Maternal adversity and epigenetic and behavioral programming across generations

母亲的逆境以及跨代的表观遗传和行为编程

• 批准号: 8518849
• 负责人: Miklos Toth
• 金额: $ 58.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518849
• 关键词: Affective; Amygdaloid structure; Animal Model; Anxiety; Architecture; Area; Autistic Disorder; Behavior; Behavioral; Brain; Brain region; Candidate Disease Gene; Cell Adhesion Molecules; Cells; Chemicals; Childhood; Cognitive; CpG Cluster; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Modification Process; DNMT3a; Data; Development; Disease; Emotional; Endotoxins; Environment; Epigenetic Process; Event; Exposure to; Gene Expression; Gene Proteins; Generations; Genes; Genetic; Genetic screening method; Genome; Genomics; Genotype; Goals; Health; Hippocampus (Brain); Hypermethylation; Incidence; Infection; Lead; Life; Link; Lipopolysaccharides; Maps; Mental Depression; Mental disorders; Methylation; Modality; Modeling; Modification; Molecular; Morphology; Mothers; Neuraxis; Neurodevelopmental Disorder; Neuronal Differentiation; Neuronal Plasticity; Neurons; Nucleus Accumbens; Pathogenesis; Pattern; Phenotype; Plastics; Play; Postpartum Period; Predisposition; Pregnancy; Proteins; Reporting; Research; Rewards; Role; Sensory; Serotonin Receptor 5-HT1A; Specificity; Stress; Synapses; Testing; Trauma; Work; base; chromatin modification; chromatin protein; cost; dentate gyrus; early childhood; epigenome; fetal; granule cell; immune activation; maternal separation; maternal stress; novel; offspring; postnatal; prenatal; prevent; programs; promoter; public health relevance; receptor; segregation; social; synaptic function; synaptogenesis; therapy development; transmission process

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.

描述（由申请人提供）：妊娠和产后母亲环境对于日后精神疾病的易感性发挥着重要作用。尽管人们认识到产前和产后逆境（例如孕产妇感染和儿童期逆境和创伤）的社会成本，但我们对这些疾病发病机制的了解非常有限。通过使用母体逆境的动物模型，我们发现了中枢神经系统特定神经元 DNA 甲基化的改变，这些改变通过基因表达的调节，使后代容易焦虑并增加压力反应。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。该应用将探索三种不同母体逆境模型中 DNA 甲基化的谱系、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。这些研究将有助于识别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来预防或逆转早年逆境的负面影响。