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Modulation of hypercapnic respiratory response by cholinergic transmission in the commissural nucleus of the solitary tract

  • Werner I. Furuya
  • Mirian Bassi
  • José V. Menani
  • Eduardo Colombari
  • Daniel B. Zoccal
  • Débora S. A. ColombariEmail author
Integrative physiology
  • 7 Downloads
Part of the following topical collections:
  1. Integrative Physiology

Abstract

The nucleus of the solitary tract (NTS) is an important area of the brainstem that receives and integrates afferent cardiorespiratory sensorial information, including those from arterial chemoreceptors and baroreceptors. It was described that acetylcholine (ACh) in the commissural subnucleus of the NTS (cNTS) promotes an increase in the phrenic nerve activity (PNA) and antagonism of nicotinic receptors in the same region reduces the magnitude of tachypneic response to peripheral chemoreceptor stimulation, suggesting a functional role of cholinergic transmission within the cNTS in the chemosensory control of respiratory activity. In the present study, we investigated whether cholinergic receptor antagonism in the cNTS modifies the sympathetic and respiratory reflex responses to hypercapnia. Using an arterially perfused in situ preparation of juvenile male Holtzman rats, we found that the nicotinic antagonist (mecamylamine, 5 mM), but not the muscarinic antagonist (atropine, 5 mM), into the cNTS attenuated the hypercapnia-induced increase of hypoglossal activity. Furthermore, mecamylamine in the cNTS potentiated the generation of late-expiratory (late-E) activity in abdominal nerve induced by hypercapnia. None of the cholinergic antagonists microinjected in the cNTS changed either the sympathetic or the phrenic nerve responses to hypercapnia. Our data provide evidence for the role of cholinergic transmission in the cNTS, acting on nicotinic receptors, modulating the hypoglossal and abdominal responses to hypercapnia.

Keywords

Hypercapnia Nicotinic receptors Muscarinic receptors Acetylcholine Brainstem Chemoreflex 

Notes

Author contributions

Furuya WI performed all the experiments, analyzed data, and wrote the paper. Colombari DSA and Zoccal DB designed the experiments, analyzed the data, and wrote the paper. Colombari E, Bassi M, and Menani JV analyzed the data and revised manuscript.

Funding information

This research was supported by Conselho Nacional de Pesquisa (CNPq 425,586/2016–2; 304,873/2014–4; 408,950/2018–8, 310,331/2017–0), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2013/22526–4, 2013/17251–6, and 2015/234677), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES – Finance Code 001). This work is part of the requirements to obtain a PhD degree by Werner I. Furuya in the Joint Graduate Program in Physiological Sciences PIPGCF UFSCar/UNESP.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interests.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

424_2019_2341_MOESM1_ESM.pdf (336 kb)
ESM 1 (PDF 335 kb).

