title: Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice.
abstract: 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.
authors.affiliation: Veterans Affairs Boston Healthcare System and Harvard Medical School, West Roxbury, Massachusetts 02132, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.forename: Carlos
authors.initials: C
authors.lastname: Blanco-Centurion
authors.forename: RodaRani
authors.initials: R
authors.lastname: Konadhode
authors.forename: Suraiya
authors.initials: S
authors.lastname: Begum
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Pelluru
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gerashchenko
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Anthony N
authors.initials: AN
authors.lastname: van den Pol
authors.forename: Priyattam J
authors.initials: PJ
authors.lastname: Shiromani
mesh_terms: D000818:Animals; D002385:Cataplexy / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005838:Genotype; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000235:genetics / Q000628:therapy*; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D000068797:Orexins; D012890:Sleep; D020530:Subthalamus / Q000378:metabolism*
chemical_list: C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins