Delayed Orexin Signaling Consolidates Wakefulness and Sleep: Physiology and Modeling

Abstract

Diniz Behn CG, Kopell N, Brown EN, Mochizuki T, Scammell TE. Delayed orexin signaling consolidates wakefulness and sleep: physiology and modeling. J Neurophysiol 99: 3090 -3103, 2008. First published April 16, 2008 doi:10.1152/jn.01243.2007. 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 Ͻ1 min. Since orexin neurons often begin firing several seconds before the onset of waking, this suggests a surprisingly delayed onset (Ͼ1 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. I N T R O D U C T I O NOrexin-producing neurons play an essential role in the regulation of wakefulness and sleep. Loss of the orexin neurons or the orexin neuropeptides (orexin-A and -B, also known as hypocretin-1 and -2) causes narcolepsy, a common sleep disorder characterized by excessive daytime sleepiness, rapid eye movement (REM) sleep soon after sleep onset, disturbed nocturnal sleep, and cataplexy (Dauvilliers et al. 2007;Scammell 2003). Mice, rats, and dogs with disrupted orexin signaling all have sleepiness and cataplexy strikingly similar to that seen in people with narcolepsy (Beuckmann et al. 2004; Chemelli et al. 1999;Hungs and Mignot 2001).These features of narcolepsy highlight the necessity of orexins, but little is understood about how the orexin neurons dynamically interact with other wake-and sleep-regulatory nuclei to modulate sleep/wake behavior. The orexin neurons are strictly wake-active (Lee et al. 2005;Mileykovskiy et al. 2005) and send excitatory projections to many state-regulatory nuclei . Although orexin knockout (OXKO) mice have normal hourly amounts of wakefulness and sleep, their wake bouts are much s...

Control of arousal by the orexin neurons

“…Mutant mice lacking the orexin peptides, orexin neurons, or orexin receptors are unable to sustain long periods of wakefulness and have frequent transitions between sleep/wake states (Figure 2a) [27,28,30–32]. Survival analysis of the durations of wakefulness bouts (Figure 2b) reveals that mice lacking orexins wake normally from sleep but have difficulty producing long-lasting bouts of wakefulness [33] and transition frequently between wakefulness and sleep [34]. Perhaps, in the absence of sustained excitatory signals from the orexin neurons, other arousal-promoting neurons have uncoordinated or inappropriate patterns of activity, resulting in low thresholds for crossing between states and poorly sustained wakefulness.…”

“…In addition, optogenetic studies demonstrate that selective activation of the orexin neurons increases the probability of waking from either NREM or REM sleep [50], though this awakening is slow, often occurring about 25 s after stimulation. Further arguing against a principal role for orexins in driving awakenings, mice that lack orexins have a normal probability of spontaneously waking from NREM sleep [33], suggesting that most awakenings are mediated by other systems. Nevertheless, orexin signaling is clearly necessary for the maintenance of wakefulness because acutely reducing the firing of orexin neurons or blocking orexin receptors reduces wakefulness [51,52,53•].…”

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

“…recently, several nonparametric and nonlinear methods to assess rest-activity rhythms have been introduced. [26][27][28][29] These techniques have provided insights into altered rest-activity patterns associated with development, aging, and disease and have highlighted differences that are not detectable with standard linear power spectral analysis. consistent with this trend, state space analysis provides a novel, non-categorical method for analyzing sleep/wake behavior.…”

Circadian regulation of sleep–wake behaviour in nocturnal rats requires multiple signals from suprachiasmatic nucleus

“…To assess the patterning of sleep-wake behaviour in the model, we compared the per cent time in each state, mean bout durations and number of bouts with published data describing these summary statistics in rats during 12 h light and dark periods [69]. These statistics provide a general characterization of sleep-wake patterning; however, owing to the non-Gaussian distribution of wake and sleep bouts across species [71][72][73][74], more detailed characterization of the fine architecture of sleepwake behaviour is desirable. Future work examining circadian differences in sleep-wake behaviour should consider variation in these detailed measures as well as the basic summary statistics.…”