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

Abstract

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 behavior were recorded at night (no-odor control night), followed by another recording at night in the presence of predator odor (odor night). Orexin-KO mice given the orexin gene transfer into surrogate amygdala neurons had significantly less spontaneous bouts of cataplexy, and predator odor did not induce cataplexy compared to control mice. Moreover, the mice with orexin gene transfer were awake more during the odor 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.

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

“…However, mice with such restoration have demonstrated frequent CLEs (8) in conditions with or without chocolate feeding (Table S5). Because those results suggest that endogenous orexin release in the amygdala cannot alone prevent CLEs, suppressing cataplexy in orexin-deficient mice with the ectopic overexpression of orexin peptides in the amygdala is clinically relevant but perhaps not physiological (37). Similar to our current findings, results of other studies, including our own, have shown that orexin neurons regulate the amygdala indirectly via LC noradrenergic neurons as part of modulating fear learning (38,39).…”

Hypothalamic MCH Neuron Activity Dynamics during Cataplexy of Narcolepsy

“…To synchronize the timestamps of the Ca 2+ imaging with the EEG/EMG, a TTL signal was sent from the nVoke interface console into the Doric console. After 30 min of undisturbed recording, the mouse was exposed to milk (whole milk, 2 mL) for 30 min and coyote urine (1 mL, www.predatorpee.com, Bangor, ME) for 30 min between 5:30 P.M. and 7:00 P.M. (Liu et al, 2016).…”

Orexin supplementation in narcolepsy treatment: A review

“…Cataplexy is a distinguishing symptom of narcolepsy. In animal models, cataplexy can be experimentally elicited by deletion of the orexin gene (orexin‐KO mice), leaving the neurons intact. In these mice, orexin gene transfer to neurons in the lateral hypothalamus using replication‐defective herpes simplex virus 1 (HSV‐1) reduces cataplexy and restores normal sleep‐wake behavior during the 4‐day lifetime of the vector .…”