Delayed Orexin Signaling Consolidates Wakefulness and Sleep: Physiology and Modeling

1 Department of Neurology, Beth Israel Deaconess Medical Center, Boston; 2 Department of Mathematics and Center for BioDynamics, Boston University; and 3 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts Submitted 10 November 2007; accepted in final form 10 April 2008 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) 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. Address for reprint requests and other correspondence: C. Diniz Behn, University of Michigan, Department of Mathematics, 2074 East Hall, 530 Church Street, Ann Arbor, MI 48109 (E-mail: cdbehn{at}umich.edu )