Monitoring the activity of mice within their home cage is proving to be a powerful tool for revealing subtle and early-onset phenotypes in mouse models. Video-tracking, in particular, lends itself to automated machine-learning technologies that have the potential to improve the manual annotations carried out by humans. This type of recording and analysis is particularly powerful in objective phenotyping, monitoring behaviors with no experimenter intervention. Automated home-cage testing allows the recording of non-evoked voluntary behaviors, which do not require any contact with the animal or exposure to specialist equipment. By avoiding stress deriving from handling, this approach, on the one hand, increases the welfare of experimental animals and, on the other hand, increases the reliability of results excluding confounding effects of stress on behavior. In this study, we show that the monitoring of climbing on the wire cage lid of a standard individually ventilated cage (IVC) yields reproducible data reflecting complex phenotypes of individual mouse inbred strains and of a widely used model of neurodegeneration, the N171-82Q mouse model of Huntington’s disease (HD). Measurements in the home-cage environment allowed for the collection of comprehensive motor activity data, which revealed sexual dimorphism, daily biphasic changes, and aging-related decrease in healthy C57BL/6J mice. Furthermore, home-cage recording of climbing allowed early detection of motor impairment in the N171-82Q HD mouse model. Integrating cage-floor activity with cage-lid activity (climbing) has the potential to greatly enhance the characterization of mouse strains, detecting early and subtle signs of disease and increasing reproducibility in preclinical studies.

Monitoring the activity of mice within their home cage is proving to be a powerful tool for revealing subtle and early-onset phenotypes in mouse models. Video tracking, in particular, lends itself to automated machine-learning technologies that have the potential to improve the manual annotations carried out by humans. This type of recording and analysis is particularly powerful in objective phenotyping, monitoring behaviors with no experimenter intervention. In this study, we focus on non-evoked voluntary behaviors, which do not require any contact with the animal or exposure to specialist equipment. We show that the monitoring of climbing on the wire cage lid of a standard individually ventilated cage (IVC) yields reproducible data reflecting complex phenotypes of individual mouse inbred strains and of a widely used mouse model of neurodegeneration. In addition, performing such measurements in the home-cage environment, over several 24-hour periods, allows for the collection of comprehensive behavioral and activity data, which reveals prolific sexual dimorphism and biphasic changes in locomotor activity. Here we present data from home-cage analysis, which reveals the complexity of unprovoked behavior in both wild-type and mutant mice. This has the potential to greatly enhance the characterization of mouse strains, detect early and subtle signs of disease and increase reproducibility in preclinical studies.

FUS (Fused in sarcoma) is a ubiquitously expressed RNA binding protein, which is mislocalized and aggregated in some forms of frontotemporal dementia (FTD), whilst mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. Most studies have focused on the role of FUS in motor neuron degeneration, although it is unknown whether FUS mutations affect other cell and tissue types, and the neurodevelopmental impact of FUS mutation on the nervous system is unclear. Here we studied pleiotropic phenotypes in a physiological knock-in mouse model carrying a partially humanised FUSDelta14 mutation in homozygosity. We performed RNA sequencing of six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) and found that the genes and pathways affected were generally tissue-specific and showed few commonalities. Phenotypic assessment of homozygous FUSDelta14 mice revealed systemic metabolic alterations related to the pathway changes identified. Homozygous FUSDelta14 brains displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with fatal seizures in early adult life. Altogether, our data supports a wide-ranging role for FUS, and suggests that the disease aetiology of FUS mutation can include developmental and pleiotropic phenotypes.