Epigenetic programming by maternal behaviour

Individual differences in gene expression and behaviour are the result of an interaction between a given set of genes and a variety of environmental conditions. The study of epigenetics focuses on the nature of this interaction. The early developmental period in the life of a mammal is exquisitely sensitive to environmental cues. One critical question is how is the genome capable of adapting to these developmental or environmental signals? Building on an established rodent model, in which the effects of maternal care have been demonstrated to regulate the development and expression of neurobiological and behavioural measures in offspring as adults, the current project concerns how events during the first week of life can have sustained effects on gene expression, which persist throughout the life of the organism.The research presented in this thesis demonstrates how one facet of mothering style leads to a cascade of molecular and cellular changes, resulting in life-long alterations in the nature of stress responses and neuron survival. Frequent licking/grooming by rat mothers alters DNA methylation of the hippocampal glucocorticoid receptor (GR) gene and acetylation of histones early in life, providing a mechanism for these permanent changes in stress responses. Through postnatal cross-fostering studies, I was able to directly study how an identical gene within the same rat strain is expressed and regulated under the different developmental environments and how such effects on gene expression persist through life. I have also examined the potential for reversibility of the long-term consequences of postnatal environment and have demonstrated that both GR levels and the nature of stress responses exhibit a high degree of plasticity in adulthood in response to both pharmacological intervention and dietary amino-acid supplementation. These results demonstrate that the epigenomic marks established early in life through a behavioural mode of programming, are dynamically maintained and potentially reversible in the adult brain. These results contrast with the very dogmatic view that the genome is rendered fixed and immutable. I next questioned the global effects of early-in-life experience on the hippocampal transcriptome and anxiety-mediated behaviours in adulthood. Microarray analysis revealed > 900 different maternal care-responsive mRNA transcripts. These results suggest that effects of early life experience have a stable and broad effect on the hippocampal transcriptome, which may play a role in the development of anxiety-mediated behaviours through life. Finally, both in vivo and in vitro studies show that maternal behaviour increases GR expression in the offspring via increased hippocampal serotonergic tone accompanied by increased histone acetylase transferase activity, histone acetylation and DNA demethylation mediated by the transcription factor NGFI-A.In summary, this research demonstrates that an epigenetic state of a gene can be established through early-in-life experience, and is potentially reversible in adulthood. We predict that epigenetic modifications of targeted regulatory sequences in response to variations in environmental conditions might serve as a major source of variation in biological and behavioural phenotypes. In the case of GR, the resulting individual differences in behavioural and physiological responses to stress are thought to be a major risk factor for the development of psychiatric and physical illness. Thus, in addition to contributing to our understanding of how gene-environment interactions shape development, our work provides a mechanism that can be targeted for therapeutic intervention to potentially reduce the prevalence of these disorders