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Science's STKE  10 Jun 2003:
Vol. 2003, Issue 186, pp. tw215-TW215
DOI: 10.1126/stke.2003.186.tw215

The neurobehavioral states of wakefulness, rapid eye movement (REM) sleep, and non-REM sleep are characterized by distinct patterns of neuronal activity, as well as by differences in consciousness, responsiveness to stimuli, and muscle tone. The narcolepsy-cataplexy syndrome, which involves the loss of orexin-containing hypothalamic neurons, is associated with disturbances of the normal pattern of sleep and wakefulness, including overwhelming sleepiness, non-REM "sleep attacks," sleep-onset hallucinations, and cataplexy--a sudden, emotionally triggered loss of postural muscle tone. Cataplexy and sleep-onset hallucinations represent an intrusion of the REM state into wakefulness and are believed to reflect a neurological disturbance distinct from that underlying the inability to stay awake. Willie et al. investigated mutant mice lacking either orexins or the type 2 orexin receptor (OX2R) and discovered that, whereas both experienced similar non-REM sleep disturbances, the mice lacking orexin were more severely cataplectic. The authors used behavioral, pharmacological, and electrophysiological (electroencephalograms and electromyograms) analysis to characterize two classes of "behavioral arrests": abrupt arrests, analogous to human cataplectic attacks, and gradual arrests, equivalent to human sleep attacks. Both mutants exhibited disruptions of wakefulness and similar susceptibility to gradual arrests. The orexin-knockout mice, however, were more susceptible to abrupt arrests. Calcium imaging experiments in brain slices from wild-type mice and mice lacking OX2R indicated that OX2R was required for orexin-mediated stimulation of neurons in the tuberomammillary nucleus, a structure implicated in promoting wakefulness and suppressing non-REM sleep. Thus, OX2R seems to be critical to narcoleptic disruption of patterns of non-REM sleep and wakefulness, whereas OX2R-independent pathways play an important role in dysregulation of REM sleep.

J. T. Willie, R. M. Chemelli, C. M. Sinton, S. Tokita, S. C. Williams, Y. Y. Kisanuki, J. N. Marcus, C. Lee, J. K. Elmquist, K. A. Kohlmeier, C. S. Leonard, J. A. Richardson, R. E. Hammer, M. Yanagisawa, Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 38, 715-730 (2003). [Online Journal]

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