References

  1. 1.
    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 587:3539–3559.  https://doi.org/10.1113/jphysiol.2008.167502 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    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.  https://doi.org/10.1016/j.neuroscience.2011.06.005 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Barnett WH, Abdala AP, Paton JF, Rybak IA, Zoccal DB, Molkov YI (2017) Chemoreception and neuroplasticity in respiratory circuits. Exp Neurol 287:153–164.  https://doi.org/10.1016/j.expneurol.2016.05.036 CrossRefPubMedGoogle Scholar
  4. 4.
    Barnett WH, Jenkin SEM, Milsom WK, Paton JFR, Abdala AP, Molkov YI, Zoccal DB (2018) The Kölliker-Fuse nucleus orchestrates the timing of expiratory abdominal nerve bursting. J Neurophysiol 119:401–412.  https://doi.org/10.1152/jn.00499.2017 CrossRefPubMedGoogle Scholar
  5. 5.
    Biancardi V, Bicego KC, Almeida MC, Gargaglioni LH (2008) Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflugers Arch 455:1119–1128.  https://doi.org/10.1007/s00424-007-0338-8 CrossRefPubMedGoogle Scholar
  6. 6.
    Bianchi AL, Denavit-Saubie M, Champagnat J (1995) Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol Rev 75:1–45CrossRefGoogle Scholar
  7. 7.
    Burke PG, Kanbar R, Basting TM, Hodges WM, Viar KE, Stornetta RL, Guyenet PG (2015) State-dependent control of breathing by the retrotrapezoid nucleus. J Physiol 593:2909–2926.  https://doi.org/10.1113/JP270053 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cinelli E, Iovino L, Bongianni F, Pantaleo T, Mutolo D (2018) Inhibitory modulation of the cough reflex by acetylcholine in the caudal nucleus tractus solitarii of the rabbit. Respir Physiol Neurobiol 257:93–99.  https://doi.org/10.1016/j.resp.2018.01.011 CrossRefPubMedGoogle Scholar
  9. 9.
    Ciriello J, Hochstenbach SL, Roder S (1994) Central projections of baroreceptor and chemoreceptor afferents fibers in the rat. In: Barraco IRA (ed) Nucleus of the solitary tract. CRC Press, Boca Raton, pp 35–50Google Scholar
  10. 10.
    Colombari E, Sato MA, Cravo SL, Bergamaschi CT, Campos RR Jr, Lopes OU (2001) Role of medulla oblongata in hypertension. Hypertension 38:549–554CrossRefGoogle Scholar
  11. 11.
    Colombari DSA, Colombari E, Freiria-Oliveira AH, Antunes VR, Yao ST, Hindmarch C, Ferguson AV, Fry M, Murphy D, Paton JFR (2011) Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration. J Physiol 589:4457–4471CrossRefGoogle Scholar
  12. 12.
    Conrad SC, Nichols NL, Ritucci NA, Dean JB, Putnam RW (2009) Development of chemosensitivity in neurons from the nucleus tractus solitarii (NTS) of neonatal rats. Respir Physiol Neurobiol 166:4–12.  https://doi.org/10.1016/j.resp.2008.11.005 CrossRefPubMedGoogle Scholar
  13. 13.
    Costa-Silva JH, Zoccal DB, Machado BH (2010) Glutamatergic antagonism in the NTS decreases post-inspiratory drive and changes phrenic and sympathetic coupling during chemoreflex activation. J Neurophysiol 103:2095–2106.  https://doi.org/10.1152/jn.00802.2009 CrossRefPubMedGoogle Scholar
  14. 14.
    Day TA, Wilson RJ (2007) Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation. J Physiol 578:843–857.  https://doi.org/10.1113/jphysiol.2006.119594 CrossRefPubMedGoogle Scholar
  15. 15.
    de Britto AA, Moraes DJ (2017) Non-chemosensitive parafacial neurons simultaneously regulate active expiration and airway patency under hypercapnia in rats. J Physiol 595:2043–2064.  https://doi.org/10.1113/JP273335 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fu C, Xue J, Wang R, Chen J, Ma L, Liu Y, Wang X, Guo F, Zhang Y, Zhang X, Wang S (2017) Chemosensitive Phox2b-expressing neurons are crucial for hypercapnic ventilatory response in the nucleus tractus solitarius. J Physiol 595:4973–4989.  https://doi.org/10.1113/JP274437 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Funk GD, Zwicker JD, Selvaratnam R, Robinson DM (2011) Noradrenergic modulation of hypoglossal motoneuron excitability: developmental and putative state-dependent mechanisms. Arch Ital Biol 149:426–453.  https://doi.org/10.4449/aib.v149i4.1271 CrossRefPubMedGoogle Scholar
