Delayed orexin signaling consolidates wakefulness and sleep: Physiology and modeling

被引:51
作者
Behn, C. G. Diniz [1 ,2 ,3 ]
Kopell, N. [2 ,3 ]
Brown, E. N. [4 ]
Mochizuki, T. [1 ]
Scammell, T. E. [1 ]
机构
[1] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA
[2] Boston Univ, Dept Math, Boston, MA 02215 USA
[3] Univ Michigan, Ctr BioDynam, Ann Arbor, MI 48109 USA
[4] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA
关键词
D O I
10.1152/jn.01243.2007
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Orexin-producing neurons are clearly essential for the regulation of wakefulness and sleep because loss of these cells produces narcolepsy. However, little is understood about how these neurons dynamically interact with other wake- and sleep-regulatory nuclei to control behavioral states. Using survival analysis of wake bouts in wild-type and orexin knockout mice, we found that orexins are necessary for the maintenance of long bouts of wakefulness, but orexin deficiency has little impact on wake bouts <1 min. Since orexin neurons often begin firing several seconds before the onset of waking, this suggests a surprisingly delayed onset (>1 min) of functional effects. This delay has important implications for understanding the control of wakefulness and sleep because increasing evidence suggests that different mechanisms are involved in the production of brief and sustained wake bouts. We incorporated these findings into a mathematical model of the mouse sleep/wake network. Orexins excite monoaminergic neurons and we hypothesize that orexins increase the monoaminergic inhibition of sleep-promoting neurons in the ventrolateral preoptic nucleus. We modeled orexin effects as a time-dependent increase in the strength of inhibition from wake- to sleep-promoting populations and the resulting simulated behavior accurately reflects the fragmented sleep/wake behavior of narcolepsy and leads to several predictions. By integrating neurophysiology of the sleep/wake network with emergent properties of behavioral data, this model provides a novel framework for investigating network dynamics and mechanisms associated with normal and pathologic sleep/wake behavior.
引用
收藏
页码:3090 / 3103
页数:14
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