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1 Department of Autonomic Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Respirology, Chiba University Graduate School of Medicine, Chiba, Japan
2 Chiba, Japan; Department of Autonomic Physiology, Chiba University Graduate School of Medicine, Chiba, Japan
3 Department of Molecular & Integrative Physiology, Chiba University Graduate School of Medicine, Chiba, Japan
4 Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States; Exploratory Research for Advance Technology Yanagisawa Orphan Project, Japan Science and Technology Corporation, Tokyo, Japan
5 Chiba, Japan; Department of Respirology, Chiba University Graduate School of Medicine, Chiba, Japan
6 Department of Molecular & Integrative Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Autonomic Physiology, Chiba University Graduate School of Medicine, Chiba, Japan
* To whom correspondence should be addressed. E-mail: kuwaki{at}faculty.chiba-u.jp.
Respiratory long term facilitation (LTF) is a long-lasting (> hr) augmentation of respiratory motor output that occurs even after cessation of hypoxic stimuli, is serotonin-dependent, and 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, 5x 5-min 10% O2), sustained hypoxia (SH, 25-min 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 hours 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 indices 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 LTF cannot prevent sleep apnea, at least in mice.
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  H. Wadhwa, C. Gradinaru, G. J. Gates, M. S. Badr, and J. H. Mateika Impact of intermittent hypoxia on long-term facilitation of minute ventilation and heart rate variability in men and women: do sex differences exist? J Appl Physiol, June 1, 2008; 104(6): 1625 - 1633. [Abstract] [Full Text] [PDF]
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