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

Huan Tang ^1,2,3, Huijie Shen ^1,2,3, Zhiyun Ji ⁴

⁰Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.

Sleep and Biological Rhythms +

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March 13, 2024

View abstract on PubMed

Summary

Chronic intermittent hypoxia (CIH), mimicking obstructive sleep apnea (OSA), induced anxiety-like behaviors in mice. This anxiety persisted even after re-oxygenation, suggesting long-term CIH effects on the orexin system.

Area Of Science

Neuroscience
Sleep Medicine
Behavioral Biology

Background

Orexin is crucial for regulating arousal and sleep-wake states.
A potential link exists between orexin, narcolepsy, and obstructive sleep apnea (OSA).
Chronic intermittent hypoxia (CIH) is a key feature of OSA, impacting physiological functions.

Purpose Of The Study

To investigate the effects of long-term CIH on locomotor activity and the orexin system in mice.
To explore the role of orexin receptors (OX1R and OX2R) in CIH-induced changes.
To determine if re-oxygenation can reverse the observed behavioral and molecular alterations.

Main Methods

A mouse model of chronic intermittent hypoxia (CIH) was established for 28 weeks.
Locomotor activity was assessed using the open field test.
mRNA expression of orexin, OX1R, and OX2R was quantified in the hypothalamus, cerebral cortex, and brainstem.

Main Results

Long-term CIH induced significant anxiety-like behavior, which persisted for up to 4 weeks after re-oxygenation.
Orexin mRNA expression was upregulated in the hypothalamus following CIH.
CIH downregulated OX1R mRNA in the cerebral cortex and brainstem; re-oxygenation did not reverse these changes.

Conclusions

Long-term CIH can lead to persistent anxiety-like behavior, potentially mediated by alterations in the orexin system.
The observed downregulation of OX1R suggests its involvement in the anxiety-related symptoms associated with CIH.
Re-oxygenation following prolonged CIH is insufficient to reverse these neurobiological and behavioral effects.

Keywords:

Chronic intermittent hypoxia Obstructive sleep apnea Orexin Orexin receptors Re-oxygenation