Intermittent but not sustained hypoxia activates orexin-containing neurons in mice

• Effect of hypoxia (10% O2) on orexin neuronal activity was examined.
• Intemittent but not sustained hypoxia activated orexin-containing neurons.
• Orexin neurons may defend against hypoxia in a pattern sensitive manner.

Hypothalamic orexin-containing neurons are activated by CO2 and contribute to hypercapnic ventilatory activation. However, their role in oxygen-related regulation of breathing is not well defined. In this study, we examined whether an experimental model mimicking apnea-induced repetitive hypoxemia (intermittent hypoxia [IH]) activates orexin-containing neurons. Mice were exposed to IH (5 × 5 min at 10% O2), intermittent hyperoxia (IO; 5 × 5 min at 50% O2), sustained hypoxia (SH; 25 min at 10% O2), or sham stimulation. Their brains were examined using double immunohistochemical staining for orexin and c-Fos. The results indicated that IH (25.8 ± 3.0%), but not SH (9.0 ± 1.5%) activated orexin-containing neurons when compared to IO (5.5 ± 0.6%) and sham stimulation (5.9 ± 1.4%). These results correlate with those of our previous work showing that IH-induced respiratory long-term facilitation is dependent on orexin-containing neurons. Taken together, orexin contributes to repetitive hypoxia-induced respiratory activation and the hypoxic activation of orexin-containing neurons is pattern dependent.