Effects of sex and estrous cycle on sleep and cataplexy in narcoleptic mice

Abstract

Abstract Narcolepsy type 1 (NT1) is a rare neurology disorder caused by the loss of orexin/hypocretin neurons. NT1 is characterized by excessive daytime sleepiness, sleep and wake fragmentation, and cataplexy. These symptoms have been equally described in both women and men, although influences of gender and hormonal cycles have been poorly studied. Unfortunately, most studies with NT1 preclinical mouse models, use only male mice to limit potential variations due to the hormonal cycle. Therefore, whether gender and/or hormonal cycles impact the expression of narcoleptic symptoms remains to be determined. To address this question, we analyzed vigilance states and cataplexy in 20 female and 17 male adult orexin knock-out narcoleptic mice, with half of the females being recorded over multiple days. Mice had access to chocolate to encourage the occurrence of cataplectic episodes. A vaginal smear was performed daily in female mice to establish the state of the estrous cycle (EC) of the previous recorded night. We found that vigilance states were more fragmented in males than females, and that females had less paradoxical sleep (p = 0.0315) but more cataplexy (p = 0.0375). Interestingly, sleep and wake features were unchanged across the female EC, but the total amount of cataplexy was doubled during estrus compared to other stages of the cycle (p = 0.001), due to a large increase in the number of cataplexy episodes (p = 0.0002). Altogether these data highlight sex differences in the expression of narcolepsy symptoms in orexin knock-out mice. Notably, cataplexy occurrence was greatly influenced by estrous cycle. Whether it is due to hormonal changes would need to be further explored.