Gene–environment interactions and construct validity in preclinical models of psychiatric disorders

The contributions of genetic risk factors to susceptibility for brain disorders are often so closely intertwined with environmental factors that studying genes in isolation cannot provide the full picture of pathogenesis. With recent advances in our understanding of psychiatric genetics and environmental modifiers we are now in a position to develop more accurate animal models of psychiatric disorders which exemplify the complex interaction of genes and environment. Here, we consider some of the insights that have emerged from studying the relationship between defined genetic alterations and environmental factors in rodent models. A key issue in such animal models is the optimization of construct validity, at both genetic and environmental levels. Standard housing of laboratory mice and rats generally includes ad libitum food access and limited opportunity for physical exercise, leading to metabolic dysfunction under control conditions, and thus reducing validity of animal models with respect to clinical populations. A related issue, of specific relevance to neuroscientists, is that most standard-housed rodents have limited opportunity for sensory and cognitive stimulation, which in turn provides reduced incentive for complex motor activity. Decades of research using environmental enrichment has demonstrated beneficial effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. One interpretation of such studies is that environmentally enriched animals more closely approximate average human levels of cognitive and sensorimotor stimulation, whereas the standard housing currently used in most laboratories models a more sedentary state of reduced mental and physical activity and abnormal stress levels. The use of such standard housing as a single environmental variable may limit the capacity for preclinical models to translate into successful clinical trials. Therefore, there is a need to optimize ‘environmental construct validity’ in animal models, while maintaining comparability between laboratories, so as to ensure optimal scientific and medical outcomes. Utilizing more sophisticated models to elucidate the relative contributions of genetic and environmental factors will allow for improved construct, face and predictive validity, thus facilitating the identification of novel therapeutic targets.

Research Highlights
► There is a complex interplay between genes and environment in psychiatric illness.
► Modeling of genetic and environmental factors is reviewed, focusing on mouse models.
► ‘Environmental construct validity’ and standard housing of rodent models are discussed.
► Models incorporating gene-environment interactions can elucidate pathogenic mechanisms.
► Environmental modulation of pathogenesis may identify drug targets for `enviromimetics'.