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Reflex regulation of breathing by the paratrigeminal nucleus via multiple bulbar circuits

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Abstract

Sensory neurons of the jugular vagal ganglia innervate the respiratory tract and project to the poorly studied medullary paratrigeminal nucleus. In the present study, we used neuroanatomical tracing, pharmacology and physiology in guinea pig to investigate the paratrigeminal neural circuits mediating jugular ganglia-evoked respiratory reflexes. Retrogradely traced laryngeal jugular ganglia neurons were largely (> 60%) unmyelinated and expressed the neuropeptide substance P and calcitonin gene-related peptide, although a population (~ 30%) of larger diameter myelinated jugular neurons was defined by the expression of vGlut1. Within the brainstem, vagal afferent terminals were confined to the caudal two-thirds of the paratrigeminal nucleus. Electrical stimulation of the laryngeal mucosa evoked a vagally mediated respiratory slowing that was mimicked by laryngeal capsaicin application. These laryngeal reflexes were modestly reduced by neuropeptide receptor antagonist microinjections into the paratrigeminal nucleus, but abolished by ionotropic glutamate receptor antagonists. d,l-Homocysteic acid microinjections into the paratrigeminal nucleus mimicked the laryngeal-evoked respiratory slowing, whereas capsaicin microinjections evoked a persistent tachypnoea that was insensitive to glutamatergic inhibition but abolished by neuropeptide receptor antagonists. Extensive projections from paratrigeminal neurons were anterogradely traced throughout the pontomedullary respiratory column. Dual retrograde tracing from pontine and ventrolateral medullary termination sites, as well as immunohistochemical staining for calbindin and neurokinin 1 receptors, supported the existence of different subpopulations of paratrigeminal neurons. Collectively, these data provide anatomical and functional evidence for at least two types of post-synaptic paratrigeminal neurons involved in respiratory reflexes, highlighting an unrecognised complexity in sensory processing in this region of the brainstem.

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References

  • Alheid GF, Milsom WK, McCrimmon DR (2004) Pontine influences on breathing: an overview. Respir Physiol Neurobiol 143:104–114

    Article  Google Scholar 

  • Alheid GF, Jiao W, McCrimmon DR (2011) Caudal nuclei of the rat nucleus of the solitary tract differentially innervate respiratory compartments within the ventrolateral medulla. Neuroscience 190:207–227

    Article  CAS  Google Scholar 

  • Alioto OE, Lindsey CJ, Koepp J, Caous CA (2008) Sensory sciatic nerve afferent inputs to the dorsal lateral medulla in the rat. Auton Neurosci 140:80–87

    Article  CAS  Google Scholar 

  • Altschuler SM, Bao XM, Bieger D, Hopkins DA, Miselis RR (1989) Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J Comp Neurol 283:248–268

    Article  CAS  Google Scholar 

  • Bailey TW, Jin YH, Doyle MW, Andresen MC (2002) Vanilloid-sensitive afferents activate neurons with prominent A-type potassium currents in nucleus tractus solitarius. J Neurosci 22:8230–8237

    Article  CAS  Google Scholar 

  • Bautista TG, Dutschmann M (2014) Inhibition of the pontine Kolliker-Fuse nucleus abolishes eupneic inspiratory hypoglossal motor discharge in rat. Neuroscience 267:22–29

    Article  CAS  Google Scholar 

  • Bianchi AL, Gestreau C (2009) The brainstem respiratory network: an overview of a half century of research. Respir Physiol Neurobiol 168:4–12

    Article  Google Scholar 

  • Bongianni F, Mutolo D, Nardone F, Pantaleo T (2005) Ionotropic glutamate receptors mediate excitatory drive to caudal medullary expiratory neurons in the rabbit. Brain Res 1056:145–157

    Article  CAS  Google Scholar 

  • Canning BJ, Mori N (2011) Encoding of the cough reflex in anesthetized guinea pigs. Am J Physiol Integr Comp Physiol 300:369–377

    Article  Google Scholar 

  • Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ (2004) Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 557:543–558

    Article  CAS  Google Scholar 

  • Caous CA, Buck HdS, Lindsey CJ (2001) Neuronal connections of the paratrigeminal nucleus: a topographic analysis of neurons projecting to bulbar, pontine and thalamic nuclei related to cardiovascular, respiratory and sensory functions. Auton Neurosci 94:14–24

