Delayed orexin signaling consolidates wake and sleep : physiology and modeling

Orexin-producing neurons are clearly essential for the regulation of wakefulness and sleep as loss of these cells produces narcolepsy. However, little is understood about how these neurons dynamically interact with other wakeand 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 shorter than one minute. Since orexin neurons often begin firing several seconds before the onset of wake, this suggests a surprisingly delayed onset (> 1 min) of functional effects. This delay has important implications for understanding the control of wake and sleep as 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 timedependent increase in the strength of inhibition from waketo 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.