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1 Autonomic Physiology, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
2 Molecular & Integrative Physiology, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
3 Howard Hughes Medical Institute, Department of Molecular Genetics, 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
4 Molecular and Integrative Physiology, Chiba University Grad .School of Medicine, Chiba, Japan; Autonomic Physiology, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
* To whom correspondence should be addressed. E-mail: kuwaki{at}faculty.chiba-u.jp.
Exogenous administration of orexin can promote wakefulness and respiration. Here we examined whether intrinsic orexin participates in the control of breathing in a vigilance state-dependent manner. Ventilation was recorded together with electroencephalography and electromyography for 6 hrs during the daytime in prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates. Respiratory parameters were separately determined during quiet wakefulness (QW), slow wave sleep (SWS), or rapid eye movement (REM) sleep. Basal ventilation was normal in ORX-KO, irrespective of vigilance states. The hypercapnic ventilatory response during QW in ORX-KO (0.19±0.01 (mL/min/g)/% CO2) was significantly smaller than that in WT mice (0.38±0.04 (mL/min/g)/% CO2) whereas the responses during SWS and REM in ORX-KO were comparable to those in WT mice. Hypoxic responses during wake and sleep periods were not different between the genotypes. Spontaneous but not post-sigh sleep apneas were more frequent in ORX-KO than in WT littermates during both SWS and REM sleep. Our findings suggest that orexin plays a crucial role both in CO2-sensitivity during wakefulness and in preserving ventilation stability during sleep.
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