MAternal Diabetes and neuropsychiAtric vulnerability in offspring: role of DNA methylation – MADAM

Co-morbidities associated with diabetes represent a significant human and financial burden. There is increasing evidence that co-morbidities such as depression, share pathophysiological and mechanistic origins with diabetes type 2 (T2D). Indeed, T2D is associated with high levels of depression, which is associated with increased risk for all-cause mortality. Inversely, depression is also associated with an increased risk to develop T2D later in life. As such, detailed investigation of these associated pathologies will not only contribute to alleviating their burden, but also provide fundamental insight into the pathophysiological processes underlying T2D. There is increasing evidence that the origins of both depression and T2D are based in inflammatory cytokine-mediated innate immunity, and/or the hypothalamus-pituitary-adrenal axis. Both potential mechanisms have been shown to lead to stable lifelong phenotypes sharing common elements including behavioral changes, depression, as well as an increased risk for T2D. Epigenetic processes such as DNA methylation integrate the environment and inherited traits to predispose individuals to diseases. For T2D and depression, the evidence is growing that disease loci are epigenetically regulated, and that epigenotypes may be transmitted from one generation to the next and play a significant role in disease development. Currently, obese animal models, induced by long lasting exposure to very high fat diets or genetically induced by mutations do not adequately reflect the full human T2D clinical context. Indeed, T2D is not always associated with obesity and it is being diagnosed at increasingly young ages, resulting in a growing number of the women at childbearing age or pregnant with T2D. This raises important public health concerns as to the impact of early life (in utero) exposure to T2D on brain development, especially as this is coupled with an alarming, co-incident, increase T2D in the pediatric population in the last decades.
MADAM aims to unravel the mechanisms underlying the link between T2D and depression using a unique preclinical model of non obese T2D in Goto-­Kakizaki (GK) rats. This model involves not only genetic components but also epigenetically mediated early life exposure to T2D. Our project uses the complementary expertise of the 3 partners (GK rat model of T2D, behavioral neuroscience, and the epigenetics of stress) to explore the hypothesised link between T2D and neuropsychiatric vulnerability through epigenetic processes. Using a unique combination of breeding, cross-fostering, and embryo transfer experiments coupled with a complete behavioral, endocrine, and epigenetic characterisation, we will investigate the role of the maternal epigenotype and behavior, as well as the diabetic in-utero environment experienced by rat pups in the emergence of both the anxious-depressive and diabetic phenotypes. We will examine if the GK rat behavioral phenotype emerges before or after the metabolic alterations associated with the subsequent onset of T2D. Additionally, we will identify the contribution of epigenetic factors in the emergence of anxious-depressive phenotype in diabetic subjects, and whether the anxious-depressive phenotype in diabetic subjects is reversible by strategies targeting HPA axis dysfunctions. The overall impact of this project will be to improve our understanding of the epigenetic origins of both T2D and depression. We aim to identify potential novel mechanisms and exploitable modalities to concurrently treat both T2D and depression. More importantly, by identifying early environmental factors to disease pathogenesis, open new routes to the prevention of T2D and psychiatric co-morbidity associated.