The Effects of the Levels of Hypoxia in the Olfactory Nervous System in Mouse Model

Abstract

Purpose

Intermittent hypoxia (IH) results in low-grade inflammation, sympathetic overactivity, and oxidative stress. However, the specific effects of IH on olfaction have not yet been directly assessed and remain unclear. Therefore, the purpose of this study was to investigate the cytotoxic effects of IH exposure on the mouse olfactory epithelium and the relationship between the concentration of hypoxia and the degree of destruction of the olfactory system.

Methods

Thirty mice were randomly divided into six groups: control (room air for 4 weeks), recovery control (room air for 5 weeks), IH 5% oxygen concentration, IH 7% oxygen concentration, recovery 5% hypoxia, and recovery 7% hypoxia groups. Mice in the two hypoxia groups were exposed to 5% and 7% oxygen for 4 weeks. Mice in the two recovery groups were exposed to room air for 1 week after 4 weeks of hypoxia period.

Results

Based on, the olfactory marker protein (OMP), Olfr1507, ADCY3, and GNAL were lower, whereas S100b and NGFRAP1 messenger RNA (mRNA) levels were higher in the 5% hypoxia group than those in the control group in the olfactory neuroepithelium. In the brain tissue, the changes in RNA analysis for Olfr 1507, OMP, ADCY, and GNAL mRNA were not typical. However, NeuN and GFAP levels were decreased under 5% hypoxia in the brain tissue. In the recovery state, CNPase, S100b and NeuN levels were increased significantly in both the olfactory neuroepithelium and brain tissue in the 5% hypoxia group. The change in RNA activity in PCR was much higher in the 5% hypoxia group than in the 7% hypoxia group.

Conclusions

Our findings suggest that IH damages the olfactory neuroepithelium and brain tissue in mouse model. The activity of olfactory marker genes and neurogenesis in the olfactory neuroepithelium were decreased. The levels of oxygen may be affect changes in the olfactory neuroepithelium. The olfactory ensheathing cell may be a major factor in the recovery of the olfactory neuroepithelium.

Keywords

olfaction hypoxia olfactory dysfunction olfactory regeneration olfactory system olfactory epithelium brain

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References

Zhao

Wang

Gao

, et al. Olfactory ensheathing cell apoptosis induced by hypoxia and serum deprivation. Neurosci Lett. 2007;421(3):197–202.

Salihoğlu

Kendirli

Altundağ

, et al. The effect of obstructive sleep apnea on olfactory functions. Laryngoscope. 2014;124(9):2190–2194.

De Paula

Tolstykh

Mifflin

. Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs. Am J Phys Regul Integr Comp Phys. 2007;292(6):R2259–R2265.

Miyamoto

Iwanami

Suzuki

Inoue

Hirata

. Odor identification test as an indicator of idiopathic REM sleep behavior disorder. Mov Dis. 2009;24(2):268–273.

Pinto

Wang

Chen

Zhan

Wei

. The effect of nasal structure on olfactory function in patients with OSA. Eur Arch Otorhinolaryngol. 2015;272(2):357–362.

Günbey

Güzel

Karlı

Ünal

. The relationships between the clinical and polysomnographic findings and the olfactory function in patients with obstructive sleep apnea syndrome. Sleep Breath. 2015;19(4):1301–1307.

Arnaud

Dematteis

Pepin

, et al. Obstructive sleep apnea, immuno-inflammation, and atherosclerosis. Semin Immunopathol. 2009;31(1):113–125.

Baguet

Barone-Rochette

Tamisier

, et al. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol. 2012;9(12):679–688.

Bert

. La pression barometrique: recherches de physiologies experimentale. Parus: Masson; 1878.4. Kobrick JL, Zwick H, Witt CE, Devine JA. Effects of Extended Hypoxia on Night Vision. Aviat Space Environ Med 1984;55(3):191-195.

10.

Kuehn

Welsch

Zahnert

Hummel

. Changes of pressure and humidity affect olfactory function. Eur Arch Otorhinolaryngol. 2008;265(3):299–302.

11.

Salihoğlu

Kendirli

Altundağ

, et al. The effect of obstructive sleep apnea on olfactory functions. Laryngoscope. 2014;124(9):2190–2194.

