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The Journal of Neuroscience, July 14, 2004, 24(28):6291-6300; doi:10.1523/JNEUROSCI.0586-04.2004
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Behavioral/Systems/Cognitive
Behavioral State Instability in Orexin Knock-Out Mice
Takatoshi Mochizuki,1 Amanda Crocker,1 Sarah McCormack,1 Masashi Yanagisawa,2 Takeshi Sakurai,3 andThomas E. Scammell1 1Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, 2Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, and 3Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
Narcolepsy is caused by a lack of orexin (hypocretin), but the physiologic process that underlies the sleepiness of narcolepsy is unknown. Using orexin knock-out (KO) mice as a model of narcolepsy, we critically tested the three leading hypotheses: poor circadian control of sleep and wakefulness, inadequate activation of arousal regions, or abnormal sleep homeostasis. Compared with wild-type (WT) littermates, orexin KO mice had essentially normal amounts of sleep and wake, but wake and non-rapid eye movement (NREM) bouts were very brief, with many more transitions between all behavioral states. In constant darkness, orexin KO mice had normal amplitude and timing of sleep-wake rhythms, providing no evidence for disordered circadian control. When placed in a new, clean cage, both groups of mice remained awake for
45 min, demonstrating that, even in the absence of orexin, fundamental arousal regions can be engaged to produce sustained wakefulness. After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal. These experiments demonstrate that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. Instead, the fragmented behavior of orexin KO mice may be best described as behavioral state instability, with apparently low thresholds to transition between states.
Key words: orexin; hypocretin; narcolepsy; sleepiness; transitions; sleep
Received Feb 18, 2004; revised May 6, 2004; accepted May 20, 2004.
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