Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior

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The etiology of many neurodevelopmental disorders including autism, schizophrenia and attention-deficit hyperactive disorder remains poorly understood. It is accepted that environmental factors may be involved and that the heritability of those conditions is relatively high. Numerous epidemiological and genome-wide association studies in affected populations have identified environmental factors and candidate genes increasing the susceptibility to those conditions. However, those genetic and environmental factors can only account for a small percentage of the clinical cases. This suggests that additional environmental influences remain unidentified, and that the majority of the heritable component of those conditions is of non-genetic origin. We hypothesize that brain overexposure to thyroid hormone during development is an important factor contributing to both the environmental and non-genetic heritable components in the etiology of neurodevelopmental disorders. To test this hypothesis, we will use mouse models with genetic and epigenetic deficiency in DIO3, the main brain determinant controlling thyroid hormone action. In Specific Aim #1, we will determine what are the consequences of allele-specific inactivation of Dio3 globally or specifically in neurons for the brain programs of gene expression, adult brain structure and behavior. In Specific Aim #2, we will profile the fetal and neonatal brain expression and the adult brain structure and behavior of genetically normal mouse descendants of ancestral mice that were exposed to an excess of thyroid hormone during development. We will compare the results of developmental gene expression in different parts of the brain with their adult behavior and with the altered epigenome of exposed ancestors to define which brain developmental programs, brain regions, brain functions, and related neurodevelopmental disorders that are affected by abnormal epigenetic inheritance originated in ancestral overexposure to thyroid hormones. Based on the abnormal regulation of circadian rhythms that is typically associated with neurodevelopmental disorders and is also observed in mice lacking the Dio3 gene, we will identify the molecular and developmental basis by which developmental exposure to thyroid hormone excess leads to the abnormal programming of the circadian clock (Specific Aim #3). We anticipate that our work will greatly advance our understanding of the etiology of complex neurodevelopmental conditions and demonstrate the breakthrough concept that a developmental excess of thyroid hormone influences the susceptibility to those conditions directly in the present generation and indirectly in descendants via epigenetic mechanisms of inheritance.