PT - JOURNAL ARTICLE AU - Meng Liu AU - Carlos Blanco-Centurion AU - RodaRani Konadhode AU - Suraiya Begum AU - Dheeraj Pelluru AU - Dmitry Gerashchenko AU - Takeshi Sakurai AU - Masashi Yanagisawa AU - Anthony N. van den Pol AU - Priyattam J. Shiromani TI - Orexin Gene Transfer into Zona Incerta Neurons Suppresses Muscle Paralysis in Narcoleptic Mice AID - 10.1523/JNEUROSCI.6069-10.2011 DP - 2011 Apr 20 TA - The Journal of Neuroscience PG - 6028--6040 VI - 31 IP - 16 4099 - http://www.jneurosci.org/content/31/16/6028.short 4100 - http://www.jneurosci.org/content/31/16/6028.full SO - J. Neurosci.2011 Apr 20; 31 AB - Cataplexy, a sudden unexpected muscle paralysis, is a debilitating symptom of the neurodegenerative sleep disorder, narcolepsy. During these attacks, the person is paralyzed, but fully conscious and aware of their surroundings. To identify 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 neurons in the ZI or LH had no such effect, indicating site specificity. In transgenic mice lacking orexin neurons but given rAAV-orexin, detectable levels of orexin-A were evident in the CSF, indicating release of the peptide from 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.