Hydrogen Sulfide Production in the Medullary Respiratory Center Modulates the Neural Circuit for Respiratory Pattern and Rhythm Generations

Overview

Journal Sci Rep

Specialty Science

Date 2023 Dec 4

PMID 38049443

Authors

Minako Okazaki

Masayuki Matsumoto

Tadachika Koganezawa

Affiliations

Soon will be listed here.

Abstract

Hydrogen sulfide (HS), which is synthesized in the brain, modulates the neural network. Recently, the importance of HS in respiratory central pattern generation has been recognized, yet the function of HS in the medullary respiratory network remains poorly understood. Here, to evaluate the functional roles of HS in the medullary respiratory network, the Bötzinger complex (BötC), the pre-Bötzinger complex (preBötC), and the rostral ventral respiratory group (rVRG), we observed the effects of inhibition of HS synthesis at each region on the respiratory pattern by using an in situ arterially perfused preparation of decerebrated male rats. After microinjection of an HS synthase inhibitor, cystathionine β-synthase, into the BötC or preBötC, the amplitude of the inspiratory burst decreased and the respiratory frequency increased according to shorter expiration and inspiration, respectively. These alterations were abolished or attenuated in the presence of a blocker of excitatory synaptic transmission. On the other hand, after microinjection of the HS synthase inhibitor into the rVRG, the amplitude of the inspiratory burst was attenuated, and the respiratory frequency decreased, which was the opposite effect to those obtained by blockade of inhibitory synaptic transmission at the rVRG. These results suggest that HS synthesized in the BötC and preBötC functions to limit respiratory frequency by sustaining the respiratory phase and to maintain the power of inspiration. In contrast, HS synthesized in the rVRG functions to promote respiratory frequency by modulating the interval of inspiration and to maintain the power of inspiration. The underlying mechanism might facilitate excitatory synaptic transmission and/or attenuate inhibitory synaptic transmission.

References

Marutani E, Morita M, Hirai S, Kai S, Grange R, Miyazaki Y . Sulfide catabolism ameliorates hypoxic brain injury. Nat Commun. 2021; 12(1):3108. PMC: 8149856. DOI: 10.1038/s41467-021-23363-x. View

Baertsch N, Severs L, Anderson T, Ramirez J . A spatially dynamic network underlies the generation of inspiratory behaviors. Proc Natl Acad Sci U S A. 2019; 116(15):7493-7502. PMC: 6462111. DOI: 10.1073/pnas.1900523116. View

Abe K, Kimura H . The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996; 16(3):1066-71. PMC: 6578817. View

Donatti A, Soriano R, Sabino J, Branco L . Endogenous hydrogen sulfide in the rostral ventrolateral medulla/Bötzinger complex downregulates ventilatory responses to hypoxia. Respir Physiol Neurobiol. 2014; 200:97-104. DOI: 10.1016/j.resp.2014.06.007. View

Kimura H . Hydrogen sulfide induces cyclic AMP and modulates the NMDA receptor. Biochem Biophys Res Commun. 2000; 267(1):129-33. DOI: 10.1006/bbrc.1999.1915. View

Jiang C, Lipski J . Extensive monosynaptic inhibition of ventral respiratory group neurons by augmenting neurons in the Bötzinger complex in the cat. Exp Brain Res. 1990; 81(3):639-48. DOI: 10.1007/BF02423514. View

Carroll M, Ramirez J . Cycle-by-cycle assembly of respiratory network activity is dynamic and stochastic. J Neurophysiol. 2012; 109(2):296-305. PMC: 3545454. DOI: 10.1152/jn.00830.2011. View

Rybak I, Abdala A, Markin S, Paton J, Smith J . Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation. Prog Brain Res. 2007; 165:201-20. PMC: 2408750. DOI: 10.1016/S0079-6123(06)65013-9. View

Ezure K, Tanaka I, Kondo M . Glycine is used as a transmitter by decrementing expiratory neurons of the ventrolateral medulla in the rat. J Neurosci. 2003; 23(26):8941-8. PMC: 6740399. View

10.

Ashhad S, Kam K, Del Negro C, Feldman J . Breathing Rhythm and Pattern and Their Influence on Emotion. Annu Rev Neurosci. 2022; 45:223-247. PMC: 9840384. DOI: 10.1146/annurev-neuro-090121-014424. View

11.

Paton J . A working heart-brainstem preparation of the mouse. J Neurosci Methods. 1996; 65(1):63-8. DOI: 10.1016/0165-0270(95)00147-6. View

12.

Marchenko V, Koizumi H, Mosher B, Koshiya N, Tariq M, Bezdudnaya T . Perturbations of Respiratory Rhythm and Pattern by Disrupting Synaptic Inhibition within Pre-Bötzinger and Bötzinger Complexes. eNeuro. 2016; 3(2). PMC: 4867025. DOI: 10.1523/ENEURO.0011-16.2016. View

13.

Guo Q, Jin S, Wang X, Wang R, Xiao L, He R . Hydrogen sulfide in the rostral ventrolateral medulla inhibits sympathetic vasomotor tone through ATP-sensitive K+ channels. J Pharmacol Exp Ther. 2011; 338(2):458-65. DOI: 10.1124/jpet.111.180711. View

14.

Krohn F, Novello M, van der Giessen R, De Zeeuw C, Pel J, Bosman L . The integrated brain network that controls respiration. Elife. 2023; 12. PMC: 9995121. DOI: 10.7554/eLife.83654. View

15.

Anderson T, Garcia 3rd A, Baertsch N, Pollak J, Bloom J, Wei A . A novel excitatory network for the control of breathing. Nature. 2016; 536(7614):76-80. PMC: 5479418. DOI: 10.1038/nature18944. View

16.

Kuwana S, Tsunekawa N, Yanagawa Y, Okada Y, Kuribayashi J, Obata K . Electrophysiological and morphological characteristics of GABAergic respiratory neurons in the mouse pre-Bötzinger complex. Eur J Neurosci. 2006; 23(3):667-74. DOI: 10.1111/j.1460-9568.2006.04591.x. View

17.

Pierrefiche O, Schwarzacher S, Bischoff A, Richter D . Blockade of synaptic inhibition within the pre-Bötzinger complex in the cat suppresses respiratory rhythm generation in vivo. J Physiol. 1998; 509 ( Pt 1):245-54. PMC: 2230938. DOI: 10.1111/j.1469-7793.1998.245bo.x. View

18.

Sabino J, Oliveira L, Soriano R, Kwiatkoski M, Branco L, da Silva G . Role of hydrogen sulfide in ventilatory responses to hypercapnia in the medullary raphe of adult rats. Exp Physiol. 2021; 106(9):1992-2001. DOI: 10.1113/EP089335. View

19.

Chen L, Zhang J, Ding Y, Li H, Nie L, Yan X . K(ATP) channels of parafacial respiratory group (pFRG) neurons are involved in H2S-mediated central inhibition of respiratory rhythm in medullary slices of neonatal rats. Brain Res. 2013; 1527:141-8. DOI: 10.1016/j.brainres.2013.07.009. View

20.

Gerasimova E, Yakovleva O, Zefirov A, Sitdikova G . Role of ryanodine receptors in the effects of hydrogen sulfide on transmitter release from the frog motor nerve ending. Bull Exp Biol Med. 2013; 155(1):11-3. DOI: 10.1007/s10517-013-2067-7. View