Orexin gene transfer into the amygdala suppresses both spontaneous and emotion-induced cataplexy in orexin-knockout mice

• Published in: The European journal of neuroscience Vol. 43; no. 5; pp. 681 - 688
• Main Authors: Liu, Meng, Blanco-Centurion, Carlos, Konadhode, Roda Rani, Luan, Liju, Shiromani, Priyattam J.
• Format: Journal Article
• Language: English
• Published: France Blackwell Publishing Ltd 01.03.2016
• Subjects: amygdala; Amygdala - metabolism; Amygdala - physiology; Animals; Cataplexy - metabolism; Cataplexy - therapy; emotion; Emotions; Female; Genetic Therapy; Male; Mice; Mice, Inbred C57BL; narcolepsy; orexin; Orexins - genetics; Orexins - metabolism; predator odour; sleep; Sleep, REM; sleep; amygdala; emotion; orexin; predator odour; narcolepsy
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.13158

Narcolepsy is a chronic sleep disorder linked to the loss of orexin‐producing neurons in the hypothalamus. Cataplexy, a sudden loss of muscle tone during waking, is an important distinguishing symptom of narcolepsy and it is often triggered by strong emotions. The neural circuit underlying cataplexy attacks is not known, but is likely to involve the amygdala, a region implicated in regulating emotions. In mice models of narcolepsy, transfer of the orexin gene into surrogate neurons has been successful in ameliorating narcoleptic symptoms. However, it is not known whether this method also blocks cataplexy triggered by strong emotions. To examine this possibility, the gene encoding mouse prepro‐orexin was transferred into amygdala neurons of orexin‐knockout (KO) mice (rAAV‐orexin; n = 8). Orexin‐KO mice that did not receive gene transfer (no‐rAAV; n = 7) or received only the reporter gene (rAAV‐GFP; n = 7) served as controls. Three weeks later, the animal's sleep and behaviour were recorded at night (no‐odour control night), followed by another recording at night in the presence of predator odour (odour night). Orexin‐KO mice given the orexin gene transfer into surrogate amygdala neurons had significantly less spontaneous bouts of cataplexy, and predator odour did not induce cataplexy compared with control mice. Moreover, the mice with orexin gene transfer were awake more during the odour night. These results demonstrate that orexin gene transfer into amygdala neurons can suppress both spontaneous and emotion‐induced cataplexy attacks in narcoleptic mice. It suggests that manipulating amygdala pathways is a potential strategy for treating cataplexy in narcolepsy. Cataplexy is an important distinguishing symptom of narcolepsy and it is often triggered by strong emotions. Here we transferred orexin gene into amygdala neurons of orexin knockout mice. Three weeks later, mice were exposed to predator odor coyote urine and the animal's sleep and behavior were recorded. Results demonstrated that orexin gene transfer into amygdala neurons can suppress both spontaneous and emotion‐induced cataplexy attacks in narcoleptic mice. It suggests that manipulating amygdala pathways is a potential strategy for treating cataplexy in narcolepsy.