Lessons From Sleepy Mice: Narcolepsy and the Orexin Neuropeptide System

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Title: Lessons From Sleepy Mice: Narcolepsy and the Orexin Neuropeptide System
Author: Willie, Jon Timothy
Abstract: The hypothalamic orexin neuropeptide system is a neuronal pathway regulating behavioral vigilance states and metabolic functions . Orexins activate the orexin receptors type 1 and type 2 (OX2R ) . Melanin -concentrating hormone (MCH ) is an anatomically -related peptide that may have complementary functions . Orexin null (orexin - / - ) mice exhibit a behavioral and electroencephalographic phenotype similar to narcolepsy -cataplexy , a neurological disorder caused by orexin deficiency . Narcolepsy -cataplexy consists of inability to maintain wakefulness , abnormal intrusions of rapid -eye -movement (REM ) sleep and related phenomena (i .e . cataplexy ) into wakefulness , and poorly characterized metabolic abnormalities . I demonstrate that both OX2R - / - and orexin - / - mice are unable to maintain wakefulness normally . In contrast , OX2R - / - mice are only mildly affected with abnormalities of REM sleep , whereas orexin - / - mice are severely affected . Thus , the profound dysregulation of REM sleep control unique to the narcolepsy -cataplexy syndrome emerges from loss of signaling through both OX2R -dependent and OX2R -independent pathways . Transgenic mice , in which orexin neurons are ablated , fail to respond normally to fasting with increased wakefulness and activity indicating that orexin neurons provide a crucial link between energy balance and arousal . Orexin - / - and MCH - / - mice have increased and decreased adiposity and susceptibility to diet -induced obesity , respectively . While orexin - / - mice exhibit sleepiness and cataplexy , MCH - / - mice are more wakeful than wild -type mice . Orexin - / - ;MCH - / - exhibit exacerbation of the narcolepsy phenotype , indicating that orexin and MCH complementarily regulate behavioral stabilty . Mice that ectopically overexpress orexin in the brain exhibit reduced body weight and resistance to diet -induced obesity , inability to maintain sleep , and reduced REM sleep with abnormal myoclonic activity relative to wild -type controls , providing further evidence that orexin alters homeostatic set -points of both energy metabolism and sleep /wakefulnuss . Modafinil , a stimulant used to treat narcoleptics , effectively increases wakefulness but does not suppress cataplexy in orexin - / - mice , indicating that orexin is not required for the wake -promoting action of the drug . By contrast , expression of an orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of REM sleep in the absence of endogenous orexin neurons . Thus , orexin neuron -ablated mice retain the ability to respond to orexin neuropeptides and orexin receptor agonists would likely contribute to treating human narcolepsy .
URI: http : / /hdl .handle .net /2152 .5 /699
Date: 2005-04-29

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Lessons From Sleepy Mice: Narcolepsy and the Orexin Neuropeptide System. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /699 .

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