Longitudinal Characterization of Diurnal Rhythms of Activity and Core Body Temperature in the zQ175 Knock-in Mouse Model of Huntington’s Disease: Genotype and Sex Interactions

Abstract

Huntington’s disease (HD) is a progressive, dominantly-inherited neurodegenerative disorder with no effective treatment. Understanding the pathophysiological alterations that occur in HD, particularly in the premanifest stage, is critical to target interventions prior to significant neuronal loss. The zQ175 HD model is a novel knock-in mouse containing an expanded CAG repeat sequence within the native murine huntington gene that more closely replicates the genetic context of HD patients. Here, we report preliminary data characterizing longitudinal changes in activity and core body temperature (Tb) across disease progression. At 5-6 wks of age, homozygous (HOM), heterozygous (HET) and wildtype (WT) male and female zQ175 mice (n=8-12) were implanted for EEG/EMG recordings along with telemeters for the recording of activity and Tb. Once recovered from surgery, Tb and activity were recorded continuously from the home cage environment under a 12:12 LD cycle until 50 weeks of age. Sleep deprivations of 1, 3 and 6 hour durations were performed at 8, 12, 16, 24, 32 and 48 wks of age. Body weight was measured biweekly as an indicator of health status. In both sexes, body weight was less in HET and HOM mice compared to WT, an effect that increased with age, and occurred earlier in HOM mice. Relative to WT, body weight at 48 wks was 26.4% and 41.7% lower in male and 12.6% and 22.2% lower in female HET and HOM mice, respectively. At 8 wks, there were no genotypic differences in the activity profiles of male zQ175 mice. By 12 wks, average dark period activity in HOM mice decreased relative to WT and was 25.8% less at 48 wks of age. Deficits in activity were also present in female HOM mice and, at 48 wks, average dark period activity was attenuated by 57.4% and 46.9% vs. WT and HET mice, respectively. Changes in Tb in HOM mice during the dark period paralleled activity levels and also decreased with age. Average Tb at 48 wks decreased by 0.55°C vs. WT in male, and by 0.87°C in female HOM mice. No difference in average dark period Tb was apparent between WT and HET mice of either sex at this age. Sleep deprivation led to dramatic increases in activity and Tb in all genotypes; however, these responses were attenuated in HET and HOM mice from 16 wks. These initial findings demonstrate that mutant huntingtin expression in this model causes progressive motor and thermoregulatory deficits with significant genotype and sex differences. Ongoing analyses of sleep/wake rhythms and EEG biomarkers of disease progression in zQ175 mice will be useful to determine the potential of this model in preclinical drug development