Environmental Enrichment and Gene–Environment Interactions in Mouse Models of Brain Disorders

Abstract

Environmental enrichment studies of transgenic and mutant mouse models of brain disorders have facilitated exploration of gene × environment interactions and experience-dependent plasticity in response to enhanced mental and physical activity. Environmental enrichment was first shown to have beneficial effects in a transgenic mouse model of Huntington’s disease, followed by models of Alzheimer’s disease and other neurodegenerative disorders, as well as various neurodevelopmental and psychiatric disorders, including Rett syndrome and schizophrenia. Research involving mouse models of these various brain disorders has generally shown that environmental enrichment ameliorates brain dysfunction and associated behavioral signs, although the extent of beneficial effects may depend both on the specific model and the exact nature of the environmental manipulation. In some cases, specific cellular changes, such as enhancement of cortical synaptogenesis and hippocampal neurogenesis, and molecular changes, such as upregulation of specific neurotrophic factors and synaptic proteins, have been observed. These demonstrations of gene × environment interactions in mouse models, together with epidemiological studies, suggest that therapy based on elevated levels of mental and physical activity might benefit those at risk of, or suffering from, these brain disorders. Furthermore, environmental manipulations of these transgenic and mutant models provide insight into possible pathogenic mechanisms and may facilitate identification of novel molecular targets for therapeutic drugs (“enviromimetics”), which mimic or enhance the beneficial effects of environmental stimulation. Finally, these findings reinforce the concept that construct validity must not only be achieved at the level of genetic and molecular mediators, but should also encompass environmental modifiers, such as mental and physical activity levels, to ensure optimization of valid models that lead to successful clinical trials.