Maternal adversity and epigenetic and behavioral programming across generations

描述(由申请人提供)：孕期和产后的母体环境在以后的生活中对精神疾病的易感性起着重要的作用。尽管人们认识到产前和产后逆境的社会代价，如母体感染和儿童逆境和创伤，但我们对这些疾病的发病机制的了解非常有限。通过使用母体逆境的动物模型，我们确定了中枢神经系统特定神经元中DNA甲基化的修饰，这种修饰通过基因表达的调节，使后代更容易受到焦虑和增加应激反应的影响。这些修饰发生在编码涉及突触发生和突触功能的蛋白质的基因上，这表明行为异常是由突触的多项功能缺陷引起的。这项应用将探索DNA甲基化在三种不同的母体逆境模型中的谱、特异性、分布和功能意义，以及这些修改如何破坏神经元分化、突触发生和情绪行为的正常发育轨迹。这些研究将有助于确定关键的神经发育基因和蛋白质，这些基因和蛋白质可以通过药物靶向预防或逆转早期生活逆境的负面影响。

DESCRIPTION (provided by applicant): The gestational and postpartum maternal environment plays an important role in developing susceptibility to psychiatric disorders later in life. Although the societal cost of prenatal and postnatal adversity, such as maternal infection and childhood adversity and trauma, is recognized, our understanding of the pathogenesis of these conditions is very limited. By using animal models of maternal adversity, we identified modifications in DNA methylation in specific neurons in the central nervous system that, via the modulation of gene expression, predispose the offspring to anxiety and increased stress responsiveness. These modifications occur at genes that encode proteins involved in synaptogenesis and synaptic functions indicating that the behavioral abnormalities are caused by multiple functional deficits at the synapse. This application will explore the spectrum, specificity, distribution and functional significance of DNA methylation in three different models of maternal adversity with construct validity and how these modifications derail the normal developmental trajectory of neuronal differentiation, synaptogenesis and emotional behavior. These studies will help identifying key neurodevelopmental genes and proteins that can be pharmacologically targeted to prevent or reverse the negative effects of early life adversity.