With an understanding that orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics (with their loss causing narcolepsy), researchers funded by the Australian Research Council sought to explain the stabilizing effects of Orx via a quantitative model.
A new model of sleep-wake physiology was developed that includes Orx. According to the study titled “A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake”, “Using established physiological knowledge, the model addresses a key shortcoming in current understanding of narcolepsy by providing a clear physiological explanation of how arousal state instability stems from Orx loss. A physiologically plausible set of parameters is able to reproduce previously reported sleep-wake behavior, explain many features of the narcoleptic phenotype, and make new predictions.”
The main results are as follows:
• The new model produces realistic dynamics, including firing rates, relevant drives, and the temporal organization of sleep and wake periods.
• Fragmented sleep-wake time series characteristic of the narcoleptic phenotype are generated by simulating a reduction in orexin levels, yielding reduced daytime arousal with a constant daily total duration of sleep, without altering any other parameters or drives.
• The model predicts a shift of the sleep-wake schedule toward a morning chronotype with reduction in orexin levels, a prediction that may have relevance in understanding the increase in morningness and sleep-wake fragmentation with aging.
• While previous models have captured sleep inertia using ad hoc processes, an asymmetry between sleep-to-wake and wake-to-sleep transitions is predicted to result from adding Orx to the model, producing sleep inertia on the timescale of Orx dynamics. This timescale is shown to affect all state transitions, including naps during normal wake periods and awakenings during normal sleep periods.