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The dorsal and the ventral side of hypoglossal motor nucleus showed different response to chronic intermittent hypoxia in rats

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Purpose

To study neurochemical reactions to chronic intermittent hypoxia (CIH) in the hypoglossal nucleus (HN) of rats.

Methods

Adult male Sprague-Dawley rats (n = 12) were randomly divided into two groups (the CIH and the control group). The CIH rats were housed in a hypoxic chamber with the fraction of oxygen volume alternating between 21% and 5% by providing air for 60 s and then providing nitrogen for 60 s from 8:30 am to 16:30 pm each day for 35 days. The control group was housed in a cabin with normal oxygen levels. We studied the expression of c-fos protein, 5-hydroxytryptamine (5-HT) positive terminals, and its 2A receptors in hypoglossal nuclei by immunohistochemistry.

Results

The expression of c-fos, 5-HT positive terminals, and accordingly 5-HT 2A receptors in the CIH group were significantly higher than that in the controls (p < 0.05). The ventral side of the HN showed a clearly higher expression of 5-HT and its 2A receptors than the dorsal side (p < 0.05).

Conclusion

There were 2 responses of the HN to CIH. First, CIH induced a higher expression of 5-HT positive terminals and its 2A receptors, and second, this reaction was much more evident in ventral side than in the dorsal side. We postulate that these responses may serve to be a protective and compensatory mechanism for CIH.

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Availability of data and material

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. White DP (2006) The pathogenesis of obstructive sleep apnea: advances in the past 100 years. Am J Respir Cell Mol Biol 34:1–6

    CAS  PubMed  Google Scholar 

  2. Bucks RS, Olaithe M, Rosenzweig I, Morrell MJ (2017) Reviewing the relationship between OSA and cognition: where do we go from here? Respirology 22:1253–1261

    PubMed  Google Scholar 

  3. Suratt PM, Mctier RF, Wilhoit SC (1988) Upper airway muscle activation is augmented in patients with obstructive sleep apnea compared with that in normal subjects. Am Rev Respir Dis 137:889–894

    CAS  PubMed  Google Scholar 

  4. Rodenstein DO, Dooms G, Thomas Y, Liistro G, Stanescu DC, Culée C, Aubert-Tulkens G (1990) Pharyngeal shape and dimension in healthy subjects, snorers, and patients with obstructive sleep apnea. Thorax 45:722–727

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Whyte A, Gibson D (2018) Imaging of adult obstructive sleep apnoea. Eur J Radiol 102:176–187

    PubMed  Google Scholar 

  6. Mezzanotte WS, Tangel DJ, White DP (1992) Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 89:1571–1579

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hendricks JC, Petrof BJ, Panckeri K, Pack AI (1993) Upper airway dilating muscle hyperactivity during non-rapid eye movement sleep in English bulldogs. Am Rev Respir Dis 148:185–194

    CAS  PubMed  Google Scholar 

  8. Saboisky JP, Butler JE, Mckenzie DK, Gorman RB, Trinder JA, White DP, Gandevia SC (2007) Neural drive to human genioglossus in obstructive sleep apnoea. J Physiol 585:135–146

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Oliven R, Cohen G, Dotan Y, Somri M, Schwartz AR, Oliven A (2018) Alteration in upper airway dilator muscle coactivation during sleep: comparison of patients with obstructive sleep apnea and healthy subjects. J Appl Physiol 124:421–429

    CAS  PubMed  Google Scholar 

  10. Mezzanotte WS, Tangel DJ, White DP (1996) Influence of sleep onset on upper-airway muscle activity in apnea patients versus normal controls. Am J Respir Crit Care Med 153:1880–1887

    CAS  PubMed  Google Scholar 

  11. Oliven R, Cohen G, Somri M, Schwartz AR, Oliven A (2019) Spectral analysis of peri-pharyngeal muscles’ EMG in patients with OSA and healthy subjects. Respir Physiol Neurobiol 260:53–57

    PubMed  Google Scholar 

  12. Lowe AA (1980) The neural regulation of tongue movements. Prog Neurobiol 15:295–344

    CAS  PubMed  Google Scholar 

  13. Berger AJ (2011) Development of synaptic transmission to respiratory motoneurons. Respir Physiol Neurobiol 179:34–42

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Schwartz AR, Eisele DW, Hari A, Testerman R, Erickson D, Smith P (1996) Electrical stimulation of the lingual musculature in obstructive sleep apnea. J Appl Physiol 81:643–652

