Epigenetic regulation of oxytocin pathways in the maternal brain

母体大脑催产素途径的表观遗传调控

• 批准号: 9752956
• 负责人: Allison M. Perkeybile
• 金额: $ 6.56万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752956
• 关键词: Animal Model; Behavior; Biological; Biology; Birth; Blood; Brain; Brain region; Caregivers; Caring; Characteristics; Childbirth; Complement; DNA Methylation; Data; Development; Epigenetic Process; Exposure to; Female; Functional disorder; Gene Expression; Genetic; Goals; Human; Incidence; Intention; Lactation; Maternal Behavior; Measures; Methylation; Modeling; Modification; Molecular Genetics; Mothers; Neuroendocrinology; Neuropeptides; Nulliparity; Oxytocin; Oxytocin Receptor; Pathway interactions; Peptides; Peripheral; Plasma; Play; Polymerase Chain Reaction; Postpartum Depression; Postpartum Period; Pregnancy; Receptor Gene; Regulation; Research; Research Proposals; Retrieval; Risk Factors; Role; Sampling; Shapes; Siblings; Sister; Site; Social Behavior; Social support; Study models; System; Techniques; Time; Tissues; Training; Variant; Weaning; Woman; Work; anxiety-like behavior; brain tissue; cohort; comparison group; depressive behavior; depressive symptoms; epigenetic marker; epigenetic regulation; experience; experimental study; insight; interest; maternal anxiety; maternal stress; novel marker; nursing mothers; offspring; postnatal; postnatal period; prairie vole; pregnant; pup; receptor; response; role model; skills; social; translational model

Project Summary: Postpartum depression (PPD) is highly prevalent in new mothers, with incidence rates estimated to be as high as 1 in 5 mothers, yet we know little about its underlying biology. Several risk factors have been identified, including maternal stress and poor social support in the time around birth. More recently, the neuropeptide oxytocin (OT) has also been implicated in PPD. Variation in circulating levels of OT has been associated with development of PPD and epigenetic modification of the OT receptor gene, OXTR, has been implicated as a risk factor. The proposed experiments seek to model several characteristics of PPD using the prairie vole, including epigenetic regulation of Oxtr, the role of social support before birth and in the postnatal period, and maternal care and anxiety-like behaviors, all in an effort to understand the role OT pathways play in regulating various characteristics associated with PPD. Oxtr DNA methylation and gene expression will be measured at multiple time points across gestation in pregnant females and immediately following birth in new mothers and non-pregnant sister controls to examine the shift in epigenetic regulation of Oxtr across pregnancy. At these same time points, levels of plasma OT will also be examined across pregnancy or soon after birth to characterize changes in the OT peptide in response to pregnancy and birth of offspring. The combination of data on the peptide and epigenetic regulation of its receptor will provide a broad understanding of how the birth experience impacts OT pathways. The persistence of these epigenetic markers will be examined in additional mothers and non-pregnant sister controls either one week after birth or one week after weaning of offspring, after the mother has stopped lactating. This will provide insight into whether these markers on Oxtr are long lasting and if they are dependent on the mother nursing offspring. A lack of social support in the time around childbirth is a known risk factor for PPD in women. Therefore, additional mothers will give birth and rear offspring with or without a social partner present to determine the impact of social support on epigenetic regulation of Oxtr, maternal care of offspring, and maternal anxiety-like and depressive behaviors. The proposed experiments seek to develop a more complete animal model of PPD, one that incorporates both environmental (social support) and genetic (Oxtr epigenetic regulation) components, to gain a better understanding of the development of PPD. This model has the potential to provide valuable information on how pregnancy, birth, and lactation effect functioning of OT pathways to shape the maternal brain.

项目摘要：产后抑郁症（PPD）在新妈妈中非常普遍，发病率很高 估计高达5分之一的母亲，但我们对它的基本生物学知之甚少。几个风险因素 已经被确定了，包括孕产妇的压力和出生时期的社会支持不佳。最近， 神经肽催产素（OT）也与PPD有关。循环水平的差异已经 与OT受体基因的PPD发展和表观遗传学修饰有关OXTR 被暗示为危险因素。提出的实验试图使用 草原vole，包括OXTR的表观遗传调节，出生前和出生后社会支持的作用 时期以及孕产妇护理和类似焦虑的行为，都是为了了解途径的角色 在调节与PPD相关的各种特征方面。 Oxtr DNA甲基化和基因表达将是 在妊娠女性的妊娠期间多个时间点测量，并在出生后立即进行。 母亲和非怀孕的姐妹对照，以检查OXTR的表观遗传调节的转移 怀孕。在同一时间点，还将在怀孕期间或很快检查血浆OT水平 出生后，响应妊娠和后代的出生来表征OT肽的变化。这 关于其受体的肽和表观遗传调节的数据的组合将提供广泛的理解 关于出生体验如何影响OT途径。这些表观遗传标记的持久性将是 在出生后一周或一周后，在其他母亲和非怀孕的姐妹控制中检查 母亲停止泌乳后，后代断奶。这将提供有关这些是否的见解 OXTR上的标记持久，如果它们取决于母亲护理后代。缺乏社交 在分娩周围的时间里的支持是女性PPD的已知危险因素。因此，其他母亲 有或没有社会伴侣在场的情况下，将出生和后代，以确定社会的影响 支持OXTR的表观遗传调节，后代的母亲护理以及孕产妇焦虑和抑郁症 行为。拟议的实验旨在开发更完整的PPD动物模型，该模型 同时结合环境（社会支持）和遗传（Oxtr表观遗传调节）成分，以获得 更好地了解PPD的发展。该模型有可能提供宝贵的 有关OT途径的怀孕，出生和泌乳效应如何塑造母体的信息 脑。