Gene-environment interactions modulating brain function within and between generations

Each of us can trace our origins from conception, with the information in our genomes and epigenomes guiding development, and environmental factors modulating this trajectory over time. We have been interested in how genes and environment combine to sculpt brain development and function, in health and disease. We have examined the role of various molecular and cellular mediators, and environmental modulators, as they influence healthy cognitive and affective function on the one hand, and cognitive and affective disorders on the other.

Huntington’s disease (HD) is one of over 50 tandem-repeat disorders and involves neurodegeneration leading to psychiatric, cognitive and motor symptoms. In a preclinical model of HD, expressing the tandem-repeat mutation, we have demonstrated that environmental enrichment (enhanced cognitive stimulation and physical activity) can delay onset of endophenotypes modelling depression, dementia and movement disorders. These findings have been extended to include stress and exercise interventions, and environmental manipulations in models of other neurological and psychiatric disorders, including autism, schizophrenia, depression and anxiety disorders. Our molecular and cellular investigations have revealed key pathways implicated in the therapeutic impacts of environmental stimuli and identified novel therapeutic targets. We have also discovered altered brain-body interactions, including the first evidence of gut dysbiosis (dysregulated microbiota) in HD, and a preclinical model of schizophrenia. Ongoing studies are exploring the gut microbiome as a therapeutic target and the possibility that specific environmental factors may modulate brain function via microbiota-gut-brain interactions. These approaches to gene-environment interactions may facilitate the development of enviromimetics (including exercise mimetics as a subclass) for a variety of brain disorders known to be modulated by environmental stimuli.

In a parallel program of research, we have been exploring epigenetic inheritance via the paternal lineage. We have discovered the transgenerational effects of various paternal environmental exposures. Our findings reveal significant experience-dependent effects on cognitive and affective function of offspring via epigenetic inheritance. We are investigating the impacts of specific environmental and pharmacological factors, including exercise and stress-hormone elevation, and the relevance of these discoveries in mice to human transgenerational epigenetics and associated ‘epigenopathy’. Our ongoing studies are exploring mechanisms whereby experience can modify germ cells and associated sperm epigenetics, and how these epigenetic modifications (of mice and men) may modulate offspring phenotypes and their potential susceptibility to various brain disorders.