A Commentary on the Neurobiology of the Hypocretin/Orexin System

Abstract

Rarely in the history of medicine has scientific discovery moved so quickly from the report of a neurotransmitter system to a disease pathophysiology (Mignot 2001). In 1998, two groups independently identified the same neuropeptide system and called the molecules "hypocretins" and "orexins" respectively (de Lecea et al. 1998;Sakurai et al. 1998). One of the most striking findings of these initial studies was the discrete localization of hypocretin-containing cells within a very discrete region of the lateral hypothalamus. This led one group to call this peptide system "hypocretin", a term derived from hypo thalamus and se cretin (a weak-and contested-homology with secretin was noted by these authors). The established role of the perifornical region in the regulation of appetite, together with the observation that intracerebroventricular injections of the peptides induced food intake in rats, led the other group to coin the term "orexin" (orexis ϭ appetite) for this system.The discovery in 1999 that canine narcolepsy was caused by mutations in the Hypocretin receptor 2 (Hcrtr2) gene is shifting the research emphasis from appetite control to sleep regulation (Lin et al. 1999). This finding was followed by the observation that hypocretin knockout mice have sleep and behavioral abnormalities reminiscent of narcolepsy (Chemelli et al. 1999). Other studies have indicated dense projections to all monoaminergic cell groups and wake-promoting effects of hypocretins when administered centrally (Hagan et al. 1999). More recently, clinical studies have shown that most patients with narcolepsy have undetectable hypocretins in the CSF and a striking decrease in hypocretin immunoreactivity and transcript levels in the perifornical hypothalamus Thannickal et al. 2000). The most fre- quent cause of human narcolepsy is now known to be hypocretin deficiency, most probably as the result of an autoimmune attack against hypocretin-containing cells. In this commentary, I will briefly review the current knowledge regarding this system, speculate on its possible function in sleep regulation and discuss the potential importance of this system for neuropsychiatry. HYPOCRETIN/OREXINS: NEURONATOMY AND RECEPTOR SYSTEMSThe description of this system has been the object of multiple recent reviews ( Kilduff and Peyron 2000;Sutcliffe and de Lecea 2000;Hungs and Mignot 2001;Overeem et al. 2001;Willie et al. 2001) and will only be briefly outlined. Two biologically active peptides encoded by a single two-exon precursor gene, the preprohypocretin (Hcrt) locus, have been described. The precursor gene contains a signal peptide sequence, followed by a first active peptide, hypocretin-1 (or orexin-A), a second active peptide, hypocretin-2 (or orexin-B) and a C-terminal section of unknown biological activity. Endopeptidic cleavage occurs at typical dibasic residue sequences located between the hypocretin peptides and at the C-terminal of the hypocretin-2 sequence. The hypocretin-1 and hypocretin-2 regions but not the C-terminal region of the precursor ...

Perchance to dream: Solving the mystery of sleep through genetic analysis

“…Hypocretin containing cells are localized to a small portion of the lateral hypothalamus but send diffuse projections throughout the brain including areas implicated in the control of sleep and waking such as the locus coeruleus LDT/PPT (Burlet et al, 2002), nucleus pontis oralis (Xi et al, 2002), basal forebrain (Espana et al, 2001), and tuberomammillary neurons (Eriksson et al, 2001), to name a few. As stated above, disrupting hypocretin results in symptoms of narcolepsy in the mouse, dog, and humans (see Mignot, 2001 for more detailed review). Human narcolepsy is characterized by a constellation of symptoms including excessive daytime sleepiness, hypnagogic hallucinations, disturbed nocturnal sleep, cataplexy, and sleep paralysis affecting approximately 1 in 2000 people (Guilleminault, 1994).…”

Immunoreactivity of Hypothalamic Orexin-Containing Neurons in Rats in Movement Restriction and Cooling

“…Несмотря на ýто, до недавнего вре-мени механизмы развития ýтой формы патологии оставались неизвестными. Исследование системы орексин-содержащих нейронов гипоталамуса и установление их роли в развитии нарколепсии явилось самым значимым открытием в ýтой об-ласти после открытия фазы быстрого сна [6]. Попытки исследователей установить причины на-рушений функции системы орексин-содержащих нейронов гипоталамуса привели к появлению нескольких возможных теорий о патогенезе ýто-го заболевания.…”

Hepatic Encephalopathy and Sleepiness: An Interesting Connection?

“…10 Finally, the peptide hypocretin/ orexin is considered to be a major wake-promoting hypothalamic neuropeptide and a hypocretin/orexin deficiency has been documented in human narcolepsy. 11 Sleepiness is reported as a problem by 10-25% of the population, depending on the definition utilized and the population studied. 2 The clinical significance of an individual's complaint of excessive sleepiness, and thus the definition of the difference between physiological and pathological sleepiness may not be obvious.…”