    Article  CAS  Google Scholar 

  • Carstens E, Saxe I, Ralph R (1995) Brainstem neurons expressing c-Fos immunoreactivity following irritant chemical stimulation of the rat’s tongue. Neuroscience 69:939–953

    Article  CAS  Google Scholar 

  • Chan-Paley V (1978) The paratrigeminal nucleus. II. Identification and inter-relations of catecholamine axons, indoleamine axons and substance P immunoreactive cells in the neuropil. J Neurocytol 7:419–442

    Article  Google Scholar 

  • Chou Y-L, Scarupa MD, Mori N, Canning BJ (2008) Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol 295:1572–1584

    Article  Google Scholar 

  • Ciriello J, Hrycyshyn AW, Calaresu FR (1981) Glossopharyngeal and vagal afferent projections to the brain stem of the cat: a horseradish peroxidase study. J Auton Nerv Syst 4:63–79

    Article  CAS  Google Scholar 

  • Corbett EK, Sinfield JK, McWilliam PN, Deuchars J, Batten TF (2005) Differential expression of vesicualr glutamate transporters by vagal afferent terminals in rat nucleus of the solitary tract: projections from the heart preferentially express vesicular glutamate transporter 1. Neuroscience 135:133–145

    Article  CAS  Google Scholar 

  • D’Autréaux F, Coppola E, Hirsch M-R, Birchmeier C, Brunet J-F (2011) Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways. Proc Natl Acad Sci 108:20018–20023

    Article  Google Scholar 

  • de Sousa Buck H, Caous CA, Lindsey CJ (2001) Projections of the paratrigeminal nucleus to the ambiguus, rostroventrolateral and lateral reticular nuclei, and the solitary tract. Auton Neurosci 87:187–200

    Article  Google Scholar 

  • Dick TE, Bellingham MC, Richter DW (1994) Pontine respiratory neurons in anesthetized cats. Brain Res 636:259–269

    Article  CAS  Google Scholar 

  • Driessen AK, Farrell MJ, Mazzone SB, McGovern AE (2015) The role of the paratrigeminal nucleus in vagal afferent evoked respiratory reflexes: a neuroanatomical and functional study in guinea pigs. Front Physiol 6:378

    Article  Google Scholar 

  • Driessen AK, McGovern AE, Narula M, Yang SK, Keller JA, Farrell MJ, Mazzone SB (2017) Central mechanisms of airway sensation and cough hypersensitivity. Pulm Pharmacol Ther 47:9–15

    Article  CAS  Google Scholar 

  • Dutschmann M, Dick TE (2012) Pontine mechanisms of respiratory control. Compr Physiol 2:2443–2469

    PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  • Fawley JA, Hofmann ME, Andresen MC (2016) Distinct calcium sources support multiple modes of synaptic release from cranial sensory afferents. J Neurosci 36:8957–8966

    Article  CAS  Google Scholar 

  • Feil K, Herbert H (1995) Topographic organization of spinal and trigeminal somatosensory pathways to the rat parabrachial and Kolliker-Fuse nuclei. J Comp Neurol 353:506–528

    Article  CAS  Google Scholar 

  • Feldman JL, Mitchel GS, Nattie EE (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239–266

    Article  CAS  Google Scholar 

  • Fenwick AJ, Wu S-W, Peters JH (2014) Isolation of TRPV1 independent mechanisms of spontaneous and asynchronous glutamate release at primary afferent to NTS synapses. Front Neurosci 8:6

    Article  Google Scholar 

  • Geraghty DP, Mazzone SB (2002) Respiratory actions of vanilloid receptor agonists in the nucleus of the solitary tract: comparison of resiniferatoxin with non-pungent agents and anandamide. Br J Pharmacol 137:919–927

    Article  CAS  Google Scholar 

  • Hermes SM, Colbert JF, Aicher SA (2014) Differential content of vesicular glutamate transporters in subsets of vagal afferents projecting to the nucleus tractus solitarii in the rat. J Comp Neurol 522:642–653

