Sex-related differences within sleep-wake dynamics, cataplexy, and EEG fast-delta power in a narcolepsy mouse model

Narcolepsy type 1 (NT1) is a sleep-wake disorder caused by selective loss of hypocretin (HCRT, also called orexin) neurons. Although the prevalence of NT1 is equal in men and women, sex differences in NT1 symptomatology have been reported in humans and other species. Yet, most preclinical studies fail to include females, resulting in gender bias within translational drug development. We used hcrt-tTA;TetO DTA mice (NT1 mice) that lose their HCRT neurons upon dietary doxycycline removal to examine in detail the effect of sex on NT1 symptoms and sleep-wake characteristics. We recorded 24-h electroencephalography (EEG), electromyography (EMG), and video in adult male and female NT1 mice for behavioral state quantification. While conducting this study, we recognized another type of behavioral arrest different from cataplexy: shorter lasting and with high δ power. We termed these delta attacks and propose a set of criteria for quantifying these in future research. Our findings show that both sexes exhibit high behavioral state instability, which was markedly higher in females with more behavioral arrests interrupting the wake episodes. Females exhibited increased wake at the expense of sleep during the dark phase, and decreased rapid eye movement (REM) sleep during the 24-h day. During the dark phase, fast-δ (2.5-4 Hz) in non-rapid eye movement (NREM) sleep and θ (6-10 Hz) EEG spectral power in REM sleep were lower in females compared to males. We demonstrate that biologically driven sex-related differences exist in the symptomatology of NT1 mice which calls for including both sexes in future research.