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Roles of glutamate and GABA of the Kölliker-Fuse nucleus in generating the cardiovascular chemoreflex

  • Neuroscience
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Abstract

The Kölliker-Fuse (KF) nucleus is a part of the parabrachial complex, located in the dorsolateral pons. It is involved in the chemoreflex-evoked cardiovascular and respiratory changes, but the role of GABA and glutamate in cardiovascular chemoreflex has not been shown yet. This study was performed to determine the role of GABA, glutamate, and their interaction in the KF, in cardiovascular chemoreflex in anesthetized rat. The antagonists were microinjected into the KF, and arterial pressure, heart rate, and single-unit responses were recorded simultaneously. The chemoreflex was evoked by i.v. injection of KCN, consisted of a short pressor followed by long bradycardia responses. Both responses were significantly attenuated by injection of a synaptic blocker (CoCl2) into the KF, confirming involvement of the KF in generating the reflex. Microinjection of AP5, an NMDA receptor antagonist, into the KF significantly attenuated the pressor and bradycardia responses, while blocking the AMPA receptors by CNQX had no significant effect. Blockade of GABAA receptors by bicuculline methiodide (BMI) potentiated both responses. Co-injection of BMI and CNQX potentiated the responses too. Co-injection of BMI and AP5 had no significant effect on the pressor response but significantly attenuated the bradycardia response. In conclusion, the KF plays a role in generating cardiovascular chemoreflex via its glutamate NMDA but not AMPA receptors. GABA inhibits both components of this reflex through GABAA receptors. There is an interaction between GABAA and NMDA receptors in regulating the bradycardia response of the reflex. Single-unit results were also presented which were correlated with and supported the homodynamic findings.

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References

  1. Accorsi-Mendonca D, Bonagamba LG, Leao RM, Machado BH (2009) Are L-glutamate and ATP cotransmitters of the peripheral chemoreflex in the rat nucleus tractus solitarius? Exp Physiol 94:38–45. https://doi.org/10.1113/expphysiol.2008.043653

    Article  CAS  PubMed  Google Scholar 

  2. Baker TL, Netick A, Dement WC (1981) Sleep-related apneic and apneustic breathing following pneumotaxic lesion and vagotomy. Respir Physiol 46:271–294. https://doi.org/10.1016/0034-5687(81)90127-4

    Article  CAS  PubMed  Google Scholar 

  3. Berquin P, Cayetanot F, Gros F, Larnicol N (2000) Postnatal changes in Fos-like immunoreactivity evoked by hypoxia in the rat brainstem and hypothalamus. Brain Res 877:149–159. https://doi.org/10.1016/s0006-8993(00)02632-9

    Article  CAS  PubMed  Google Scholar 

  4. Bodineau L, Larnicol N (2001) Brainstem and hypothalamic areas activated by tissue hypoxia: Fos-like immunoreactivity induced by carbon monoxide inhalation in the rat. Neuroscience 108:643–653. https://doi.org/10.1016/s0306-4522(01)00442-0

    Article  CAS  PubMed  Google Scholar 

  5. Braga VA, Burmeister MA, Sharma RV, Davisson RL (2008) Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry. Am J Physiol Regul Integr Comp Physiol 295:R1168–R1174. https://doi.org/10.1152/ajpregu.90375.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Damasceno RS, Takakura AC, Moreira TS (2014) Regulation of the chemosensory control of breathing by Kolliker-Fuse neurons. Am J Physiol Regul Integr Comp Physiol 307:R57–R67. https://doi.org/10.1152/ajpregu.00024.2014

    Article  CAS  PubMed  Google Scholar 

  7. Damasceno RS, Takakura AC, Moreira TS (2015) Respiratory and sympathetic chemoreflex regulation by Kolliker-Fuse neurons in rats. Pflugers Arch 467:231–239. https://doi.org/10.1007/s00424-014-1525-z

    Article  CAS  PubMed  Google Scholar 

  8. Dampney RA, Horiuchi J (2003) Functional organisation of central cardiovascular pathways: studies using c-fos gene expression. Prog Neurobiol 71:359–384. https://doi.org/10.1016/j.pneurobio.2003.11.001

    Article  CAS  PubMed  Google Scholar 

  9. Dawid Milner MS, Lara JP, Lopez de Miguel MP, Lopez-Gonzalez MV, Spyer KM, Gonzalez-Baron S (2003) A5 region modulation of the cardiorespiratory responses evoked from parabrachial cell bodies in the anaesthetised rat. Brain Res 982:108–118. https://doi.org/10.1016/s0006-8993(03)03005-1

    Article  CAS  PubMed  Google Scholar 

  10. Dobbins EG, Feldman JL (1994) Brainstem network controlling descending drive to phrenic motoneurons in rat. J Comp Neurol 347:64–86. https://doi.org/10.1002/cne.903470106

