A physical understanding and quantification for the regulation of orexin on sleep

The orexinergic neurons located in the lateral hypothalamus play a vital role in maintaining wakefulness and regulating sleep stability. Previous research has demonstrated that the absence of orexin (Orx) can trigger narcolepsy, a condition characterized by frequent shifts between wakefulness and sleep. However, the specific mechanisms and temporal patterns through which Orx regulates wakefulness/sleep are not fully understood. In this study, we developed a new model that combines the classical Phillips-Robinson sleep model with the Orx network. Our model incorporates a recently discovered indirect inhibition of Orx on sleep-promoting neurons in the ventrolateral preoptic nucleus. By integrating appropriate physiological parameters, our model successfully replicated the dynamic behavior of normal sleep under the influence of circadian drive and homeostatic processes. Furthermore, our results from the new sleep model unveiled two distinct effects of Orx: excitation of wake-active neurons and inhibition of sleep-active neurons. The excitation effect helps to sustain wakefulness, while the inhibition effect contributes to arousal, consistent with experimental findings [De Luca et al., Nat. Commun. 13, 4163 (2022)]. Moreover, we utilized the theory of potential landscapes to investigate the physical mechanisms underlying the frequent transitions observed in narcolepsy. The topography of the underlying landscape delineated the brain's capacity to transition between different states. Additionally, we examined the impact of Orx on barrier height. Our analysis demonstrated that a reduced level of Orx led to a bistable state with an extremely low threshold, contributing to the development of narcoleptic sleep disorder.