Maternal adversity and epigenetic and behavioral programming across generations

描述（由申请人提供）：妊娠和产后的母亲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。虽然产前和产后逆境的社会成本，如母亲感染和童年逆境和创伤，是公认的，我们对这些条件的发病机制的理解是非常有限的。通过使用母体逆境的动物模型，我们发现了中枢神经系统中特定神经元DNA甲基化的改变，通过基因表达的调节，使后代易患焦虑和增加应激反应。这些修饰发生在编码参与突触发生和突触功能的蛋白质的基因上，表明行为异常是由突触的多种功能缺陷引起的。本研究将探讨三种不同母体逆境模型中DNA甲基化的频谱、特异性、分布和功能意义，以及这些修饰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理学靶向来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.