12.

Magliulo

De Vincentiis

Iannella

, et al. Olfactory evaluation in obstructive sleep apnoea patients. Acta Otorhinolaryngol Ital. 2018;38(4):338–345.

13.

Rolls

. Taste, olfactory, and food texture processing in the brain, and the control of food intake. Physiol Behav. 2005;85(1):45–56.

14.

Takahashi

Nakashima

Hong

Watanabe

. The smell of danger: a behavioral and neural analysis of predator odor-induced fear. Neurosci Biobehav Rev. 2005;29(8):1157–1167.

15.

Saraiva

Kondoh

Yoon

Hernandez

Buck

. Combinatorial effects of odorants on mouse behavior. Proc Natl Acad Sci. 2016;113(23):E3300–E3306.

16.

Stepank

. Influence of hypobaric hypoxia on the human sense of smell. In: Thesis (Master of Public Health). Galvestone: The University of Texas Graduate School of Biomedical Sciences; 2002.

17.

Altundağ

Salihoglu

Çayönü

, et al. The effect of high altitude on olfactory functions. Eur Arch Otorhinolaryngol. 2014;271(3):615–618.

18.

Kühn

Welsch

Zahnert

Hummel

. Is olfactory function impaired in moderate height? Laryngorhinootologie. 2009;88(9):583–586.

19.

Doğan

Muluk

Şahin

. Olfactory bulb volume and olfactory sulcus depth in patients with OSA: an MRI evaluation. Ear Nose Throat J. 2020;99(7):442–447.

20.

Hernández-Soto

Villasana-Salazar

Pinedo-Vargas

Peña-Ortega

. Chronic intermittent hypoxia alters main olfactory bulb activity and olfaction. Exp Neurol. 2021;340:113653.

21.

Shin

Ahn

Yang

, et al. The effect of sleep disordered breathing on olfactory functions: analysis by apnea–hypopnea index. Clin Exp Otorhinolaryngol. 2017;10(1):71–76.

22.

Drobyshevsky

Robinson

Derrick

, et al. Sensory deficits and olfactory system injury detected by novel application of MEMRI in newborn rabbit after antenatal hypoxia-ischemia. Neuroimage. 2006;32(3):1106–1112.

23.

Moran

Rowley 3rd

Jafek

Lovell

. The fine structure of the olfactory mucosa in man. J Neurocytol. 1982;11(5):721–746.

24.

Morrison

Costanzo

. Morphology of the human olfactory epithelium. J Comp Neurol. 1990;297(1):1–13.

25.

Verhaagen

Oestreicher

Gispen

Margolis

. The expression of the growth associated protein B50/GAP43 in the olfactory system of neonatal and adult rats. J Neurosci Off J Soc Neurosci. 1989;9(2):683–691.

26.

Holbrook

Curry

Lin

Schwob

. Immunohistochemical characterization of human olfactory tissue. Laryngoscope. 2011;121(8):1687–1701.

27.

Kim

Park

Kim

. Olfactory ensheathing cells mediate neuroplastic mechanisms after olfactory training in mouse model. Am J Rhinol Allergy. 2020;34(2):217–229.

28.

Kim

Park

Kim

. Differences in mechanisms of steroid therapy and olfactory training for olfactory loss in mice. Am J Rhinol Allergy. 2020;34(6):810–821.

29.

Deumens

Koopmans

Lemmens

, et al. Neurite outgrowth promoting effects of enriched and mixed OEC/ONF cultures. Neurosci Lett. 2006;397(1-2):20–24.

30.

Pourié

Akchiche

Millot

, et al. The fate of transplanted olfactory progenitors is conditioned by the cell phenotypes of the receiver brain tissue in cocultures. Int J Mol Sci. 2020;21(19):7249.

31.

Reske

Kellermann

Shah

, et al. Impact of valence and age on olfactory induced brain activation in healthy women. Behav Neurosci. 2010;124(3):414–422.

32.

Wang

Sun

Yang

. Early aging effect on the function of the human central olfactory system. J Gerontol A Biol Sci Med Sci. 2017;72(8):1007–1014.