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: 10610029
• 负责人: CAROL SUE CARTER PORGES
• 金额: $ 7.74万
• 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/10610029
• 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：使用分娩干预措施，例如使用外源性催产素引产或加速产程 过去 30 年来，通过剖腹产手术分娩的人数急剧增加。这些干预措施有 有助于降低孕产妇和婴儿死亡率，但对母亲的长期影响并没有 很好理解。出生时高水平的外源性催产素会显着下调催产素受体 在子宫里。该受体在塑造母体大脑催产素活性中所起的作用尚不清楚。新兴 研究已开始将这些分娩干预措施与孕产妇心理健康，特别是产后联系起来 沮丧。多达五分之一的新妈妈患有产后抑郁症，但我们对此知之甚少 这种疾病的基础生物学。已经确定了一些风险因素，包括循环系统的变化 催产素水平和催产素受体基因 OXTR 的表观遗传修饰。的共同用途是 出生期间外源性催产素可能通过 OXTR 表观遗传对催产素功能产生长期影响 途径，进而导致催产素系统功能障碍，增加产后风险 沮丧。我们建议探索生育干预、OXTR 表观遗传标记变化之间的联系， 和高度社会化的草原田鼠的母性行为，具有三个具体目标：（1）完善新的 旨在模拟和研究人类分娩实践的选定特征的转化动物范式，（2） 检验改变出生时催产素水平的假设，无论是通过引产还是剖腹产，将 通过对 OXTR 的表观遗传效应影响母亲的行为和大脑，以及 (3) 获得更深入的了解 了解与生育相关的干预措施可能具有持久功能和表观遗传的机制 对母亲造成的后果。鉴于 OXTR 之间的联系，我们将重点关注 OXTR 改变的表观遗传调控。 催产素受体、生育干预和产后抑郁症。 OXTR DNA 甲基化的自然模式， 羟甲基化和基因转录将在整个妊娠期和阴道分娩后表征 深入了解塑造母体大脑的表观遗传机制，以响应自然的、未经操纵的 出生经历。在分娩前使用外源性催产素来模拟女性的引产， 将在中央和外周组织中检查这些相同的表观遗传标记，以研究出生时如何 较高水平的催产素可以改变新妈妈的长期 OXTR 功能和母亲行为。剖腹产 分娩还将用于检查相反出生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释放催产素的人。拟议的实验旨在开发一种更 母亲催产素系统在出生经历后功能的完整动物模型，特别是 通过 DNA 甲基化和羟甲基化对受体基因进行表观遗传控制。这些实验将 提供有关怀孕、分娩和常见分娩干预措施如何影响胎儿功能的宝贵信息 催产素途径塑造母体大脑。