Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness

Abstract

In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.

Figures

Fig. 1.

Daily variation in CSF concentrations of cortisol (top) and hypocretin-1 (middle) as well as locomotor activity (bottom). Data from experiments 1 (solid line) and 2 (circle) are shown as average ± SEM. A dashed line connects the control time point with a sample taken at the same time, but after 5 hr of wake extension or daytime control in experiment 2. Arrows indicate time of CSF sampling. An axis break is placed at the top to allow for viewing of all data without compression of the y-axis. Activity data are binned in 30 min intervals. Times of scheduled darkness are shown as dark bars along the x-axis. All data from experiment 1 are double-plotted along the x-axis.

Fig. 2.

The effects of wake extension on CSF cortisol (top right) and CSF hypocretin-1 (bottom right) in individual squirrel monkeys are shown alongside the effects of the daytime wake extension control (cortisol, top left; hypocretin-1, bottom left) in the same monkeys. Males are represented by a shaded box and females by an open circle. The left side of each panel represents samples taken with no investigator presence preceding the CSF collection, whereas the right side of each panel is a sample taken at the same clock time, but after 5 hr of investigator presence. The average ± SEM percentage change for the group is shown for CSF cortisol (top inset) and CSF hypocretin-1 (bottom inset).