Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice

Cataplexy,asudden unexpected muscle paralysis,is a debilitating symptomofthe neurodegenerative sleep disorder, narcolepsy. During these attacks, the personisparalyzed, but fully conscious and awareoftheir surroundings.Toidentify potential neurons that might serve as surrogate orexin neurons to suppress such attacks, the gene for orexin (hypocretin), a peptide lost in most human narcoleptics, was delivered into the brains of the orexin-ataxin-3 transgenic mouse model of human narcolepsy. Three weeks after the recombinant adenoassociated virus (rAAV)-mediated orexin gene transfer, sleep-wake behavior was assessed. rAAV-orexin gene delivery into neurons of the zona incerta (ZI), or the lateral hypothalamus (LH) blocked cataplexy. Orexin gene transfer into the striatum or in the melanin-concentrating hormone neuronsin the ZI or LH hadno such effect, indicating site specificity. Intransgenic mice lacking orexin neurons butgivenrAAV-orexin, detectable levelsoforexin-A wereevidentintheCSF, indicating releaseofthe peptidefrom the surrogate neurons. Retrograde tracer studies showed that the amygdala innervates the ZI consistent with evidence that strong emotions trigger cataplexy. In turn, the ZI projects to the locus ceruleus, indicating that the ZI is part of a circuit that stabilizes motor tone. Our results indicate that these neurons might also be recruited to block the muscle paralysis in narcolepsy.