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mise à jour du 8 mai 2002
  Nature Reviews Neuroscience
2002; 3; 339-349
 The hypocretins: setting the arousal threshold
J. Gregor Sutcliffe & Luis de Lecea
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,California
 Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat Sato-Suzuki I
Yawning: an evolutionary perspective Smith EO


Preface : 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. Schematic model of neurotransmitter circuits that are involved in the three states of vigilance.
Summary : 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, Hcrtr1and 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 sleepÐwake 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.