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

Meng Liu, Carlos Blanco-Centurion, Rodarani Konadhode, Suraiya Begum, Dheeraj Pelluru, Dmitry Gerashchenko, Takeshi Sakurai, Masashi Yanagisawa, Anthony N. van den Pol, Priyattam J. Shiromani

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6028-6040
Number of pages13
JournalJournal of Neuroscience
Volume31
Issue number16
DOIs
StatePublished - Apr 20 2011

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Paralysis
Cataplexy
Neurons
Narcolepsy
Muscles
Lateral Hypothalamic Area
Genes
Viruses
Locus Coeruleus
Amygdala
Neurodegenerative Diseases
Transgenic Mice
Zona Incerta
Sleep
Emotions
Peptides
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liu, M., Blanco-Centurion, C., Konadhode, R., Begum, S., Pelluru, D., Gerashchenko, D., ... Shiromani, P. J. (2011). Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. Journal of Neuroscience, 31(16), 6028-6040. https://doi.org/10.1523/JNEUROSCI.6069-10.2011

Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. / Liu, Meng; Blanco-Centurion, Carlos; Konadhode, Rodarani; Begum, Suraiya; Pelluru, Dheeraj; Gerashchenko, Dmitry; Sakurai, Takeshi; Yanagisawa, Masashi; van den Pol, Anthony N.; Shiromani, Priyattam J.

In: Journal of Neuroscience, Vol. 31, No. 16, 20.04.2011, p. 6028-6040.

Research output: Contribution to journalArticle

Liu, M, Blanco-Centurion, C, Konadhode, R, Begum, S, Pelluru, D, Gerashchenko, D, Sakurai, T, Yanagisawa, M, van den Pol, AN & Shiromani, PJ 2011, 'Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice', Journal of Neuroscience, vol. 31, no. 16, pp. 6028-6040. https://doi.org/10.1523/JNEUROSCI.6069-10.2011
Liu M, Blanco-Centurion C, Konadhode R, Begum S, Pelluru D, Gerashchenko D et al. Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. Journal of Neuroscience. 2011 Apr 20;31(16):6028-6040. https://doi.org/10.1523/JNEUROSCI.6069-10.2011
Liu, Meng ; Blanco-Centurion, Carlos ; Konadhode, Rodarani ; Begum, Suraiya ; Pelluru, Dheeraj ; Gerashchenko, Dmitry ; Sakurai, Takeshi ; Yanagisawa, Masashi ; van den Pol, Anthony N. ; Shiromani, Priyattam J. / Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 16. pp. 6028-6040.
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