title: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California 94304, USA.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Zeitzer
authors.forename: Christine L
authors.initials: CL
authors.lastname: Buckmaster
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Parker
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hauck
authors.forename: David M
authors.initials: DM
authors.lastname: Lyons
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D002352:Carrier Proteins / Q000134:cerebrospinal fluid*; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006854:Hydrocortisone / Q000097:blood / Q000134:cerebrospinal fluid; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000502:physiology; D009479:Neuropeptides / Q000134:cerebrospinal fluid*; D000068797:Orexins; D017440:Photoperiod; D010913:Pituitary-Adrenal System / Q000378:metabolism; D012453:Saimiri; D012892:Sleep Deprivation / Q000503:physiopathology; D014851:Wakefulness / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D006854:Hydrocortisone