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  • Review Article
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The hypocretins: Setting the arousal threshold

Nature Reviews Neuroscience volume 3, pages 339–348 (2002)Cite this article

Key Points

  • The hypocretins (orexins), Hcrt1 and Hcrt2, are expressed only in a few thousand neurons in the dorsolateral hypothalamus. These secreted peptides are found in both rat and human brain, and a gene for their precursor (preprohypocretin) is also found in pufferfish and frog species. The gene, Hcrt, seems to have arisen by genetic rearrangement of the secretin gene.

  • There are two G-protein-coupled receptors for the hypocretins, Hcrtr1 and Hcrtr2. They have different distributions within the brain and bind the two hypocretin peptides with different affinities. The hypocretin neurons of the hypothalamus project widely to many areas of the brain, consistent with the expression of the hypocretin receptors.

  • The hypocretins are found in dense-core vesicles at synapses and can be neuroexcitatory. They can increase the presynaptic release of neurotransmitters and can also have a postsynaptic effect by opening Ca2+ channels in the plasma membrane.

  • Intracerebroventricular administration of hypocretin in rats increases short-term food consumption, and food deprivation can lead to increased concentrations of hypocretin peptides in the hypothalamus. Although these and other observations point to a function for the hypocretins in the control of feeding, it is unclear whether this is a primary role. Findings that relate to the feeding-related activities of the hypocretins have been inconsistent, and it is possible that their influence on feeding might be indirect, through their effects on arousal.

  • Studies of three colonies of dogs in which narcolepsy was inherited showed that the affected gene in each case was the Hcrtr2 gene. Mice in which the Hcrt gene is inactivated show a marked narcoleptic-like phenotype, whereas knocking out either of the hypocretin receptor genes produces a milder phenotype. Knocking out both receptor genes reproduces the severe Hcrt knockout phenotype. In humans with narcolepsy, concentrations of hypocretins are severely reduced and hypocretin neurons are reduced in number or missing altogether, indicating that human narcolepsy results from degeneration of these neurons, possibly as a result of an autoimmune process.

  • It is clear that the hypocretins are central to the control of sleep and arousal. The hypocretin neurons project to areas involved in these processes, including the ascending reticular activating system, and hypocretin levels fluctuate across the sleep–wake cycle and increase with sleep deprivation. Hypocretin neurons activate brainstem 'REM-off' neurons (which are active during wakefulness but not during rapid eye movement (REM) sleep) during arousal to maintain the awake state, and reduce the activity of 'REM-on' neurons (active during both wakefulness and REM sleep), acting as a gate to entry into REM sleep. A fuller understanding of the functions of the hypocretins and the control of sleep and arousal will aid the treatment of narcolepsy and other sleep disorders.

  • Patients with narcolepsy and animals with mutations in the hypocretin system also show reduced feeding together with increased weight. It is proposed that the effect of the hypocretins on feeding behaviour comes from a 'resetting' of the metabolic 'set point' in patients and animal models in which hypocretin signalling is perturbed. In this model, the hypocretins provide a means by which metabolic needs can influence arousal, rather than being orexigenic or anorexigenic per se.

Abstract

Over a short period in the late 1990s, three groups converged on the discovery of a neuropeptide system, centred in the dorsolateral hypothalamus, that regulates arousal states, influences feeding and is implicated in the sleep disorder narcolepsy. Subsequent studies have illuminated many aspects of the circuitry of the hypocretin (also called orexin) system, which also influences hormone secretion and autonomic homeostasis, and have led to the hypothesis that most human narcolepsies result from an autoimmune attack against the hypocretin-producing neurons. The biochemical, physiological and anatomical components that regulate the switch between waking and sleeping are becoming clear. The rapidity with which the hypocretin story has emerged is a testament to both the conceptual and the technical evolution of genomic science in the past two decades.

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Figure 1: The first glimpse of the hypocretin system.
Figure 2: Preprohypocretin and the hypocretins.
Figure 3: Localization of hypocretin.
Figure 4: Local iontophoretic administration of Hcrt1 to the locus coeruleus stimulates expression of c-Fos in noradrenergic neurons.
Figure 5: Schematic model of neurotransmitter circuits that are involved in the three states of vigilance.

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Acknowledgements

Supported in part by grants from the National Institutes of Health and Digital Gene Technologies. We thank A. Spier, C. Alvarez, V. Fabre, E. Thomas, P. Hedlund, C. Ploix and P. Danielson for helpful criticism of the manuscript, and our many collaborators who have shared this trail.

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  1. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    J. Gregor Sutcliffe & Luis de Lecea

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Correspondence to J. Gregor Sutcliffe.

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DATABASES

LocusLink

Hcrt

Hcrtr1

Hcrtr2

Medscape DrugInfo

Modafinil

OMIM

Guillain-Barré syndrome

narcolepsy

FURTHER INFORMATION

Encyclopedia of Life Sciences

hypothalamus

peptide neurotransmitters and hormones

sleep

sleep disorders

Glossary

OPEN-SYSTEM ANALYSIS

Analysis of all the mRNAs that are expressed by a tissue without regard to whether the mRNAs have previously been identified. The contrasting approach is to measure the expression of known mRNAs, as is done in cDNA array (chip) studies.

MASS SPECTROMETRY

A technique in which a compound is bombarded with an electron beam of sufficient energy to fragment the molecule. The cations that are produced are accelerated in a vacuum through a magnetic field, and sorted on the basis of mass-to-charge ratio. The ratio is roughly equivalent to the molecular weight of the fragment.

CIRCULARLY PERMUTED

The rearrangement of a string of nucleotides or amino acids in which all elements of the string maintain their orientation and immediate neighbours, except for those elements that were at the ends of the string before the rearrangement and those that form the new ends, as if the string had formed a circle and then opened at a different point. At the genetic level, this process is thought to occur by gene duplications to form a tandem structure, followed by deletions from opposite ends of the tandem.

TETRODOTOXIN

A potent marine neurotoxin that blocks voltage-gated sodium channels. Tetrodotoxin was originally isolated from the tetraodon pufferfish.

C-FOS

An immediate early gene that is rapidly turned on when many types of neuron increase their activity. It can therefore be used to identify responsive neurons.

PENETRANCE

The proportion of genotypically mutant organisms that show the mutant phenotype. If all genotypically mutant individuals show the mutant phenotype, then the genotype is said to be completely penetrant.

SAPORIN TARGETING

Saporin is a ribosome-inactivating toxin. When coupled to Hcrt2 and administered locally, the conjugate targets and kills neurons bearing hypocretin receptors.

DOMINANT NEGATIVE

Describes a mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

SET POINT

In a homeostatically regulated phenomenon, the set point is the value that the system strives to maintain; for example, a body weight set point.

ALLOSTASIS

The maintenance of stability at any level outside the normal range is achieved by varying the internal milieu to match perceived and anticipated environmental demands. When demands on an individual are chronic, the set point for functioning is altered and might be maintained at that point indefinitely. Although this altered set point might seem appropriate to the conditions, it could be in the pathological range, in that any further perturbation can produce dysregulation.

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Sutcliffe, J., de Lecea, L. The hypocretins: Setting the arousal threshold. Nat Rev Neurosci 3, 339–348 (2002). https://doi.org/10.1038/nrn808

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