    CAS  PubMed  Google Scholar 

  15. Cascella M (2016) The intercalatus nucleus of Staderini. J Hist Neurosci 25:408–419

    PubMed  Google Scholar 

  16. McClung JR, Goldberg SJ (2002) Organization of the hypoglossal motoneurons that innervate the horizontal and oblique components of the genioglossus muscle in the rat. Brain Res 950:321–324

    CAS  PubMed  Google Scholar 

  17. Wu X, Lu H, Hu L, Gong W, Wang J, Fu C, Liu Z, Li S (2017) Chronic intermittent hypoxia affects endogenous serotonergic inputs and expression of synaptic proteins in rat hypoglossal nucleus. Am J Transl Res 9:546–557

    PubMed  PubMed Central  Google Scholar 

  18. Nie X, Zhou L, Wang A, Jin H, Qin Z, Pang J, Wang W, Kang J (2017) Noradrenergic activation of hypoglossal nucleus modulates the central regulation of genioglossus in chronic intermittent hypoxic rats. Front Neurol 8:171

    PubMed  PubMed Central  Google Scholar 

  19. Liu ZL, Wu X, Luo YJ, Wang L, Qu WM, Li SQ, Huang ZL (2016) Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons. J Neurochem 137:277–286

    CAS  PubMed  Google Scholar 

  20. Waldvogel HJ, Biggins FM, Singh A, Arasaratnam CJ, Faull RLM (2019) Variable colocalisation of GABAA receptor subunits and glycine receptors on neurons in the human hypoglossal nucleus. J Chem Neuroanat 97:99–111

    CAS  PubMed  Google Scholar 

  21. Volgin DV, Fay R, Kubin L (2003) Postnatal development of serotonin 1B, 2 A and 2C receptors in brainstem motoneurons. Eur J Neurosci 17:1179–1188

    PubMed  Google Scholar 

  22. Rukhadze I, Fenik VB, Benincasa KE, Price A, Kubin L (2010) Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med 182:1321–1329

    PubMed  PubMed Central  Google Scholar 

  23. Bayliss DA, Viana F, Talley EM, Berger AJ (1997) Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms. Respir Physiol 110:139–150

    CAS  PubMed  Google Scholar 

  24. Iwasaki K, Komiya H, Kakizaki M, Miyoshi C, Abe M, Sakimura K, Funato H, Yanagisawa M (2018) Ablation of central serotonergic neurons decreased REM sleep and attenuated arousal response. Front Neurosci 12:535

    PubMed  PubMed Central  Google Scholar 

  25. Trulson ME, Trulson VM (1982) Activity of nucleus raphe pallidus neurons across the sleep-waking cycle in freely moving cats. Brain Res 237:232–237

    CAS  PubMed  Google Scholar 

  26. Joo JY, Schaukowitch K, Farbiak L, Kilaru G, Kim TK (2016) Stimulus-specific combinatorial functionality of neuronal c-fos enhancers. Nat Neurosci 19:75–83

    CAS  PubMed  Google Scholar 

  27. Yin X, Zhang X, Lv C, Li C, Yu Y, Wang X, Han F (2015) Protocatechuic acid ameliorates neurocognitive functions impairment induced by chronic intermittent hypoxia. Sci Rep 5:14507

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Itoh H, Yagi M, Fushida S, Tani T, Hashimoto T, Shimizu K, Miwa K (2000) Activation of immediate early gene, c-fos, and c-jun in the rat small intestine after ischemia/reperfusion. Transplantation 69:598–604

    CAS  PubMed  Google Scholar 

  29. Heurteaux C, Bertaina V, Widmann C, Lazdunski M (1993) K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid β-protein precursor genes and neuronal death in rat hippocampus. Proc Natl Acad Sci U S A 90:9431–9435

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Paxinos G, Watson C (1985) Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 13:139–143

    CAS  PubMed  Google Scholar 

  31. Pae EK, Hyatt JP, Wu J, Chien P (2007) Short-term electrical stimulation alters tongue muscle fibre type composition. Arch Oral Biol 52:544–551

