Sex differences in sleep architecture in a mouse model of Huntington's disease

Abstract

Sleep and circadian rhythm disturbances are common features of Huntington's 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 presentation and 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 sleep and exhibited a more fragmented sleep than the other groups. Finally, in response to 6 h of sleep deprivation, both genotypes and sexes displayed the predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model.

Scheduled feeding improves sleep in a mouse model of Huntington’s disease

“…The male BACHD mice exhibit more severe deficits in activity rhythms and motor coordination than females (Kuljis et al ., 2016). In recent work, we also documented sex differences in the EEG-defined sleep/wake cycle of BACHD mice at 3-months of age (Chiem et al, 2024). We found male BACHD mice exhibited reduced amounts of NREM sleep in the day, a feature which is not seen in the female BACHD.…”

“…Young BACHD mice exhibit modest changes in the EEG spectra compared to WT mice with sex differences also noted (Chiem et al, 2024). To investigate the possible impact of TRF on the EEG spectra, we quantified the power values in the frontoparietal cortical region during NREM sleep.…”

“…While acknowledging these shortcomings, we feel that this mutant provides a model with strong construct and face validity. In a series of studies, we have detailed the progression of sleep, circadian, and cardiovascular deficits along with sex differences in the BACHD model (Kudo et al, 2011;Schroeder et al, 2016;Kuljis et al, 2016;Park et al, 2021;Chiem et al, 2024).…”

“…While acknowledging these shortcomings, we feel that this mutant provides a model with strong construct and face validity. In a series of studies, we have detailed the progression of sleep, circadian, and cardiovascular deficits along with sex differences in the BACHD model (Kudo et al, 2011; Schroeder et al, 2016; Kuljis et al, 2016; 2018; Park et al, 2021; Chiem et al, 2024). These studies demonstrate that these mutants exhibit deficits in core neurodegenerative disorder-related symptoms and encourage our use of this model for circadian-based interventions.…”

“…The R6/2 mouse model of HD exhibits increased activity during the day and sleep fragmentation (Morton et al, 2005; Kantor et al, 2013) and the Q175 model has been shown to display increased wakefulness and decreased NREM sleep during the light phase (Loh et al, 2013; Fisher et al, 2016). In addition, the BACHD mouse model of HD exhibits sleep/wake architecture disruptions (Kudo et al, 2011), with sex differences in these disturbances (Chiem et al, 2024). Overall, there is comprehensive evidence of abnormal electroencephalography (EEG)-defined sleep architecture in mouse (Kantor et al, 2013; Fisher et al, 2013; Lebreton et al, 2015, Fisher et al, 2016) and sheep (Schneider et al, 2021, Vas et al, 2021) models of HD.…”