Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin

Jiro Terada, Akira Nakamura, Wei Zhang, Masashi Yanagisawa, Takayuki Kuriyama, Yasuichiro Fukuda, Tomoyuki Kuwaki

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Respiratory longterm facilitation (LTF) is a long-lasting (>1 h) augmentation of respiratory motor output that occurs even after cessation of hypoxic stimuli, is serotonin-dependent, and is thought to prevent sleep-disordered breathing such as sleep apnea. Raphe nuclei, which modulate several physiological functions through serotonin, receive dense projections from orexin-containing neurons in the hypothalamus. We examined possible contributions of orexin to ventilatory LTF by measuring respiration in freely moving prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates before, during, and after exposure to intermittent hypoxia (IH; 5 X 5 min at 10% O2), sustained hypoxia (SH; 25 min at 10% O2), or sham stimulation. Respiratory data during quiet wakefulness (QW), slow wave sleep (SWS), and rapid-eye-movement sleep were separately calculated. Baseline ventilation before hypoxic stimulation and acute responses during stimulation did not differ between the ORX-KO and WT mice, although ventilation depended on vigilance state. Whereas the WT showed augmented minute ventilation (by 20.0 ± 4.5% during QW and 26.5 ± 5.3% during SWS; n = 8) for 2 h following IH, ORX-KO showed no significant increase (by -3.1 ± 4.6% during QW and 0.3 ± 5.2% during SWS; n = 8). Both genotypes showed no LTF after SH or sham stimulation. Sleep apnea indexes did not change following IH, even when LTF appeared in the WT mice. We conclude that LTF occurs during both sleep and wake periods, that orexin is necessary for eliciting LTF, and that LTF cannot prevent sleep apnea, at least in mice.

Original languageEnglish (US)
Pages (from-to)499-507
Number of pages9
JournalJournal of applied physiology
Issue number2
StatePublished - Feb 2008


  • Behavioral state control
  • Hypothalamus
  • Intermittent hypoxia
  • Plasticity
  • Respiration

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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