    Article  CAS  PubMed  Google Scholar 

  11. Dutschmann M, Dick TE (2012) Pontine mechanisms of respiratory control. Compr Physiol 2:2443–2469. https://doi.org/10.1002/cphy.c100015

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dutschmann M, Herbert H (1998) NMDA and GABAA receptors in the rat Kolliker-fuse area control cardiorespiratory responses evoked by trigeminal ethmoidal nerve stimulation. J Physiol 510(Pt 3):793–804. https://doi.org/10.1111/j.1469-7793.1998.793bj.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ellenberger HH, Feldman JL (1990) Brainstem connections of the rostral ventral respiratory group of the rat. Brain Res 513:35–42. https://doi.org/10.1016/0006-8993(90)91086-v

    Article  CAS  PubMed  Google Scholar 

  14. Fulwiler CE, Saper CB (1984) Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res 319:229–259. https://doi.org/10.1016/0165-0173(84)90012-2

    Article  CAS  PubMed  Google Scholar 

  15. Guo Z, Li P, Longhurst JC (2002) Central pathways in the pons and midbrain involved in cardiac sympathoexcitatory reflexes in cats. Neuroscience 113:435–447. https://doi.org/10.1016/s0306-4522(02)00173-2

    Article  CAS  Google Scholar 

  16. Guthmann A, Herbert H (1999) Expression of N-methyl-D-aspartate receptor subunits in the rat parabrachial and Kolliker-Fuse nuclei and in selected pontomedullary brainstem nuclei. J Comp Neurol 415:501–517

    Article  CAS  Google Scholar 

  17. Haibara AS, Tamashiro E, Olivan MV, Bonagamba LG, Machado BH (2002) Involvement of the parabrachial nucleus in the pressor response to chemoreflex activation in awake rats. Auton Neurosci Basic Clin 101:60–67. https://doi.org/10.1016/s1566-0702(02)00210-2

    Article  Google Scholar 

  18. Head GA, McCarty R (1987) Vagal and sympathetic components of the heart rate range and gain of the baroreceptor-heart rate reflex in conscious rats. J Auton Nerv Syst 21:203–213. https://doi.org/10.1016/0165-1838(87)90023-3

    Article  CAS  PubMed  Google Scholar 

  19. Herbert H, Moga MM, Saper CB (1990) Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J Comp Neurol 293:540–580. https://doi.org/10.1002/cne.902930404

    Article  CAS  PubMed  Google Scholar 

  20. Hirooka Y, Polson JW, Potts PD, Dampney RA (1997) Hypoxia-induced Fos expression in neurons projecting to the pressor region in the rostral ventrolateral medulla. Neuroscience 80:1209–1224. https://doi.org/10.1016/s0306-4522(97)00111-5

    Article  CAS  PubMed  Google Scholar 

  21. Horiuchi J, Potts PD, Polson JW, Dampney RA (1999) Distribution of neurons projecting to the rostral ventrolateral medullary pressor region that are activated by sustained hypotension. Neuroscience 89:1319–1329. https://doi.org/10.1016/s0306-4522(98)00399-6

    Article  CAS  PubMed  Google Scholar 

  22. Korte SM, Jaarsma D, Luiten PG, Bohus B (1992) Mesencephalic cuneiform nucleus and its ascending and descending projections serve stress-related cardiovascular responses in the rat. J Auton Nerv Syst 41:157–176. https://doi.org/10.1016/0165-1838(92)90137-6

    Article  CAS  PubMed  Google Scholar 

  23. Koshiya N, Guyenet PG (1994) Role of the pons in the carotid sympathetic chemoreflex. Am J Phys 267:R508–R518. https://doi.org/10.1152/ajpregu.1994.267.2.R508

    Article  CAS  Google Scholar 

  24. Lara JP, Parkes MJ, Silva-Carvhalo L, Izzo P, Dawid-Milner MS, Spyer KM (1994) Cardiovascular and respiratory effects of stimulation of cell bodies of the parabrachial nuclei in the anaesthetized rat. J Physiol 477:321–329. https://doi.org/10.1113/jphysiol.1994.sp020193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Loewy AD, Burton H (1978) Nuclei of the solitary tract: efferent projections to the lower brain stem and spinal cord of the cat. J Comp Neurol 181:421–449. https://doi.org/10.1002/cne.901810211

    Article  CAS  PubMed  Google Scholar 

  26. Mirzaei-Damabi N, Namvar GR, Yeganeh F, Hatam M (2018) alpha2 receptors in the lateral parabrachial nucleus generates the pressor response of the cardiovascular chemoreflex, effects of GABAA receptor. Brain Res Bull 140:190–196. https://doi.org/10.1016/j.brainresbull.2018.05.009

