The Diurnal Rhythm of Hypocretin in Young and Old F344 Rats

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Abstract
Hypocretins (HCRT-1 and HCRT-2), also known as orexins, are neuropeptides localized in neurons surrounding the perifornical region of the posterior hypothalamus. These neurons project to major arousal centers in the brain and are implicated in regulating wakefulness. In young rats and monkeys, levels of HCRT-1 are highest at the end of the wake-active period and lowest toward the end of the sleep period. However, the effects of age on the diurnal rhythm of HCRT-1 are not known. To provide such data, cerebrospinal fluid (CSF) was collected from the cisterna magna of young (2-month-old, n = 9), middle-aged (12 months, n = 10), and old (24 months, n = 10) F344 rats at 4-hour intervals, (beginning at zeitgeber [ZT]0, lights on). CSF was collected once from each rat every 4 days at 1 ZT point. After collecting the CSF at all of the time points, the rats were kept awake by gentle handling for 8 hours (ZT 0-ZT8), and the CSF was collected again at the end of the sleep-deprivation procedure. HCRT-1 levels in the CSF were determined by radioimmunoassay Basic neuroscience research lab. Old rats had significantly less HCRT-1 in the CSF versus young and middle-aged rats (P < .002) during the lights-on and lights-off periods and over the 24-hour period. In old rats, significantly low levels of HCRT-1 were evident at the end of the lights-off period (predominantly wake-active period). The old rats continued to have less HCRT-1 even after 8 hours of prolonged waking. Northern blot analysis did not show a difference in pre-proHCRT mRNA between age groups. In old rats there is a 10% decline in CSF HCRT-1 over the 24-hour period. Functionally, if there is less HCRT-1, which our findings indicated, and there is also a decline in HCRT receptor mRNA, as has been previously found, then the overall consequence would be diminished action of HCRT at target sites. This would diminish the waking drive, which in the elderly could contribute to the increased tendency to fall asleep during the normal wake period.