Long-term intermittent hypoxia induces anxiety-like behavior and affects expression of orexin and its receptors differently in the mouse brain.

Abstract

Studies have revealed a possible connection between orexin, narcolepsy, and obstructive sleep apnea (OSA). Orexin has an important role in the maintenance of arousal and wakefulness/sleeping states. To better understand the pathophysiological mechanism of OSA, we used a chronic intermittent hypoxia (CIH) model in mice to mimic OSA. In this way, we explored the effect of CIH on the locomotor activity and orexin system in the hypothalamus, cerebral cortex, and brainstem of mice. Male C57BL/6J mice (8weeks) in the CIH group were exposed in a hypoxia chamber for 8h/day for 28weeks. The re-oxygenation groups comprised the W2 group and W4 group, which were exposed to 28weeks of CIH followed by 2weeks and 4weeks of re-oxygenation, respectively. The open field test was undertaken to observe locomotor activity. mRNA expression of orexin, orexin receptor type 1 (OX1R), and OX2R mRNA was evaluated by real-time reverse transcription-quantitative polymerase chain reaction. Mice subjected to long-term CIH exhibited significant anxiety-like behavior during the light period, and this behavior lasted until 4weeks of re-oxygenation. mRNA expression of orexin was upregulated in the hypothalamus. mRNA expression of OX1R mRNA in the cerebral cortex and brainstem was downregulated by CIH. Two weeks and 4weeks of re-oxygenation could not reverse these alternations. Long-term CIH may induce anxiety-like behavior and re-oxygenation cannot reverse these behavior. Moreover, OX1R has a significant role in the anxiety-related symptoms observed in long-term CIH.