Elsevier

The Lancet Neurology

Volume 4, Issue 10, October 2005, Pages 673-682
The Lancet Neurology

Review
Hypocretins (orexins) and sleep–wake disorders

https://doi.org/10.1016/S1474-4422(05)70196-4Get rights and content

Summary

Since their discovery in 1998, the hypocretins (orexins)—peptides that are produced by a group of neurons situated in the posterolateral hypothalamus—have been shown to excite many CNS areas including many neuronal systems that regulate sleep and wakefulness. Animal studies indicate that hypocretins play a part in the regulation of various functions including arousal, muscle tone, locomotion, regulation of feeding behaviour, and neuroendocrine and autonomic functions. A link between hypocretin deficiency and narcoleptic symptoms was first shown in canine and rodent models of narcolepsy. Hypocretin deficiency, as shown by low or absent concentrations in CSF, was subsequently found in 90% of patients with sporadic narcolepsy-cataplexy, and less commonly in familial narcolepsy. In most other sleep–wake and neurological disorders, hypocretin concentrations are normal. Low concentrations were also found in hypothalamic disorders, acute traumatic brain injury, and a few other disorders. The exact function of the hypocretin system in sleep–wake regulation and its pathophysiological role in hypocretin-deficient and non-deficient narcolepsy as well as in non-narcoleptic, hypocretin-deficiency syndromes remain unclear.

Introduction

In 1998, two independent research groups simultaneously discovered two new neurotransmitter peptides: hypocretin-1 (orexin A) and hypocretin-2 (orexin B). One group observed an appetite-stimulating effect of these peptides and coined the term orexin, derived from the Greek word orexis (appetite).1 The other group suggested the name hypocretin, given its hypothalamic origin and structural similarity with the secretin family.2 In this review, we will use the term hypocretin.

Studies in rodents, dogs, and human beings revealed an involvement of hypocretins in a wide range of functions including sleep–wake, neuroendocrine, locomotor, autonomic regulation, feeding behaviour, and energy homoeostasis. In 2000, a strong association between hypocretin deficiency and narcolepsy-cataplexy was found.3 Subsequent studies, although confirming this association, showed the existence of other hypocretin-deficient disorders such as hypothalamic damage, acute traumatic brain injury, Guillain-Barré syndrome, and a few others.

In this review, we will discuss the role of hypocretins in sleep–wake regulation and its involvement in narcolepsy as well as in other sleep–wake and neurological disorders.

Section snippets

Mechanisms of sleep–wake control

The alternation of wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep is associated with distinct firing patterns of thalamocortical and corticothalamic neurons. Several brain regions (mainly in the brainstem and basal forebrain) are involved in modulating the activity of these neurons. Brainstem neurons in the laterodorsal/pedunculopontine tegmental area (LDT/PPT; acetylcholine), locus coeruleus (norepinephrine), dorsal raphe nucleus (serotonin), ventral

Anatomy

Hypocretin neurons are almost exclusively located in the posterior and lateral hypothalamus.1, 2 Their dendrites secrete excitatory hypocretin peptides (hypocretin 1 and hypocretin 2), which interact with two receptors (HCRTR1 and HCRTR2, also called OX1R and OX2R). The receptors have different distributions and functions in the CNS.10, 11, 12, 13, 14 HCRTR1 is found in the hypothalamus, ventral tegmental area, dorsal raphe nucleus, locus coeruleus, and hippocampus, and interacts mainly with

Rodents

Hypocretin-ligand knockout mice, hypocretin-receptor knockout mice, as well as mice with genetic ablation of hypocretin neurons (ataxin-3 model) show fragmented behavioural states and episodes of sudden behavioural arrest, a phenotype reminiscent of human narcolepsy with cataplexy.51, 52, 53 Transgenic rats expressing a polyglutamine-ataxin-3 fragment in hypocretin neurons present a selective postnatal loss of hypothalamic hypocretin-positive neurons and cataplexy-like episodes with abnormal

Hypocretin system and other sleep–wake disorders

In other sleep–wake disorders such as idiopathic hypersomnia, recurrent hypersomnia, sleep apnoea, post-traumatic hypersomnia, familial fatal insomnia, and restless legs syndrome, CSF hypocretin-1 concentrations are normal in most tested patients.64, 65, 66, 67, 93, 97, 98, 99 In a meta-analysis, we found low CSF hypocretin-1 concentrations in four (8%) of 53 patients with idiopathic hypersomnia, in one (3%) of 31 patients with obstructive sleep apnoea, and in none of 23 patients with

Hypocretin and other neurological disorders

In most non-narcoleptic neurological patients tested, CSF hypocretin-1 concentrations are normal.65, 110 However, in a few disorders, patients have low or undetectable hypocretin concentrations. CSF hypocretin-1 concentrations were low or undetectable in 95% of consecutive patients with acute severe or moderate traumatic brain injury, irrespective of lumbar versus spinal origin of CSF.111 This study confirmed earlier preliminary results from Ripley and colleagues,110 who reported low

Conclusions

Excitatory hypocretin neurons are situated in the posterolateral hypothalamus and project to monoaminergic, cholinergic, and GABAergic neurons. In turn, hypocretin-neuron activity is modulated by excitatory and inhibitory inputs from these systems. Hypocretin neurons are involved in many different functions, including maintenance of wakefulness, sleep–wake cycle, regulation of muscle tone and locomotion, and neuroendocrine and autonomic mechanisms. Overall, the hypocretin system is thought to

Search strategy and selection criteria

References for this review were identified by searches of MEDLINE between 1971 and July 2005, from references in relevant articles, and by searches of the authors' files. The search terms were “hypocretin”, “orexin”, “neurotransmitter”, “sleep-wake regulation”, “narcolepsy”, and “hypersomnia”. Abstracts and reports from meetings were also included. Only papers published in English were reviewed. The final reference list was generated on originality and relevance to the topics covered in

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