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.
Similar content being viewed by others
Availability of data and material
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
White DP (2006) The pathogenesis of obstructive sleep apnea: advances in the past 100 years. Am J Respir Cell Mol Biol 34:1–6
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
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
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
Whyte A, Gibson D (2018) Imaging of adult obstructive sleep apnoea. Eur J Radiol 102:176–187
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
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
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
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
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
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
Lowe AA (1980) The neural regulation of tongue movements. Prog Neurobiol 15:295–344
Berger AJ (2011) Development of synaptic transmission to respiratory motoneurons. Respir Physiol Neurobiol 179:34–42
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
Cascella M (2016) The intercalatus nucleus of Staderini. J Hist Neurosci 25:408–419
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
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
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
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
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
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
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
Bayliss DA, Viana F, Talley EM, Berger AJ (1997) Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms. Respir Physiol 110:139–150
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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).
Author information
Authors and Affiliations
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
Ethics declarations
Conflict of interest
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.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Min-Juan Zhang is co-first author.
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11325-020-02125-x