Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice:: Molecular genetic dissection of non-REM and REM sleep regulatory processes
Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice:: Molecular genetic dissection of non-REM and REM sleep regulatory processes
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DOI：
10.1016/s0896-6273(03)00330-1
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发表时间：
2003-06-05
期刊：
影响因子：
16.2
通讯作者：
Yanagisawa, M
中科院分区：
文献类型：
--
作者：
Willie, JT;Chemelli, RM;Yanagisawa, M
嗜睡-猝厥是一种与下丘脑食欲素（下丘脑分泌素）神经肽缺乏相关的神经系统疾病，由两个潜在问题组成：无法保持清醒和快速眼动（REM）睡眠进入清醒状态。在这里，我们使用行为学、电生理学和药理学标准，记录了缺乏食欲素介导信号的小鼠表现出的两种不同类型的行为阻滞。OX2R（-/-）和orexin（-/-）小鼠在非快速眼动睡眠（“睡眠发作”）中受到行为异常攻击的影响相似，并且表现出相似程度的觉醒中断。相比之下，OX2R（-/-）小鼠在快速眼动睡眠中只受到轻微的猝倒样发作的影响，而orexin（-/-）小鼠则受到严重影响。OX2Rs的缺失消除了下丘脑中食欲素诱发的组胺能神经元的兴奋，而这种兴奋控制了非快速眼动睡眠的发生。虽然清醒/非快速眼动睡眠转换的正常调节主要依赖于OX2R的激活，但发作性睡猝落综合征特有的快速眼动睡眠控制的严重失调是由OX2R依赖性和OX2R非依赖性通路的信号缺失引起的。
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.