The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness

Key Points

  • The neurological condition of narcolepsy, characterized by an orexin (hypocretin) deficiency, has shown that orexins have an important role in regulating sleep and wakefulness and in the maintenance of arousal.

  • Orexin neurons are activated during wakefulness, whereas during sleep they are inhibited.

  • Both the orexin 1 and orexin 2 receptors are involved in the regulation of sleep and wakefulness.

  • Orexin neurons regulate monoaminergic and cholinergic nuclei in the brain stem to regulate sleep and wakefulness.

  • Orexin neurons also have links with the arcuate nucleus that regulates feeding, and with the dopaminergic reward system in the ventral tegmental nucleus.

  • Input from the limbic system to orexin neurons might be important for emotional arousal and for sympathetic responses during emotional events.

  • The responsiveness of orexin neurons to peripheral metabolic cues, such as leptin and glucose, indicate that they might act as sensors for the metabolic status of animals.

  • These findings indicate that orexin neurons provide a crucial link between energy balance, emotion, reward systems and arousal.

Abstract

Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.

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Figure 1: Schematic drawing showing main projections of orexin neurons.
Figure 2: Sleep state abnormalities in orexin receptor-knockout mice.
Figure 3: Interactions of orexin neurons with other brain regions implicated in sleep and wakefulness.
Figure 4: Mechanisms by which the orexin system stabilizes sleep and wakefulness.

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Acknowledgements

This study was supported in part by a grant-in-aid for scientific research from The 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; the University of Tsukuba Project Research; the ERATO Yanagisawa Orphan Receptor Project from the Japan Science and Technology Corporation; and anorexia nervosa research from the Japanese Ministry of Health, Labour and Welfare.

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Supplementary information S1 (table)

Phenotypes of rodent narcolepsy models produced by genetic engineering (PDF 83 kb)

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DATABASES

OMIM

narcolepsy

FURTHER INFORMATION

Sakurai's laboratory

Glossary

Narcolepsy

A neurological condition mostly characterized by excessive daytime sleepiness, uncontrollable sleep attacks and disorder of REM sleep.

Limbic system

A collection of cortical and subcortical structures important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.

Ghrelin

Stomach-derived orexigenic peptide.

Leptin

An adipocyte-derived protein hormone that has a key role in regulating energy intake and energy expenditure.

Rapid eye movement sleep

(REM sleep) The stage of sleep characterized by rapid movements of the eyes.

Cataplexy

An episodic condition featuring loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles or inability to speak clearly) to complete body collapse.

Orthodromic and antidromic activation

Neural stimulation in the same and the opposite direction of the physiological nerve conductance, respectively.

Food anticipatory activity

(FAA). Behavioural activation induced by restricted access to food; a manifestation of the food-entrained oscillator.

mPer1

The PER1 gene is a core clock factor that has an essential role in generating circadian rhythms. mPer1 is the mouse counterpart of the human PER1 gene.

Bmal1

Bmal1 (brain and muscle arnt-like protein 1) is a putative clock gene which encodes a basic helix-loop-helix-PAS transcription factor.

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Sakurai, T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8, 171–181 (2007). https://doi.org/10.1038/nrn2092

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