    Article  CAS  Google Scholar 

  • Hether S, Misono K, Lessard A (2013) The neurokinin-3 receptor (NK3R) antagonist SB222200 prevents the apomorphine-evoked surface but not nuclear NK3R redistribution in dopaminergic neurons of the rat ventral tegmental area. Neuroscience 247:12–24

    Article  CAS  Google Scholar 

  • Hildreth CM, Goodchile AK (2010) Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiacl vagal outflow in the rat. Neuroscience 11:128–139

    PubMed  Google Scholar 

  • Hofmann ME, Andresen MC (2016) Vanilloids selectively sensitize thermal glutamate release from TRPV1 expressing solitary tract afferents. Neuropharmacology 101:401–411

    Article  CAS  Google Scholar 

  • Hunter DD, Undem BJ (1999) Identification and substance P content of vagal afferent neurons innervating the epithelium of the guinea pig trachea. Am J Respir Crit Care Med 159:1943–1948

    Article  CAS  Google Scholar 

  • Ishikawa T, Isono S, Tanaka A, Tagaito Y, Nishino T (2005) Airway protective reflexes evoked by laryngeal instillation of distilled water under sevoflurane general anesthesia in children. Anesth Analg 101:1615–1618

    Article  Google Scholar 

  • Junior AB, Caous CA, Yu Y-G, Lindsey CJ (2004) Barosensitive neurons in the rat tractus solitarius and paratrigeminal nucleus: a new model for medullary, cardiovascular reflex regulation. J Physiol Pharmacol 82:474–484

    Article  Google Scholar 

  • Juranek I, Lembeck F (1997) Afferent C-fibres release substance P and glutamate. Can J Physiol Pharmacol 75:661–664

    Article  CAS  Google Scholar 

  • Koepp J, Lindsey CJ, Motta EM, Rae GA (2006) Role of the paratrigeminal nucleus in nocifensive responses of rats to chemical, thermal and mechanical stimuli applied to the hind paw. Pain 122:235–244

    Article  Google Scholar 

  • Kollarik M, Carr MJ, Ru F, Ring CJ, Hart VJ, Murdock P, Myers AC, Muroi Y, Undem BJ (2010) Transgene expression and effective gene silencing in vagal afferent neurons in vivo using recombinant adeno-associated virus vectors. J Physiol 588:4303–4315

    Article  CAS  Google Scholar 

  • Kummer W, Fischer A, Kurkowski R, Heym C (1992) The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry. Neuroscience 49:715–737

    Article  CAS  Google Scholar 

  • Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ (2008) P2 × 2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol 295:858–865

    Article  Google Scholar 

  • Lieu T, Kollarik M, Myers AC, Undem BJ (2011) Neurotrophin and GDNF family ligand receptor expression in vagal sensory nerve subtypes innervating the adult guinea pig respiratory tract. Am J Physiol Lung Cell Mol Physiol 300:790–798

    Article  Google Scholar 

  • Lindsey CJ, Buck HS, Fior-Chadi DR, Lapa RC (1997) Pressor effect mediated by bradykinin in the paratrigeminal nucleus of the rat. J Physiol 502:119–129

    Article  CAS  Google Scholar 

  • Ma WL, Zhang WB, Feng G, Cai YL (2005) Calbindin D28k-containing neurons in the paratrigeminal nucleus receive convergent nociceptive information and project to nucleus of the solitary tract in rat. Brain Res 1038:132–140

    Article  CAS  Google Scholar 

  • Ma WL, Zhang WB, Xiong KH, Guo F (2007) Visceral and orofacial somatic afferent fiber terminals converge onto the same neuron in paratrigeminal nucleus: an electron microscopic study in rats. Auton Neurosci 131:45–49

    Article  Google Scholar 

  • Mazzone SB, Canning BJ (2002) Evidence for differential reflex regulation of cholinergic and non-cholinergic parasympathetic nerves innervating the airways. Am J Respir Crit Care Med 165:1076–1083

    Article  Google Scholar 

  • Mazzone SB, Geraghty DP (1999) Respiratory action of capsaicin microinjected into the nucleus of the solitary tract: involvement of vanilloid and tachykinin receptors. Br J Pharmacol 127:473–481

    Article  CAS  Google Scholar 

  • Mazzone S, McGovern A (2008) Immunohistochemical characterization of nodose cough receptor neurons projecting to the trachea of guinea pigs. Cough 4:9–25

