Modulation of hypercapnic respiratory response by cholinergic transmission in the commissural nucleus of the solitary tract
- 7 Downloads
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.
KeywordsHypercapnia Nicotinic receptors Muscarinic receptors Acetylcholine Brainstem Chemoreflex
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.
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.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 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.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
- 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
- 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
- 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
- 20.Guyenet PG (2014) Regulation of breathing and autonomic outflows by chemoreceptors. In: Comprehensive Physiology. John Wiley & Sons, Inc.Google Scholar
- 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
- 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
- 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.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
- 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.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.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.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
- 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.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.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.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