Orexinergic modulation of breathing across vigilance states

Basal respiration and respiratory reflex regulations are considerably different during the awake and sleep states. Tidal volume and respiratory frequency diminish during sleep, and hypoxic and hypercapnic ventilatory responses also decline during sleep. Reduced metabolic demand during sleep cannot completely explain these phenomena because PaCO2 increases during sleep. In this review, I will summarize our recent discovery of the possible contribution of orexin, a hypothalamic neuropeptide, to the vigilance state-dependent adjustment of central respiratory regulation. Orexin-deficient mice show an attenuated hypercapnic ventilatory response during the awake but not during the sleep period, whereas basal ventilation remained normal, irrespective of the vigilance state. Orexin supplementation remedied the defect, and the administration of an orexin receptor antagonist to wild-type mice mimicked the abnormality. Orexin-deficient mice also showed frequent sleep apneas and loss of repetitive intermittent hypoxia-induced ventilatory long-term facilitation. Hence, it is possible that the orexin system is one of the essential modulators required for coordinating the circuits controlling respiration and behavior.