    Article  Google Scholar 

  • Mazzone SB, Undem BJ (2016) Vagal afferent innervation of the airways in health and disease. Physiol Rev 96:975–1024

    Article  CAS  Google Scholar 

  • McDougall SJ, Andresen MC (2013) Independent transmission of convergent visceral primary afferents in the solitary tract nucleus. J Neurophjysiol 109:507–517

    Article  Google Scholar 

  • McGovern AE, Mazzone SB (2010) Characterization of the vagal motor neurons projecting to the Guinea pig airways and esophagus. Front Neurol 17(1):153

    Google Scholar 

  • McGovern AE, Davis-Poynter N, Farrell MJ, Mazzone SB (2012) Transneuronal tracing of airways-related sensory circuitry using herpes simplex virus 1, strain H129. Neuroscience 207:148–166

    Article  CAS  Google Scholar 

  • McGovern AE, Davis-Poynter N, Yang SK, Simmons DG, Farrell MJ, Mazzone SB (2015a) Evidence for multiple sensory circuits in the brain arising from the respiratory system: an anterograde viral tract tracing study in rodents. Brain Struct Funct 220:3683–3699

    Article  Google Scholar 

  • McGovern AE, Driessen AK, Simmons DG, Powell J, Davis-Poynter N, Farrell MJ, Mazzone SB (2015b) Distinct brainstem and forebrain circuits receiving tracheal sensory neuron inputs revealed using a novel conditional anterograde transsynaptic viral tracing system. J Neurosci 35:7041–7055

    Article  CAS  Google Scholar 

  • Mutolo D, Bongianni F, Cinelli E, Fontana GA, Pantaleo T (2008) Modulation of the cough reflex by antitussive agents within the caudal aspect of the nucleus tractus solitarii in the rabbit. Am J Physiol Integr Comp Physiol 295:243–251

    Article  Google Scholar 

  • Nassenstein C, Taylor-Clark TE, Myers AC, Ru F, Nandigama R, Bettner W, Undem BJ (2010) Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs. J Physiol 588:4769–4783

    Article  CAS  Google Scholar 

  • Panneton WM, Burton H (1981) Corneal and periocular representation within the trigeminal sensory complex in the cat studied with tranganglionic transport of horseradish peroxidase. J Comp Neurol 199:327–344

    Article  CAS  Google Scholar 

  • Panneton WM, Burton H (1985) Projections from the paratrigeminal nucleus and the medullary and spinal dorsal horns to the peribrachial area in the cat. Neuroscience 15:779–797

    Article  CAS  Google Scholar 

  • Panneton VM, Pan B, Gan Q (2017) Somatotopy in the medullary dorsal horn as a basis for orofacial reflex behaviour. Front Neurol 8:1–13

    Article  Google Scholar 

  • Pedersen KE, Meeker SN, Riccio MM, Undem BJ (1998) Selective stimulation of jugular ganglion afferent neurons in guinea pig airways by hypertonic saline. J Appl Physiol 84:499–506

    Article  CAS  Google Scholar 

  • Phelan KD, Falls WM (1989) The interstitial system of the spinal trigeminal tract in the rat: anatomical evidence for morphological and functional heterogeneity. Somatosens Mot Res 6:367–399

    Article  CAS  Google Scholar 

  • Pinto ML, de Cassia Machado R, Schoorlemmer GH, Colombari E, de Cássia Ribeiro da Silva Lapa R (2006) Topographic organization of the projections from the interstitial system of the spinal trigeminal tract to the parabrachial nucleus in the rat. Brain Res 1113(1):137–145

    Article  CAS  Google Scholar 

  • Ramirez JM, Doi A, Garcia AJ 3rd, Elsen FP, Kock H, Wei AD (2012) The cellular building blocks of breathing. Compr Physiol 2:2683–2731

    CAS  PubMed  PubMed Central  Google Scholar 

  • Riccio MM, Kummer W, Biglari B, Myers AC, Undem BJ (1996) Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways. J Physiol 496:521–530

    Article  CAS  Google Scholar 

  • Rogoz K, Stjärne L, Kullander K, Lagerström MC (2015) VGLUT2 controls heat and punctuate hyperalgesia associated with nerve injury via TRPV1-Cre primary afferents. PLoS One 10:e0116568

