TY - JOUR
T1 - Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice
T2 - Molecular genetic dissection of non-REM and REM sleep regulatory processes
AU - Willie, Jon T.
AU - Chemelli, Richard M.
AU - Sinton, Christopher M.
AU - Tokita, Shigeru
AU - Williams, S. Clay
AU - Kisanuki, Yaz Y.
AU - Marcus, Jacob N.
AU - Lee, Charlotte
AU - Elmquist, Joel K
AU - Kohlmeier, Kristi A.
AU - Leonard, Christopher S.
AU - Richardson, James A
AU - Hammer, Robert E
AU - Yanagisawa, Masashi
N1 - Funding Information:
We thank M. Nakazato for assistance with the RIA method; M.S. Brown and M. Mieda for critical reading of the manuscript; S.A. Dixon and S. Seyedkalal for technical support; and S. Nishino for sharing his unpublished observations. M.Y. is an investigator, and S.T. and Y.Y.K. are former Associates of the Howard Hughes Medical Institute. J.T.W. is a joint fellow of the Department of Cellular and Molecular Biology and Medical Scientist Training programs of the University of Texas Southwestern Medical Center at Dallas. This work was supported in part by research grants from the Perot Family Foundation and Exploratory Research for Advanced Technology of Japan Science and Technology Corporation to M.Y., National Institutes of Health grants NS27881 and HL64150 to C.S.L., and NIH grants DK56116 and MH61583 to J.K.E.
PY - 2003/6/5
Y1 - 2003/6/5
N2 - Narcolepsy-cataplexy, a neurological disorder associated with the absence of hypothalamic orexin (hypocretin) neuropeptides, consists of two underlying problems: inability to maintain wakefulness and intrusion of rapid eye movement (REM) sleep into wakefulness. Here we document, using behavioral, electrophysiological, and pharmacological criteria, two distinct classes of behavioral arrests exhibited by mice deficient in orexin-mediated signaling. Both OX2R-/- and orexin-/- mice are similarly affected with behaviorally abnormal attacks of non-REM sleep ("sleep attacks") and show similar degrees of disrupted wakefulness. In contrast, OX2R-/- mice are only mildly affected with cataplexy-like attacks of REM sleep, whereas orexin-/- mice are severely affected. Absence of OX2Rs eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset. While normal regulation of wake/non-REM sleep transitions depends critically upon OX2R activation, the profound dysregulation of REM sleep control unique to the narcolepsy-cataplexy syndrome emerges from loss of signaling through both OX2R-dependent and OX2R-independent pathways.
AB - Narcolepsy-cataplexy, a neurological disorder associated with the absence of hypothalamic orexin (hypocretin) neuropeptides, consists of two underlying problems: inability to maintain wakefulness and intrusion of rapid eye movement (REM) sleep into wakefulness. Here we document, using behavioral, electrophysiological, and pharmacological criteria, two distinct classes of behavioral arrests exhibited by mice deficient in orexin-mediated signaling. Both OX2R-/- and orexin-/- mice are similarly affected with behaviorally abnormal attacks of non-REM sleep ("sleep attacks") and show similar degrees of disrupted wakefulness. In contrast, OX2R-/- mice are only mildly affected with cataplexy-like attacks of REM sleep, whereas orexin-/- mice are severely affected. Absence of OX2Rs eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset. While normal regulation of wake/non-REM sleep transitions depends critically upon OX2R activation, the profound dysregulation of REM sleep control unique to the narcolepsy-cataplexy syndrome emerges from loss of signaling through both OX2R-dependent and OX2R-independent pathways.
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U2 - 10.1016/S0896-6273(03)00330-1
DO - 10.1016/S0896-6273(03)00330-1
M3 - Article
C2 - 12797957
AN - SCOPUS:0038724250
SN - 0896-6273
VL - 38
SP - 715
EP - 730
JO - Neuron
JF - Neuron
IS - 5
ER -