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.

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…Remarkably, this ectopic orexin expression was not associated with a reduction in hypersomnolence, sleep attacks, or any detectable changes in sleep architecture, indicating that activity of the zona incerta has a specific role in stabilizing motor tone that is typically disrupted in cataplectic attacks. Retrograde tracer mapping found these neurons to receive inputs from the amygdala and to innervate the locus ceruleus, suggesting a possible pathway connecting emotional state with muscle paralysis associated with REM sleep (Liu et al, 2011). Together, these studies begin to round out our understanding of the role of orexin signaling in narcolepsy/cataplexy and, in so doing, its function in arousal and vigilance state.…”

“…In Ox/Atx mice, the prevalence of behavioral arrest episodes was attenuated by adenoassociated virus-mediated expression of prepro-orexin selectively in the zona incerta region of the hypothalamus (Liu et al, 2011). Remarkably, this ectopic orexin expression was not associated with a reduction in hypersomnolence, sleep attacks, or any detectable changes in sleep architecture, indicating that activity of the zona incerta has a specific role in stabilizing motor tone that is typically disrupted in cataplectic attacks.…”

Phylogeny in Sleep Medicine

“…Gene replacement therapy in orexin-deficient mice restores sleep consolidation and the timing of REM sleep, but does not improve cataplexy [74], whereas gene transfer into the zona incerta in orexin-deficient mice improved cataplexy, but did not improve sleep fragmentation [75]. In humans, an orexin antagonist has recently been demonstrated to improve sleep in insomniac humans [76].…”

Recent progress in orexin/hypocretin physiology and pharmacology

“…(29) and (40 -42) ]. Short-term genetic manipulation with transgene expression (35,43) or siRNA (44) has been applied even in intact animals, often by viral delivery.…”

“…On the other hand, selective OX 2 block has been suggested to be more benefi cial for sleep induction than dual block (21) . The selective postnatal loss of orexinergic neurons in PPO-pro-ataxin-3 mice and rats causes a strong narcoleptic phenotype (36,37) , which can be ameliorated by ectopic PPO overexpression (38,43) . Restoration of OX 2 receptor expression in the posterior hypothalamus (including tuberomamillary nucleus) reverses the sleepiness in conditionally reversible OX 2 -ko mice (65) .…”