What's wrong with my mouse cage? Methodological considerations for modeling lifestyle factors and gene-environment...

The mechanistic understanding of lifestyle contributions to disease has been largely driven by work in laboratory rodent models using environmental interventions. These interventions show an array of methodologies and sometimes unclear collective conclusions, hampering clinical interpretations. Here we discuss environmental enrichment, exercise and stress interventions to illustrate how different protocols can affect the interpretations of environmental factors in disease. We use Huntington's disease (HD) as an example because its mouse models exhibit excellent validity and HD was the first genetic animal model in which environmental stimulation was found to be beneficial. We make a number of observations and recommendations. Firstly, environmental enrichment and voluntary exercise generally show benefits across laboratories and mouse models. However, the extent to which these environmental interventions have beneficial effects depends on parameters such as the structural complexity of the cage in the case of enrichment, the timing of the intervention and the nature of the control conditions. In particular, clinical interpretations should consider deprived control living conditions and the ethological relevance of the enrichment. Secondly, stress can have negative effects on the phenotype in mouse models of HD and other brain disorders. When modeling stress, the effects of more than one type of experimental stressor should be investigated due to the heterogeneity and complexity of stress responses. With stress in particular, but ideally in all studies, both sexes should be used and the randomized group sizes need to be sufficiently powered to detect any sex effects. Opportunities for clinical translation will be guided by the 'environmental construct validity' of the preclinical data, including the culmination of complementary protocols across multiple animal models. Environmental interventions in mouse models of HD provide illustrative examples of how valid preclinical studies can lead to conclusions relevant to clinical populations.