    Article  Google Scholar 

  • Saxon DW, Hopkins DA (1998) Efferent and collateral organization of paratrigeminal nucleus projections: an anterograde and retrograde fluorescent tracer study in the rat. J Comp Neurol 402:93–110

    Article  CAS  Google Scholar 

  • Smith JC, Abdala AP, Borgmann A, Rybak IA, Paton JF (2013) Brainstem respiratory networks: building blocks and microcircuits. Trends Neurosci 36:152–162

    Article  CAS  Google Scholar 

  • Springall DR, Cadieux A, Oliveira H, Su H, Royston D, Polak JM (1987) Retrograde tracing shows that CGRP-immunoreactive nerves of rat trachea and lung originate from vagal and dorsal root ganglia. J Aunton Nerv Syst 20:155–166

    Article  CAS  Google Scholar 

  • Stanic D, Dhingra RR, Dutschmann M (2018) Expression of the transcription factor FoxP2 in brainstem respiratory circuits of adult rat is restricted to upper-airway pre-motor areas. Resp Physiol Neurobiol 250:14–18

    Article  CAS  Google Scholar 

  • Tsujimura T, Udemgba C, Inoue M, Canning BJ (2013) Laryngeal and tracheal afferent nerve stimulation evokes swallowing in anaesthetized guinea pigs. J Physiol 591:4667–4679

    Article  CAS  Google Scholar 

  • Undem BJ, Nassenstein C (2009) Airway nerves and dyspnea associated with inflammatory airway disease. Resp Physiol Neurobiol 167:36–44

    Article  Google Scholar 

  • Undem BJ, Chuaychoo B, Lee M-G, Weinreich D, Myers AC, Kollarik M (2004) Subtypes of vagal afferent C-fibres in guinea-pig lungs. J Physiol 556:905–917

    Article  CAS  Google Scholar 

  • Undem BJ, Zaccone E, McGarvey L, Mazzone SB (2015) Neural dysfunction following respiratory viral infection as a cause of chronic cough hypersensitivity. Pulm Pharmacol Ther 33:52–56

    Article  CAS  Google Scholar 

  • Yu YG, Caous CA, Balan AC, Rae GA, Lindsey CJ (2002) Cardiovascular responses to sciatic nerve stimulation are blocked by paratrigeminal nucleus lesion. Auton Neurosci 98:70–74

    Article  Google Scholar 

  • Zhou Q, Imbe H, Dubner R, Ren K (1999) Persistent Fos protein expression after orofacial deep or cutaneous tissue inflammation in rats: implications for persistent orofacial pain. J Comp Neurol 412:276–291

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by Grants to Dr. SB Mazzone and Dr MJ Farrell from the National Health and Medical Research Council (NHMRC) of Australia [1078943].

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Authors and Affiliations

  1. Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, 3010, Australia

    Alexandria K. Driessen, Alice E. McGovern & Stuart B. Mazzone

  2. Department of Medical Imaging and Radiation Sciences, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    Michael J. Farrell

  3. The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3010, Australia

    Mathias Dutschmann & Davor Stanic

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  1. Alexandria K. Driessen
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  2. Michael J. Farrell
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  4. Davor Stanic
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  5. Alice E. McGovern
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  6. Stuart B. Mazzone
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Contributions

AKD conducted experiments, contributed to drafting and editing the manuscript. MJF contributed to experimental design and manuscript editing. AEM conducted experiments, contributed to drafting and editing manuscript. SBM conceived experiments, contributed to writing and editing of the manuscript. All authors contributed to the interpretation of the data.

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Correspondence to Alexandria K. Driessen or Stuart B. Mazzone.

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The authors declare no competing financial interests.

Animal welfare

Animals were housed in a standard environment and given ad libitum access to water and food. All animal experiments were approved by an accredited institutional Animal Ethics Committee.

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Driessen, A.K., Farrell, M.J., Dutschmann, M. et al. Reflex regulation of breathing by the paratrigeminal nucleus via multiple bulbar circuits. Brain Struct Funct 223, 4005–4022 (2018). https://doi.org/10.1007/s00429-018-1732-z

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