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Transgenerational epigenetic inheritance modulating brain function, behaviour and cognition

We investigate how genetic and environmental factors combine to cause specific cognitive and affective disorders,including Huntington’s disease, dementia, depression, anxiety disorders, schizophrenia and autism spectrum disorders. Our research also links data at behavioural and cognitive levels to underlying cellular and molecular mechanisms.

We use a variety of behavioural tools, including automated touchscreen testing of cognition and high-throughput data analysis of vocalization and communication, that are directly translatable to clinical tests. We are establishing the extent to which experience-dependent plasticity can modulate behavioural and cognitive endophenotypes, in models with targeted genome editing. This cellular level of understanding is linked, in turn, to molecular mechanisms, including epigenetics, transcriptomics, proteomics and metabolomics.

We are also exploring the concept of ‘enviromimetics’, therapeutics that mimic or enhance the beneficial effects of cognitive stimulation and physical exercise.  Most recently, we have extended this gene-environment interaction research to studies of the microbiota-gut-brain axis and transgenerational epigenetic inheritance.

Aims

There is increasing evidence that the environment and experience of fathers, prior to conception, can affect their children via sperm epigenetics and intergenerational inheritance of acquired traits.  It is of utmost importance to unveil the underlying mechanisms as well as the exact consequences that paternal exposures (including stress, diet and infection) has on sperm epigenetics and offspring phenotypes.  

In order to better understand and prevent the 'epigenopathy' that may be produced by transgenerational epigenetic inheritance, we explore these questions using preclinical models.

The study of how environmental exposures and experiences affect sperm RNA and DNA as well as behavioural, cognitive and other phenotypes is still in its infancy.  In particular, the growing prevalence of some brain disorders implicates environmental factors (as genomes evolve very slowly), and these could be acting at least partly via epigenetic inheritance, including both the maternal and paternal lineages.  Using preclinical models we explore sperm epigenetics as well as intergenerational and transgenerational epigenetic inheritance. The period of adolescence, the transition time from childhood to adulthood, is a critical phase for the developing organism. During this time, substantial remodelling of the brain occurs in response to hormonal and physical changes. Hence, the brain is particularly sensitive to external influences, including environmental exposures that alter experience. These paternal exposures can lead to alterations in sperm non-coding RNA levels and DNA methylation.  Although there are recent indications from our lab and others that paternal environmental exposures  can epigenetically affect some aspects of the offspring phenotype, the mechanisms are unclear.

This project aims to study the impact of environmental interventions on male laboratory mice and their female and male offspring. To achieve this goal, fathers are exposed to different environmental conditions and their offspring are assayed using a variety of behavioural tasks as well as cellular/molecular approaches, to gain a comprehensive picture of offspring endophenotypes. We also use cutting-edge epigenetic approaches to elucidate the modulation of the sperm epigenome and offspring development, physiology and metabolism. Due to the high translational value of this project, the results will be crucial to our understanding of the of the epigenetic intergenerational impacts of paternal experience on molecular and cellular mediators of brain function, cognition and behaviour.

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