    Article  CAS  PubMed  Google Scholar 

  27. Mizusawa A, Ogawa H, Kikuchi Y, Hida W, Shirato K (1995) Role of the parabrachial nucleus in ventilatory responses of awake rats. J Physiol 489(Pt 3):877–884. https://doi.org/10.1113/jphysiol.1995.sp021100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nasimi A, Shafei MN, Alaei H (2012) Glutamate injection into the cuneiform nucleus in rat, produces correlated single unit activities in the Kolliker-Fuse nucleus and cardiovascular responses. Neuroscience 223:439–446. https://doi.org/10.1016/j.neuroscience.2012.07.041

    Article  CAS  PubMed  Google Scholar 

  29. Paxinose GWC (2007) The rat brain in stereotaxic coordinate. Academic Press, San Diego, California, New York

    Google Scholar 

  30. Ranjbar A, Hatam M, Nasimi A (2015) Cardiovascular and single-unit responses to L-glutamate injection into the posterior insular cortex in rat. Neuroscience 306:63–73. https://doi.org/10.1016/j.neuroscience.2015.08.025

    Article  CAS  PubMed  Google Scholar 

  31. Ricardo JA, Koh ET (1978) Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res 153:1–26. https://doi.org/10.1016/0006-8993(78)91125-3

    Article  CAS  PubMed  Google Scholar 

  32. Rikard-Bell GC, Bystrzycka EK, Nail BS (1984) Brainstem projections to the phrenic nucleus: a HRP study in the cat. Brain Res Bull 12:469–477. https://doi.org/10.1016/0361-9230(84)90162-x

    Article  CAS  PubMed  Google Scholar 

  33. Rikard-Bell GC, Bystrzycka EK, Nail BS (1985) The identification of brainstem neurones projecting to thoracic respiratory motoneurones in the cat as demonstrated by retrograde transport of HRP. Brain Res Bull 14:25–37. https://doi.org/10.1016/0361-9230(85)90174-1

    Article  CAS  PubMed  Google Scholar 

  34. Shafei MN, Nasimi A (2011) Effect of glutamate stimulation of the cuneiform nucleus on cardiovascular regulation in anesthetized rats: role of the pontine Kolliker-Fuse nucleus. Brain Res 1385:135–143. https://doi.org/10.1016/j.brainres.2011.02.046

    Article  CAS  PubMed  Google Scholar 

  35. Song G, Poon CS (2009) Lateral parabrachial nucleus mediates shortening of expiration and increase of inspiratory drive during hypercapnia. Respir Physiol Neurobiol 165:9–12. https://doi.org/10.1016/j.resp.2008.10.009

    Article  PubMed  Google Scholar 

  36. Song G, Poon CS (2009) Lateral parabrachial nucleus mediates shortening of expiration during hypoxia. Respir Physiol Neurobiol 165:1–8. https://doi.org/10.1016/j.resp.2008.10.007

    Article  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. Song G, Wang H, Xu H, Poon CS (2012) Kolliker-Fuse neurons send collateral projections to multiple hypoxia-activated and nonactivated structures in rat brainstem and spinal cord. Brain Struct Funct 217:835–858. https://doi.org/10.1007/s00429-012-0384-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 388:169–190. https://doi.org/10.1002/(sici)1096-9861(19971117)388:2<169::aid-cne1>3.0.co;2-#

    Article  CAS  PubMed  Google Scholar 

  40. Yeganeh F, Nasimi A, Hatam M (2017) Interaction of GABA and norepinephrine in the lateral division of the bed nucleus of the stria terminals in anesthetized rat, correlating single-unit and cardiovascular responses. Neuroscience 356:255–264. https://doi.org/10.1016/j.neuroscience.2017.05.044

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This manuscript was derived from a PhD thesis by Mirzaei-Damabi N. and sponsored by a grant (number: 12209) from the Vice Chancellery of Research of the Shiraz University of Medical Sciences. Ethics code for animal research: IR.SUMS.REC.1395.S947.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Nafiseh Mirzaei-Damabi, Masoumeh Hatam, Fahimeh Yeganeh & Farzaneh Ketabchi

  2. Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Ali Nasimi

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  1. Nafiseh Mirzaei-Damabi
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Correspondence to Masoumeh Hatam.

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Mirzaei-Damabi, N., Hatam, M., Yeganeh, F. et al. Roles of glutamate and GABA of the Kölliker-Fuse nucleus in generating the cardiovascular chemoreflex. Pflugers Arch - Eur J Physiol 472, 1051–1063 (2020). https://doi.org/10.1007/s00424-020-02422-0

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