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Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice

Departments of ¹Autonomic Physiology and ²Molecular and Integrative Physiology, Chiba University Graduate School of Medicine, Chiba-city, Chiba, Japan; ³Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁴Exploratory Research for Advance Technology Yanagisawa Orphan Project, Japan Science and Technology Corporation, Tokyo, Japan

Submitted 16 June 2006 ; accepted in final form 1 September 2006

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 h 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^–1·g^–1·%CO₂^–1) was significantly smaller than that in WT mice (0.38 ± 0.04 ml·min^–1·g^–1·%CO₂^–1), 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 postsigh 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.

chemostimulation; control of breathing; behavioral state control; hypothalamus

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