Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington’s Disease

• Published in: Neurotherapeutics 2019-07, Vol.16 (3), p.784-796
• Main Authors: Cabanas, Magali, Pistono, Cristiana, Puygrenier, Laura, Rakesh, Divyangana, Jeantet, Yannick, Garret, Maurice, Cho, Yoon H.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Azepines - therapeutic use; Biomedical and Life Sciences; Biomedicine; Body weight; Circadian rhythms; Cognitive ability; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - etiology; Disease Models, Animal; Female; Huntington Disease - drug therapy; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurobiology; Neurology; Neurosciences; Neurosurgery; Orexin Receptor Antagonists - therapeutic use; Orexins; Orexins - antagonists & inhibitors; Orexins - metabolism; Orexins - physiology; Original; Original Article; Sleep; Sleep and wakefulness; Sleep Disorders, Circadian Rhythm - drug therapy; Sleep Disorders, Circadian Rhythm - etiology; Triazoles - therapeutic use
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-019-00726-3

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.