Sex Differences in Sleep Phenotypes in the BACHD Mouse Model of Huntington's Disease

Sleep and circadian rhythm disturbances are common features of Huntingtons disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies as well as preclinical work indicate there may be sex differences in disease progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s), we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in sleep/wake cycles are detectable in an animal model of the disease. Electroencephalography/electromyography (EEG/EMG) was used to measure sleep/wake states and polysomnographic patterns in young adult (12 week-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age and sex matched wild-types. For both Rapid-eye movement (REM) and Non-rapid eye movement (NREM) sleep, genotypic and sex differences were detected. In particular, the BACHD males spent less time in NREM and exhibited a more fragmented sleep than the other groups. Both male and female BACHD mice exhibited significant changes in delta but not in gamma power compared to wild-type mice. Finally, in response to a 6-hrs sleep deprivation, both genotypes and sexes displayed predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model. Significance StatementSleep and circadian rhythm disturbances are common features of Huntingtons disease (HD). Using an animal model of HD and EEG measures of sleep, we found that the males were more vulnerable to sleep/wake architecture alterations and sleep fragmentation. Homeostatic recovery from sleep loss did not appear to be altered at this stage of the disease. These findings raise the possibility that sex-specific factors play a role in the HD symptom progression and that hormone-based treatments may have therapeutic utility.