Mechanisms of maternal brain changes with birth interventions

分娩干预对母亲大脑变化的机制

• 批准号: 10376791
• 负责人: CAROL SUE CARTER PORGES
• 金额: $ 64.92万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376791
• 关键词: Address; Anesthesia procedures; Animal Model; Animals; Anxiety; Behavior; Behavioral; Biology; Birth; Blood; Brain; Brain region; Caring; Cesarean section; DNA Methylation; Development; Disease; Dose; Epigenetic Process; Exposure to; Family; Female; Functional disorder; Gene Expression; Genetic Transcription; High Risk Woman; Hour; Human; Induced Labor; Infant; Infant Mortality; Intervention; Knowledge; Labor augmentation; Lactation; Link; Maternal Behavior; Maternal Mortality; Measures; Mediating; Medicine; Mental Health; Methylation; Modeling; Modification; Molecular; Mothers; Operative Surgical Procedures; Oxytocin; Oxytocin Receptor; Partner in relationship; Pathway interactions; Pattern; Peripheral; Pitocin; Play; Postpartum Depression; Postpartum Period; Pregnancy; Process; Receptor Gene; Receptor Signaling; Research; Risk; Risk Factors; Rodent; Role; Saline; Shapes; Side; Signal Transduction; Site; Social Behavior; System; Testing; Time; Tissues; Uterine Contraction; Uterus; Vaginal delivery procedure; Whole Blood; Woman; Work; behavior influence; behavior measurement; depressive symptoms; design; disorder risk; epigenetic marker; epigenetic regulation; experience; experimental study; gene function; insight; intervention effect; offspring; postnatal; prairie vole; pregnant; receptor; response; role model; social

ABSTRACT: The use of birth interventions, such as induction or augmentation of labor with exogenous oxytocin or surgical delivery via cesarean section, have risen sharply in the past 30 years. These interventions have contributed to a decline in maternal and infant mortality, but the long-term consequences for the mother are not well understood. High levels of exogenous oxytocin during birth dramatically downregulate the oxytocin receptor in the uterus. The role the receptor plays in shaping oxytocin activity in the maternal brain is unknown. Emerging research has begun to link these birth interventions to maternal mental health and specifically to postpartum depression. Postpartum depression is prevalent in as many as 1 in 5 new mothers, yet we know little about the underlying biology of this disorder. Several risk factors have been identified, including changes in circulating levels of oxytocin and epigenetic modification of the oxytocin receptor gene, OXTR. The common use of exogenous oxytocin during birth may have long-term consequences for oxytocin functioning via OXTR epigenetic pathways and, in turn, contribute to the oxytocin system dysfunction that increases risk for postpartum depression. We propose to explore the link between birth intervention, changes in epigenetic markers on OXTR, and maternal behavior in the highly social prairie vole with three specific objectives: (1) to refine a new translational animal paradigm designed to model and study selected features of human birth practices, (2) to test the hypotheses that altered oxytocin levels at birth, whether through labor induction or cesarean section, will influence the behavior and brain of the mother via epigenetic effects on OXTR, and (3) to gain a deeper knowledge of mechanisms through which birth-related interventions may have lasting functional and epigenetic consequences for the mother. We will focus on altered epigenetic regulation of OXTR given the link between the oxytocin receptor, birth interventions, and postpartum depression. The natural pattern of OXTR DNA methylation, hydroxymethylation, and gene transcription will be characterized across gestation and following vaginal birth to gain insight into epigenetic mechanisms that shape the maternal brain in response to a natural, unmanipulated birth experience. Using exogenous oxytocin administration just prior to birth to model induction of labor in women, these same epigenetic markers will be examined in central and peripheral tissues to investigate how a birth with higher levels of oxytocin can alter long-term OXTR functioning and maternal behavior in new mothers. Cesarean delivery will also be used to examine behavioral and epigenetic consequences of opposing birth experiences, or those without pulsatile release of oxytocin during labor. The proposed experiments seek to develop a more complete animal model of maternal oxytocin system functioning following the birth experience, particularly epigenetic control of the receptor gene by DNA methylation and hydroxymethylation. These experiments will provide valuable information on how pregnancy, birth, and common birth interventions effect functioning of oxytocin pathways to shape the maternal brain.

摘要：使用出生干预措施，例如用外源性催产素诱导或增加劳动 或通过剖宫产的手术分娩，在过去30年中急剧上升。这些干预措施有 导致母亲和婴儿死亡率下降，但对母亲的长期后果不是 理解。出生过程中高水平的外源性催产素显着下调了催产素受体 在子宫中。受体在塑造母体大脑中催产素活性中所起的作用尚不清楚。新兴 研究已开始将这些出生干预措施与母亲心理健康联系起来，特别是与产后 沮丧。产后抑郁症的普遍多达5个新妈妈，但我们对此一无所知 这种疾病的基础生物学。已经确定了几个危险因素，包括循环的变化 催产素受体基因的催产素和表观遗传修饰水平，Oxtr。共同用途 出生期间的外源性催产素可能会对催产素通过oxtr表观遗传产生长期影响 途径又导致催产素系统功能障碍，从而增加产后风险 沮丧。我们建议探索出生干预之间的联系，OXTR上的表观遗传标记的变化， 以及具有三个特定目标的高度社交草原田径的产妇行为：（1）改进一个新的 翻译动物范式旨在建模和研究人类出生实践的选定特征，（2） 测试改变出生时催产素水平的假设，无论是通过劳动诱导还是剖宫产，都将 通过对OXTR的表观遗传作用影响母亲的行为和大脑，（3）获得更深的 了解与出生有关的干预措施可能具有持久功能和表观遗传的机制知识 对母亲的后果。考虑到鉴于oxtr的改变的表观遗传调节 催产素受体，出生干预和产后抑郁症。 OXTR DNA甲基化的自然模式， 羟甲基化和基因转录将在妊娠期间和阴道出生后表征 深入了解表观遗传机制，这些机制响应天然，无操纵 出生经验。在诞生前使用外源性催产素给药，以模型女性的劳动诱导， 这些相同的表观遗传标记将在中央和外围组织中检查，以研究如何出生 较高水平的催产素可以改变新妈妈的长期OXTR功能和母体行为。剖宫产 交付还将用于检查反对分娩经历的行为和表观遗传后果，或 那些在分娩过程中没有脉动催产素的那些。拟议的实验试图开发更多 孕产妇催产素系统的完整动物模型在出生经验之后起作用，特别是 通过DNA甲基化和羟甲基对受体基因的表观遗传控制。这些实验会 提供有关怀孕，出生和常见出生干预措施效果的有价值信息 催产素途径以塑造母体大脑。