  18. 18.
    Furuya WI, Bassi M, Menani JV, Colombari E, Zoccal DB, Colombari DS (2014) Differential modulation of sympathetic and respiratory activities by cholinergic mechanisms in the nucleus of the solitary tract in rats. Exp Physiol 99:743–758.  https://doi.org/10.1113/expphysiol.2013.076794 CrossRefPubMedGoogle Scholar
  19. 19.
    Furuya WI, Colombari E, Ferguson AV, Colombari DS (2017) Effects of acetylcholine and cholinergic antagonists on the activity of nucleus of the solitary tract neurons. Brain Res 1659:136–141.  https://doi.org/10.1016/j.brainres.2017.01.027 CrossRefPubMedGoogle Scholar
  20. 20.
    Guyenet PG (2014) Regulation of breathing and autonomic outflows by chemoreceptors. In: Comprehensive Physiology. John Wiley & Sons, Inc.Google Scholar
  21. 21.
    Harris MB, Milsom WK (2001) Vagal feedback is essential for breathing in unanesthetized ground squirrels. Respir Physiol 125:199–212CrossRefGoogle Scholar
  22. 22.
    Helke CJ, Handelmann GE, Jacobowitz DM (1983) Choline acetyltransferase activity in the nucleus tractus solitarius: regulation by the afferent vagus nerve. Brain Res Bull 10:433–436CrossRefGoogle Scholar
  23. 23.
    Horner RL, Liu X, Gill H, Nolan P, Liu H, Sood S (1985) (2002) effects of sleep-wake state on the genioglossus vs.diaphragm muscle response to CO(2) in rats. J Appl Physiol 92:878–887.  https://doi.org/10.1152/japplphysiol.00855.2001 CrossRefGoogle Scholar
  24. 24.
    Housley GD, Sinclair JD (1988) Localization by kainic acid lesions of neurones transmitting the carotid chemoreceptor stimulus for respiration in rat. J Physiol 406:99–114.  https://doi.org/10.1113/jphysiol.1988.sp017371 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Huda R, Pollema-Mays SL, Chang Z, Alheid GF, McCrimmon DR, Martina M (2012) Acid-sensing ion channels contribute to chemosensitivity of breathing-related neurons of the nucleus of the solitary tract. J Physiol 590:4761–4775CrossRefGoogle Scholar
  26. 26.
    Jansen AH, Liu P, Weisman H, Chernick V, Nance DM (1996) Effect of sinus denervation and vagotomy on c-fos expression in the nucleus tractus solitarius after exposure to CO2. Pflugers Arch 431:876–881PubMedGoogle Scholar
  27. 27.
    John J, Bailey EF, Fregosi RF (2005) Respiratory-related discharge of genioglossus muscle motor units. Am J Respir Crit Care Med 172:1331–1337.  https://doi.org/10.1164/rccm.200505-790OC CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kobayashi RM, Palkovits M, Hruska RE, Rothschild R, Yamamura HI (1978) Regional distribution of muscarinic cholinergic receptors in rat brain. Brain Res 154:13–23CrossRefGoogle Scholar
  29. 29.
    Kubin L (2014) Sleep-wake control of the upper airway by noradrenergic neurons, with and without intermittent hypoxia. Prog Brain Res 209:255–274.  https://doi.org/10.1016/B978-0-444-63274-6.00013-8 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kubin L, Tojima H, Reignier C, Pack AI, Davies RO (1996) Interaction of serotonergic excitatory drive to hypoglossal motoneurons with carbachol-induced, REM sleep-like atonia. Sleep 19:187–195CrossRefGoogle Scholar
  31. 31.
    Kubin L, Alheid GF, Zuperku EJ, McCrimmon DR (2006) Central pathways of pulmonary and lower airway vagal afferents. J Appl Physiol (1985) 101:618–627.  https://doi.org/10.1152/japplphysiol.00252.2006 CrossRefGoogle Scholar
  32. 32.
    Leirao IP, Silva CA Jr, Gargaglioni LH, da Silva GSF (2018) Hypercapnia-induced active expiration increases in sleep and enhances ventilation in unanaesthetized rats. J Physiol 596:3271–3283.  https://doi.org/10.1113/JP274726 CrossRefPubMedGoogle Scholar
