Orexin Is Necessary For Eliciting Ventilatory Long-Term Facilitation In Mice

Respiratory long-term facilitation (LTF) is a long-lasting augmentation of respiratory motor output following intermittent hypoxia (IH), known to be serotonin-dependent. Serotonergic raphe nuclei receive dense projections from the orexin containing neurons in the hypothalamus. We have recently found that orexin modulates chemosensitivity in a vigilance state dependent manner. Moreover, a recent study has demonstrated that LTF is state-dependent. Therefore, we hypothesized that orexin might contribute to generating LTF after IH. To test this hypothesis, we examined ventilatory LTF in prepro-orexin knockout mice (ORX-KO) during sleep. Minute ventilation (VE) was measured in unanesthetized ORX-KO and wild-type littermates (WT) by body plethysmography before, during, and after exposure to IH (5×5min 10%O2) or sustained hypoxia (SH) (25min 10%O2). EEG and neck EMG were recorded concomitantly. Respiratory data during slow wave sleep (SWS) were calculated. Whereas WT showed augmented VE during SWS for 2 hours following IH, ORX-KO showed no significant increase. Both types of mice showed no LTF after SH. We concluded that orexin played an important role for eliciting ventilatory LTF during SWS in mice.