Convergence of circadian and sleep regulatory mechanisms on hypocretin-1

doi:10.1016/j.neuroscience.2004.07.049

Neuroscience

Volume 129, Issue 3, 2004, Pages 727-732

https://doi.org/10.1016/j.neuroscience.2004.07.049 Get rights and content

Abstract

Hypocretin is a potential regulator of sleep and wakefulness and its levels fluctuate with the day–night cycle with high levels during the animal's activity period. Whether the daily fluctuations are driven endogenously or by external light cycles is unknown. We investigated the circadian and homeostatic regulation of hypocretin in the absence of environmental light cycles. To this purpose we performed repetitive samplings of cerebrospinal fluid in rats through implanted microcannulas in the cisterna magna and determined hypocretin-1 levels by radioimmunoassay. These experiments were also performed in rats that received a lesion of the suprachiasmatic nucleus (SCN), a major pacemaker for circadian rhythms in mammals. The results showed sustained rhythmicity of hypocretin in constant dim red light in control animals. SCN-lesioned animals showed no circadian rhythms in hypocretin and mean hypocretin levels were remarkably low. The results indicate that the SCN is indispensable for rhythmicity in hypocretin and induces a daily increase in hypocretin levels during the animal's active phase. Additional sleep deprivation experiments were carried out to investigate homeostatic regulation of hypocretin. Hypocretin levels increased in response to sleep deprivation in both control and SCN-lesioned animals, demonstrating that sleep homeostatic control of hypocretin occurs independently from the SCN. Our data indicate that the circadian pacemaker of the SCN and sleep homeostatic mechanisms converge on one single sleep regulatory substance.

Section snippets

Animals

All experiments were performed under the approval of the Animal Experiments Ethical Committee of the Leiden University Medical Center. All efforts were made to minimize the number of animals and their suffering. Male Wistar rats (approximately 300 g; Harlan, Zeist, The Netherlands) were subjected to an SCN or sham lesion. Lesions of the SCN were made under Hypnorm/Dormicum anesthesia. An electrode (diameter 0.3 mm), insulated with Epoxylite except at the 0.5 mm tip, was stereotaxically placed

Results

Recordings of drinking activity and periodogram analysis in SCN-lesioned animals showed no significant rhythm within the circadian range (Fig. 2A, B), whereas the sham lesioned animals were rhythmic (Fig. 2C, D). In all rhythmic animals, hypocretin-1 reached lowest levels in the middle of the resting phase, and remained low until the start of their active phase. Within 4 h after onset of activity, hypocretin-1 increased and reached maximum levels (Fig. 3). Hypocretin-1 levels during the end of

Discussion

Under constant conditions a clear circadian rhythm in hypocretin-1 levels was obtained in control animals providing evidence that the 24-hour fluctuations are not imposed on the animal by the environmental light dark cycle, but are endogenous and circadian in nature. A possible confounding factor in this study may be the indirect effect of motor activity. Studies in narcoleptic and control dogs have shown increased CSF hypocretin levels with exercise (Wu et al., 2002). Hypocretin changes could

Note added in proof

After submission of the manuscript, experiments investigating the endogenous rhythm of hypocretin-1 release and its dependence on the SCN were published by Zhang et al. (2004).

Acknowledgments

We thank F. Roelandse for his help with the radioimmunoassay.

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Convergence of circadian and sleep regulatory mechanisms on hypocretin-1

Abstract

Section snippets

Animals

Results

Discussion

Note added in proof

Acknowledgments

Cell

Neuroscience

Neuron

Brain Res

Brain Res

Cell

Lancet

Brain Res

Neurobiol Dis

Brain Res

Neuron

Electroencephalogr Clin Neurophysiol

The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems

Neuroreport

Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster

J Neurosci

Sleep homeostasis and models of sleep regulation

Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms

J Neurosci

Sleep regulation in the Djungarian hamster: comparison of the dynamics leading to the slow-wave activity increase after sleep deprivation and daily torpor

Sleep

Sleep states alter neuronal activity of the suprachiasmatic nucleus

Nat Neurosci

EEG power density during nap sleep: reflection of an hourglass measuring the duration of wakefulness

J Biol Rhythms

Advanced methods for evaluating characteristic parameters (τ, α, ρ) of circadian rhythms

J Math Biol

Fos expression in orexin neurons varies with behavioural state

J Neurosci

Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation

Neuroreport