  33. 33.
    Lemes EV, Zoccal DB (2014) Vagal afferent control of abdominal expiratory activity in response to hypoxia and hypercapnia in rats. Respir Physiol Neurobiol 203:90–97.  https://doi.org/10.1016/j.resp.2014.08.011 CrossRefPubMedGoogle Scholar
  34. 34.
    Li A, Nattie E (2010) Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol 588:2935–2944.  https://doi.org/10.1113/jphysiol.2010.191288 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Machado BH (2001) Neurotransmission of the cardiovascular reflexes in the nucleus tractus solitarii of awake rats. Ann N Y Acad Sci 940:179–196CrossRefGoogle Scholar
  36. 36.
    Molkov YI, Abdala APL, Bacak BJ, Smith JC, Paton JFR, Rybak IA (2010) Late-expiratory activity: emergence and interactions with the respiratory CPG. J Neurophysiol 104:2713–2729.  https://doi.org/10.1152/jn.00334.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Molkov YI, Zoccal DB, Moraes DJ, Paton JF, Machado BH, Rybak IA (2011) Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats. J Neurophysiol 105:3080–3091.  https://doi.org/10.1152/jn.00070.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Moreira TS, Takakura AC, Colombari E, Guyenet PG (2006) Central chemoreceptors and sympathetic vasomotor outflow. J Physiol 577:369–386.  https://doi.org/10.1113/jphysiol.2006.115600 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Nakamura A, Zhang W, Yanagisawa M, Fukuda Y (1985) Kuwaki T (2007) vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102:241–248.  https://doi.org/10.1152/japplphysiol.00679.2006 CrossRefGoogle Scholar
  40. 40.
    Nattie EE, Li A (2002) CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness. J Appl Physiol (1985) 92:2119–2130.  https://doi.org/10.1152/japplphysiol.01128.2001 CrossRefGoogle Scholar
  41. 41.
    Nattie E, Li A (2008) Muscimol dialysis into the caudal aspect of the nucleus tractus solitarii of conscious rats inhibits chemoreception. Respir Physiol Neurobiol 164:394–400.  https://doi.org/10.1016/j.resp.2008.09.004 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nattie E, Li A (2012) Central chemoreceptors: locations and functions. Compr Physiol 2:221–254.  https://doi.org/10.1002/cphy.c100083 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nichols NL, Mulkey DK, Wilkinson KA, Powell FL, Dean JB, Putnam RW (2009) Characterization of the chemosensitive response of individual solitary complex neurons from adult rats. Am J Physiol Regul Integr Comp Physiol 296:R763–R773.  https://doi.org/10.1152/ajpregu.90769.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Oliveira LM, Moreira TS, Kuo FS, Mulkey DK, Takakura AC (2016) alpha1- and alpha2-adrenergic receptors in the retrotrapezoid nucleus differentially regulate breathing in anesthetized adult rats. J Neurophysiol 116:1036–1048.  https://doi.org/10.1152/jn.00023.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ritucci NA, Dean JB, Putnam RW (1997) Intracellular pH response to hypercapnia in neurons from chemosensitive areas of the medulla. Am J Phys 273:R433–R441.  https://doi.org/10.1152/ajpregu.1997.273.1.R433 CrossRefGoogle Scholar
  46. 46.
    Rosin DL, Chang DA, Guyenet PG (2006) Afferent and efferent connections of the rat retrotrapezoid nucleus. J Comp Neurol 499:64–89.  https://doi.org/10.1002/cne.21105 CrossRefPubMedGoogle Scholar
  47. 47.
    Ruggiero DA, Giuliano R, Anwar M, Stornetta R, Reis DJ (1990) Anatomical substrates of cholinergic-autonomic regulation in the rat. J Comp Neurol 292:1–53CrossRefGoogle Scholar
  48. 48.
    Rukhadze I, Kubin L (2007) Differential pontomedullary catecholaminergic projections to hypoglossal motor nucleus and viscerosensory nucleus of the solitary tract. J Chem Neuroanat 33:23–33CrossRefGoogle Scholar
