Fluctuation of extracellular hypocretin‐1 (orexin A) levels in the rat in relation to the light–dark cycle and sleep–wake activities

TLDR

Hypocretins/orexins are neuropeptides implicated in sleep regulation and the sleep disorder narcolepsy. The study aimed to examine how extracellular hypocretin‑1 levels fluctuate across a 24‑hour cycle relative to sleep–wake activity in freely moving rats. We measured extracellular hypocretin‑1 in the lateral hypothalamus and medial thalamus while recording sleep states in freely moving rats. Hypocretin‑1 levels showed a robust diurnal rhythm, rising during the dark (active) period and falling during the light (rest) period, were not linked to the amount of wake or sleep, increased markedly after 6‑hour sleep deprivation, and appear to accumulate during wakefulness and diminish with sleep, suggesting a role in counteracting sleep propensity during prolonged wakefulness.

Abstract

Abstract Hypocretins/orexins are neuropeptides implicated in sleep regulation and the sleep disorder narcolepsy. In order to examine how hypocretin activity fluctuates across 24 h with respect to the sleep–wake cycle, we measured changes in extracellular hypocretin‐1 levels in the lateral hypothalamus and medial thalamus of freely moving rats with simultaneous sleep recordings. Hypocretin levels exhibited a robust diurnal fluctuation; levels slowly increased during the dark period (active phase), and decreased during the light period (rest phase). Levels were not correlated with the amount of wake or sleep in each period. Although an acute 4 ‐ h light‐shift did not alter hypocretin levels, 6 ‐ h sleep deprivation significantly increased hypocretin release during the forced‐wake period. Hypocretin activity is, thus, likely to build up during wakefulness and decline with the occurrence of sleep. These findings, together with the fact that a difficulty in maintaining wakefulness during the daytime is one of the primary symptoms of hypocretin‐deficient narcolepsy, suggest that hypocretin activity may be critical in opposing sleep propensity during periods of prolonged wakefulness.