    PubMed  Google Scholar 

  32. Series FJ, Simoneau SA, St Pierre S, Marc I (1996) Characteristics of the genioglossus and musculus uvulae in sleep apnea hypopnea syndrome and in snorers. Am J Respir Crit Care Med 153:1870–1874

    CAS  PubMed  Google Scholar 

  33. Wealing JC, Cholanian M, Flanigan EG, Levine RB, Fregosi RF (2019) Diverse physiological properties of hypoglossal motoneurons innervating intrinsic and extrinsic tongue muscles. J Neurophysiol 122:2054–2060

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mukai T, Nagao Y, Nishioka S (2013) Preferential suppression of limbic Fos expression by intermittent hypoxia in obese diabetic mice. Neurosci Res 77:202–207

    CAS  PubMed  Google Scholar 

  35. Greenberg HE, Sica AL, Scharf SM, Ruggiero DA (1999) Expression of c-fos in the rat brainstem after chronic intermittent hypoxia. Brain Res 816:638–645

    CAS  PubMed  Google Scholar 

  36. Sica AL, Greenberg HE, Scharf SM, Ruggiero DA (2000) Chronic-intermittent hypoxia induces immediate early gene expression in the midline thalamus and epithalamus. Brain Res 883:224–228

    CAS  PubMed  Google Scholar 

  37. Das RK, Herr KB, Parkar A, Kubin L (2019) Increased tongue use enhances 5-HT 2C receptor immunostaining in hypoglossal motor nucleus. Respir Physiol Neurobiol 260:105–113

    CAS  PubMed  Google Scholar 

  38. Taranto-Montemurro L, Sands SA, Grace KP, Azarbarzin A, Messineo L, Salant R, White DP, Wellman DA (2018) Neural memory of the genioglossus muscle during sleep is stage-dependent in healthy subjects and obstructive sleep apnoea patients. J Physiol 596:5163–5173

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Schwab RJ, Gefter WB, Hoffman EA, Gupta KB, Pack AI (1993) Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis 148:1385–1400

    CAS  PubMed  Google Scholar 

  40. Schulz R, Murzabekova G, Egemnazarov B, Kraut S, Eisele HJ, Dumitrascu R, Heitmann J, Seimetz M, Witzenrath M, Ghofrani HA, Schermuly RT, Grimminger F, Seeger W, Weissmann N (2014) Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2. J Hypertens 32:300–305

    CAS  PubMed  Google Scholar 

  41. Soukhova-O'Hare GK, Shah ZA, Lei Z, Nozdrachev AD, Rao CV, Gozal D (2008) Erectile dysfunction in a murine model of sleep apnea. Am J Respir Crit Care Med 178:644–650

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang Y, Hai B, Niu X, Ai L, Cao Y, Li R, Li Y (2017) Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway. Biochem Cell Biol 95:415–420

    CAS  PubMed  Google Scholar 

  43. Liu F, Liu TW, Kang J (2018) The role of NF-kappaB-mediated JNK pathway in cognitive impairmentof sleep apnea. J Thorac Dis 10:6921–6931

    PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by the LIUGEYI Project of Jiangsu Provincial Commission of Health and Family Planning (LGY2017070), and the Develop fund of Science and Technology of Nanjing Medical University (NMUB2019025).

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Authors and Affiliations

Authors

Contributions

Conceptualization, writing, reviewing, editing, and supervision: Min Yin; data curation, writing, original draft preparation, and methodology: Rui Cao; software, validation: Min-Juan Zhang; writing, reviewing, and editing: Thian-Sze Wong; software: Jia-Chen Li; methodology: Ya-Jie Liu, Qin-Xin Zhang, Huan-Huan Wang, Ya-Wen Shi; funding acquisition: Yun-Tao Zhou.

Corresponding author

Correspondence to Min Yin.

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The authors declare that they have no conflict of interest.

Ethics approval

All procedures performed in studies was approved by the experimental animal ethics committee of Nanjing Medical University and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Informed consent was obtained from all individual participants included in the study.

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Min-Juan Zhang is co-first author.

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Cao, R., Zhang, MJ., Zhou, YT. et al. The dorsal and the ventral side of hypoglossal motor nucleus showed different response to chronic intermittent hypoxia in rats. Sleep Breath 25, 325–330 (2021). https://doi.org/10.1007/s11325-020-02125-x

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  • DOI: https://doi.org/10.1007/s11325-020-02125-x

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