History and perspectives of hypocretin/orexin research in sleep medicine

Abstract

By using forward and reverse genetics, genes involved in the pathogenesis of narcolepsy (hypocretin/orexin ligand and its receptor) in animals have been identified. Mutations in hypocretin‐related genes are extremely rare in humans, but hypocretin ligand deficiency is found in many cases. A series of these discoveries are representing the most striking progress in narcolepsy research in the last 100 years, and should continue to contribute to the development of new diagnostic tests and treatments. Impacts of the hypocretin system on sleep physiology have also rapidly increased. Hypocretins/orexins are novel hypothalamic neuropetides discovered outside the sleep research field by using subtractive polymerase chain reaction/reverse pharmacology techniques. Hypocretins are involved in various fundamental hypothalamic functions such as feeding, energy homeostasis and neuroendocrine regulation. Hypocretin neurons project to most ascending arousal systems (including monoaminergic and cholinergic systems), and generally exhibit excitatory inputs. Together with the recent finding of the sleep promoting system in the hypothalamus, especially in the γ‐amynobutyric acid (GABA)/Galanin ventrolateral preoptic area, which exhibits inhibitory inputs to these ascending systems, the hypothalamus is now recognized as the most important brain site for the sleep switch. Meanwhile, narcolepsy now appears to be a more complex condition than previously thought. The pathophysiology of the disease is involved in the abnormalities of sleep and various hypothalamic functions caused by the hypocretin deficiency, such as the changes in energy homeostasis. Narcolepsy is thus an important model to study the fundamental hypothalamic function and the links between sleep regulation, energy homeostasis and/or feeding.

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

“…Since then, several studies on the association between hypocretin and sleep-regulation have been published. [131][132][133][134][135] Hypocretin signaling is crucial for maintaining wakefulness and regulating REMS. However, it is not required to generate (REM) sleep or wakefulness, as narcoleptic patients still show these vigilance states.…”