Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington’s Disease
Huntington’s disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep–wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep–wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.
KeywordsOrexin 1 and 2 receptor antagonist Sleep Beta activity Cognitive deficits R6/1 mice
We thank Nicolas Mallet for his valuable help with preliminary experiment and Elodie Poinama and Nathalie Argenta for R6/1 mouse production, and Gill Courtand for help with image processing of immunofluorescence data.
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This work was supported by Hereditary Disease Foundation to YHC.
Compliance with Ethical Standards
All experimental procedures were approved by the Institutional Animal Care and Use Committee, Comité d’Ethique pour l’Expérimentation Animale Bordeaux, and were in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC).
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