Lessons From Sleepy Mice: Narcolepsy and the Orexin Neuropeptide System

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.