/10.1101/2020.12.22.424079
    [Crossref]
  181. Smith JC, Abdala APL, Koizumi H, Rybak IA, Paton JFR. 2007.. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. . J. Neurophysiol. 98::337087
    [Google Scholar]
  182. 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::72629
    [Google Scholar]
  183. Sohn J-W, Elmquist JK, Williams KW. 2013.. Neuronal circuits that regulate feeding behavior and metabolism. . Trends Neurosci. 36::50412
    [Google Scholar]
  184. Speck DF, Feldman JL. 1982.. The effects of microstimulation and microlesions in the ventral and dorsal respiratory groups in medulla of cat. . J. Neurosci. 2::74457
    [Google Scholar]
  185. Stucke AG, Miller JR, Prkic I, Zuperku EJ, Hopp FA, Stuth EAE. 2015.. Opioid-induced respiratory depression is only partially mediated by the preBötzinger complex in young and adult rabbits in vivo. . Anesthesiology 122::128898
    [Google Scholar]
  186. Subramanian HH, Holstege G. 2010.. Periaqueductal gray control of breathing. . In New Frontiers in Respiratory Control, ed. I Homma, H Onimaru, Y Fukuchi , pp. 35358. New York:: Springer
    [Google Scholar]
  187. Sun X, Thörn Pérez C, Halemani DN, Shao XM, Greenwood M, et al. 2019.. Opioids modulate an emergent rhythmogenic process to depress breathing. . eLife 8::e50613
    [Google Scholar]
  188. Takeda S, Eriksson LI, Yamamoto Y, Joensen H, Onimaru H, Lindahl SG. 2001.. Opioid action on respiratory neuron activity of the isolated respiratory network in newborn rats. . Anesthesiology 95::74049
    [Google Scholar]
  189. 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::53840
    [Google Scholar]
  190. Toor RUAS, Sun Q-J, Kumar NN, Le S, Hildreth CM, et al. 2019.. Neurons in the intermediate reticular nucleus coordinate postinspiratory activity, swallowing, and respiratory-sympathetic coupling in the rat. . J. Neurosci. 39::975766
    [Google Scholar]
  191. Tort ABL, Brankačk J, Draguhn A. 2018.. Respiration-entrained brain rhythms are global but often overlooked. . Trends Neurosci. 41::18697
    [Google Scholar]
  192. Tschida K, Michael V, Takatoh J, Han B-X, Zhao S, et al. 2019.. A specialized neural circuit gates social vocalizations in the mouse. . Neuron 103::45972.e4
    [Google Scholar]
  193. Varga AG, Reid BT, Kieffer BL, Levitt ES. 2020.. Differential impact of two critical respiratory centres in opioid-induced respiratory depression in awake mice. . J. Physiol. 598::189205
    [Google Scholar]
  194. Varga S, Heck DH. 2017.. Rhythms of the body, rhythms of the brain: respiration, neural oscillations, and embodied cognition. . Conscious. Cogn. 56::7790
    [Google Scholar]
  195. Vogels TP, Rajan K, Abbott LF. 2005.. Neural network dynamics. . Annu. Rev. Neurosci. 28::35776
    [Google Scholar]
  196. von Euler C. 1983.. On the central pattern generator for the basic breathing rhythmicity. . J. Appl. Physiol. 55::164759
    [Google Scholar]
  197. Wallén-Mackenzie A, Gezelius H, Thoby-Brisson M, Nygård 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::12294307
    [Google Scholar]
  198. Wang X-J. 2002.. Probabilistic decision making by slow reverberation in cortical circuits. . Neuron 36::95568
    [Google Scholar]
  199. Wei AD, Ramirez J-M. 2019.. Presynaptic mechanisms and KCNQ potassium channels modulate opioid depression of respiratory drive. . Front. Physiol. 10::1407
    [Google Scholar]
  200. 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::64457.e6
    [Google Scholar]
  201. Weng HY, Feldman JL, Leggio L, Napadow V, Park J, Price CJ. 2021.. Interventions and manipulations of interoception. . Trends Neurosci. 44::5262
    [Google Scholar]
  202. Wilson N, Karissa M, Seth P, Smith H IV, Davis NL. 2020.. Drug and opioid-involved overdose deaths—United States, 2017–2018. . MMWR Morb. Mortal. Wkly. Rep. 69::29097
    [Google Scholar]
  203. Winter SM, Fresemann J, Schnell C, Oku Y, Hirrlinger J, Hülsmann S. 2009.. Glycinergic interneurons are functionally integrated into the inspiratory network of mouse medullary slices. . Pflüg. Arch. Eur. J. Physiol. 458::45969
    [Google Scholar]
  204. Yackle K, Schwarz LA, Kam K, Sorokin JM, Huguenard JR, et al. 2017.. Breathing control center neurons that promote arousal in mice. . Science 355::141115
    [Google Scholar]
  205. Yamanishi T, Koizumi H, Navarro MA, Milescu LS, Smith JC. 2018.. Kinetic properties of persistent Na+ current orchestrate oscillatory bursting in respiratory neurons. . J. Gen. Physiol. 150::152340
    [Google Scholar]
  206. Yang CF, Feldman JL. 2018.. Efferent projections of excitatory and inhibitory preBötzinger complex neurons. . J. Comp. Neurol. 526::1389402
    [Google Scholar]
  207. Yang CF, Kim EJ, Callaway EM, Feldman JL. 2020.. Monosynaptic projections to excitatory and inhibitory preBötzinger complex neurons. . Front. Neuroanat. 14::58
    [Google Scholar]
  208. Yuksel H, Cayir Y, Kosan Z, Tastan K. 2017.. Effectiveness of breathing exercises during the second stage of labor on labor pain and duration: a randomized controlled trial. . J. Integr. Med. 15::45661
    [Google Scholar]
  209. Zelano C, Jiang H, Zhou G, Arora N, Schuele S, Rosenow J, Gottfried JA. 2016.. Nasal respiration entrains human limbic oscillations and modulates cognitive function. . J. Neurosci. 36::1244867
    [Google Scholar]
/content/journals/10.1146/annurev-neuro-090121-014424
Loading
/content/journals/10.1146/annurev-neuro-090121-014424
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