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，如使用外源性催产素引产或引产 或通过剖腹产手术分娩，在过去30年中急剧上升。这些干预措施 有助于降低孕产妇和婴儿死亡率，但对母亲的长期影响并不明显。 很好理解。出生时高水平的外源性催产素显著下调催产素受体 在子宫里受体在母体大脑中形成催产素活性的作用尚不清楚。新兴 研究已经开始将这些分娩干预措施与产妇心理健康，特别是产后心理健康联系起来。 萧条产后抑郁症在多达五分之一的新妈妈中普遍存在，但我们对产后抑郁症知之甚少。 这种疾病的潜在生物学。已经确定了几个风险因素，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。共同使用 出生时的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，反过来，有助于催产素系统功能障碍，增加产后风险 萧条我们建议探索出生干预、OXTR表观遗传标记的变化， 和母性行为的高度社会化草原田鼠有三个具体目标：（1）完善一个新的 翻译动物范式，旨在模拟和研究人类生育实践的选定特征，（2） 检验出生时催产素水平改变的假设，无论是通过引产还是剖腹产， 通过对OXTR的表观遗传效应影响母亲的行为和大脑，以及（3）获得更深层次的 了解与出生有关的干预措施可能具有持久的功能和表观遗传作用的机制 对母亲的后果。我们将集中在改变OXTR的表观遗传调控之间的联系， 催产素受体、分娩干预和产后抑郁症。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进行表征， 深入了解表观遗传机制，这些机制塑造了母亲的大脑，以应对自然的，未经操纵的 出生经历在分娩前给予外源性催产素模拟妇女引产， 这些相同的表观遗传标记将在中央和外周组织中进行检查，以研究 较高水平的催产素可以改变新妈妈的长期OXTR功能和母性行为。剖宫产 分娩也将用于检查相反的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催产素脉冲式释放的人。拟议的实验旨在开发一种更 一个完整的动物模型，母体催产素系统功能的出生后的经验，特别是 通过DNA甲基化和羟甲基化对受体基因的表观遗传控制。这些实验将 提供有关妊娠、分娩和常见分娩干预措施如何影响 催产素通路来塑造母亲的大脑。