  49. 49.
    Saiki C, Mortola JP (1996) Effect of CO2 on the metabolic and ventilatory responses to ambient temperature in conscious adult and newborn rats. J Physiol 491(Pt 1):261–269.  https://doi.org/10.1113/jphysiol.1996.sp021213 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schwartz RD, McGee R Jr, Kellar KJ (1982) Nicotinic cholinergic receptors labeled by [3H]acetylcholine in rat brain. Mol Pharmacol 22:56–62PubMedGoogle Scholar
  51. 51.
    Shihara M, Hori N, Hirooka Y, Eshima K, Akaike N, Takeshita A (1999) Cholinergic systems in the nucleus of the solitary tract of rats. Am J Physiol 276:R1141–R1148PubMedGoogle Scholar
  52. 52.
    Smith CA, Blain GM, Henderson KS, Dempsey JA (2015) Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2. J Physiol 593:4225–4243.  https://doi.org/10.1113/JP270114 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sobrinho CR, Wenker IC, Poss EM, Takakura AC, Moreira TS, Mulkey DK (2014) Purinergic signalling contributes to chemoreception in the retrotrapezoid nucleus but not the nucleus of the solitary tract or medullary raphe. J Physiol 592:1309–1323.  https://doi.org/10.1113/jphysiol.2013.268490 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Song G, Xu H, Wang H, Macdonald SM, Poon CS (2011) Hypoxia-excited neurons in NTS send axonal projections to Kolliker-fuse/parabrachial complex in dorsolateral pons. Neuroscience 175:145–153.  https://doi.org/10.1016/j.neuroscience.2010.11.065 CrossRefPubMedGoogle Scholar
  55. 55.
    Speretta GF, Lemes E, Vendramini RC, Menani JV, Zoccal DB, Colombari E, Colombari DSA, Bassi M (2018) High-fat diet increases respiratory frequency and abdominal expiratory motor activity during hypercapnia. Respir Physiol Neurobiol 258:32–39.  https://doi.org/10.1016/j.resp.2018.10.003 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Steenland HW, Liu H, Sood S, Liu X, Horner RL (2006) Respiratory activation of the genioglossus muscle involves both non-NMDA and NMDA glutamate receptors at the hypoglossal motor nucleus in vivo. Neuroscience 138:1407–1424.  https://doi.org/10.1016/j.neuroscience.2005.12.040 CrossRefPubMedGoogle Scholar
  57. 57.
    Teppema LJ, Veening JG, Kranenburg A, Dahan A, Berkenbosch A, Olievier C (1997) Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia. J Comp Neurol 388:169–190CrossRefGoogle Scholar
  58. 58.
    Van Dort CJ, Zachs DP, Kenny JD, Zheng S, Goldblum RR, Gelwan NA, Ramos DM, Nolan MA, Wang K, Weng FJ, Lin Y, Wilson MA, Brown EN (2015) Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc Natl Acad Sci U S A 112:584–589.  https://doi.org/10.1073/pnas.1423136112 CrossRefPubMedGoogle Scholar
  59. 59.
    Zhuang J, Gao X, Gao F, Xu F (2017) Mu-opioid receptors in the caudomedial NTS are critical for respiratory responses to stimulation of bronchopulmonary C-fibers and carotid body in conscious rats. Respir Physiol Neurobiol 235:71–78.  https://doi.org/10.1016/j.resp.2016.10.004 CrossRefPubMedGoogle Scholar
  60. 60.
    Zoccal DB, Furuya WI, Bassi M, Colombari DSA, Colombari E (2014) The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities. Front Physiol 5.  https://doi.org/10.3389/fphys.2014.00238
  61. 61.
    Zoccal DB, Silva JN, Barnett WH, Lemes EV, Falquetto B, Colombari E, Molkov YI, Moreira TS, Takakura AC (2018) Interaction between the retrotrapezoid nucleus and the parafacial respiratory group to regulate active expiration and sympathetic activity in rats. Am J Physiol Lung Cell Mol Physiol 315:L891–L909.  https://doi.org/10.1152/ajplung.00011.2018 CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Physiology and Pathology, School of DentistryUNESP - São Paulo State UniversityAraraquaraBrazil

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