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

Departments of 1 Autonomic Physiology, 2 Respirology, and 3 Molecular and Integrative Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; 4 Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas; and 5 Exploratory Research for Advance Technology Yanagisawa Orphan Project, Japan Science and Technology, Tokyo, Japan Submitted 28 August 2007 ; accepted in final form 18 November 2007 Respiratory long-term 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% O 2 ), sustained hypoxia (SH; 25 min at 10% O 2 ), 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. respiration; plasticity; intermittent hypoxia; behavioral state control; hypothalamus Address for reprint requests and other correspondence: T. Kuwaki, Dept. of Molecular & Integrative Physiology, Chiba Univ. Graduate School of Medicine, 1-8-1 Chuo-ku, Chiba 260-8670, Japan (e-mail: kuwaki{at}faculty.chiba-u.jp )