Activity Behaviour of Minipigs Transgenic for the Huntington Gene

Abstract

Background: To increase the reliability of translating preclinical findings to humans, large animal models, such as the transgenic (tg) Libechov minipig, were established. As minipigs possess high genetic homology with humans and have similarities in anatomy, physiology and metabolism to humans, they are considered for studying neurodegenerative diseases longitudinally. Recently, sleep abnormalities and changes in circadian rhythm in Huntington's disease (HD) patients were acknowledged to present one of the early symptoms in HD. Objective:The aim of the present study was to explore the activity behaviour of Libechov minipigs and to investigate whether tgHD and wildtype (wt) minipigs exhibit differences in activity behaviour. Furthermore, it was investigated whether activity assessments may serve as reliable endpoints for phenotyping minipigs transgenic for the Huntington gene. Methods: Activity behaviour of minipigs was studied by video recording the stables twice a week over a total study period of five weeks for a cohort of five tgHD minipigs and five wt minipigs. Statistical analysis was performed using the linear mixed model. Once a week, the distances covered by two minipigs in focus (tgHD, wt) were measured using the VideoMotionTracker ® software. Results: Libechov minipigs showed a biphasic pattern of activity, spending most of the time inactive or grubbing in litter. Differences in activity behaviour (rooting, resting and standing) were detected between wt and tgHD minipigs. The influence of the genotype on behavioural patterns was observed during circadian monitoring. TgHD minipigs covered longer distances on average and during every 24 h observation period than wt minipigs. Conclusion: Activity behaviour may be a viable marker for phenotyping minipigs transgenic for the Huntington gene. Video recordings of behavioural patterns provide a non-invasive opportunity to capture potential disease signs. Phenotypic progression including the age of disease manifestation may be explored by documentation of circadian characteristics.

Sleep and Circadian Rhythm Dysfunction in Animal Models of Huntington’s Disease

“…Research using the tgHD rat showed hyperactivity during the dark cycle and more frequent activity during the light cycle [22], suggesting circadian dysregulation. In the transgenic HD pig, one study showed that there is more frequent rooting activity in HD minipigs than in wildtype minipigs [55] that was consistent with a result indicating that during the daytime, transgenic HD minipigs rested less than wildtype minipigs [10].…”

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

“…HD patients often exhibit sleep and circadian disruptions before the onset of motor and cognitive symptoms (Colwell, 2021;Fifel & Videnovic, 2020). Similar disruption in the activity rhythms have been documented in a range of models including sheep (Morton et al, 2014), mini-pigs (Rieke et al, 2019), rodents (Bode et al, 2009;Gu et al, 2022;Kudo et al, 2011;Loh et al, 2013;Morton et al, 2005;Oakeshott et al, 2011;Woodard et al, 2017), and even Drosophila (Faragó et al, 2019;Xu et al, 2019). One limitation of activity measures is that the deficits in the rhythms could be driven by motor dysfunction, thus it is important to also demonstrate the HD-driven deficits using physiological measures.…”