Hypothalamic modulation of breathing.

Hypothalamus has long been known to be involved in the regulation of breathing. For example, many neurons are activated by hypoxia and hypercapnia and stimulation to the hypothalamus increases respiration. However, precise characters of these neurons have not well understood until recently presumably because hypothalamus is a heterogeneous structure intermingly containing many kind of neurotransmitters. The situation has dramatically changed by a discovery of hypothalamic neuropeptide orexin in 1998 and subsequent development of orexin-knockout mice in 1999. Here I summarize our recent discovery of the possible contribution of orexin 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. Hypercapnic stimulation activated orexinergic neurons in the wild-type mice. Orexin-deficient mice also showed frequent sleep apneas and loss of repetitive intermittent hypoxia-induced ventilatory and phrenic 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.