Developmental Consequences of Birth Interventions

生育干预对发育的影响

• 批准号: 8667727
• 负责人: CAROL SUE CARTER PORGES
• 金额: $ 97.77万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-11 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667727
• 关键词: Adult; Affect; Animal Model; Animals; Anxiety; Argipressin; Autonomic nervous system; Behavior; Behavioral; Biological; Birth; Birth Rate; Birthing Centers; Brain; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Child; Childbirth; Collaborations; Conduction Anesthesia; Cues; DNA Methylation; Data; Development; Developmental Biology; Discipline; Dose; Efferent Pathways; Elderly; Emotional; Endocrine; Epigenetic Process; Evaluation; Event; Exposure to; Female; Fetal Distress; Figs - dietary; Functional Imaging; Functional Magnetic Resonance Imaging; Gene Expression; Genes; Genetic; Genetic Processes; Genome; Goals; Health system; Healthy People 2010; Heart Rate; Hemorrhage; Hormones; Hospitals; Human; Image; Immune system; In Vitro; Induced Labor; Infant; Intervention; Knowledge; Life; Magnetism; Mammals; Measures; Mediating; Medical; Mental Depression; Mental Health; Messenger RNA; Methodology; Methods; Methylation; Microtus; Modeling; Modification; Molecular Biology; Molecular Neurobiology; Mothers; Nervous System Physiology; Nervous system structure; Neuroendocrinology; Neuropeptides; Neurosecretory Systems; Operative Surgical Procedures; Outcome; Oxytocin; Oxytocin Receptor; Pair Bond; Pathway interactions; Peptides; Pharmaceutical Preparations; Physiological; Physiology; Pituitary Gland; Postpartum Period; Premature Birth; Prevalence; Process; Promoter Regions; Qualifying; Radio; Recording of previous events; Reporting; Research; Research Personnel; Rodent; Rodent Model; Role; Sampling; Series; Social Behavior; Speed; Stress; Study models; Surveys; System; Telemetry; Testing; Time; Translational Research; United States; Woman; Work; base; behavior influence; behavior test; cost; design; dosage; emotion regulation; epigenome; experience; improved; in vivo; indexing; interdisciplinary approach; male; neonate; neuromechanism; novel; offspring; peptide hormone; prairie vole; premature; prevent; programs; receptor; relating to nervous system; response; risk benefit ratio; social; social attachment; tool

DESCRIPTION (provided by applicant): Oxytocin is known to regulate social behaviors, stress reactivity, mental health, cardiovascular and immune systems, in part through actions in the central and autonomic nervous systems. Preliminary studies have shown that exposure to exogenous synthetic oxytocin in early life can have long-lasting, epigenetic effects on behavior, neural systems and genes that are dependent on endogenous oxytocin. The proposed translational research will provide the first animal model specifically aimed at testing the behavioral, endocrine, autonomic and epigenetic consequences of exposure to oxytocin associated with the birth process. Although it is likely that many systems throughout the body are affected by oxytocin, we will focus initially on neural processes and genetic pathways known to be sensitive to endogenous oxytocin, including the expression of genes for oxytocin and the related peptide, arginine vasopressin (AVP), and selected receptors for each of these. Using a series of interrelated projects we will examine the consequences of (a) exposure during birth to synthetic oxytocin (Pitocin), commonly used to induce or augment later, and (b) blocking the oxytocin receptor by exposure to oxytocin antagonists (OTA), used to slow the birth process. The specific objectives of this proposal are: (1) to develop a translational animal paradigm designed to model and study selected features of human birth-interventions, (2) to test the hypothesis that the functional presence or absence of the neuropeptide, oxytocin associated with birth will influence the behavior and brain of the offspring, with effects on the oxytocin/AVP pathway (including genes for the peptides and their receptors), (3) to gain a deeper knowledge of neural mechanisms which may be affected by birth-related interventions, and (4) to identify specific epigenetic consequences of oxytocin and other birth-related interventions. Both males and females will be tested, allowing us to examine the hypothesis that the effects of birth-related interventions may be sexually dimorphic. These studies also will test the hypothesis that epigenetic mechanisms, based initially on methylation of DNA for the oxytocin receptor {OXTR), allow the epigenome to be transformed by the birth experience. The newly developed paradigms described here can be used to discover the epigenetic consequences of birth interventions and improve methods for optimizing birth outcomes. Data from this study also will inform the present understanding of the normal developmental biology of social and emotional behaviors and will aid in the evaluation of the consequences for infants of treatments commonly used to manipulate the human birth process. These studies also will increase our basic understanding of neural, autonomic, endocrine and epigenetic mechanisms that underlie fundamental mammalian behaviors, including social behaviors, emotion regulation, and behaviors indicative of anxiety and depression. The animal model used here will be the prairie vole, which has a human-like autonomic nervous system, a social system characterized by high levels of sociality and all parental behavior, long- lasting pair bonds and high levels of oxytocin Measures to be taken in later life include indices of (a) social and emotional behaviors, (b) endocrine changes including measures of endogenous oxytocin and AVP and gene expression (mRNA) for their receptors using PCR, (c) autonomic nervous system function measured by radio telemetry and indexed by heart rate and rhythmic changes in heart rate mediated by vagal efferent pathways, (d) changes in neural activation and circuitry as measured by functional magnetic imaging (fMRI) in response to social cues, and (e) measures of epigenetic modifications of the offspring's genome, using a detailed analysis of CpG DNA methylation of genes in the oxytocin pathway, such as OXTR. RELEVANCE: At present the consequences for infants of birth interventions, and in particular the effects of exposure to synthetic oxytocin (Pitocin) or drugs that interfere with endogenous oxytocin remain largely unknown. Most of 4.3 million women giving birth each year in the United States are now exposed to Pitocin, often to facilitate labor or prevent postpartum bleeding. In addition, drugs are being developed to prevent prematurity, which affects 1 in 8 children and costs $26.2 billion annually. However, whether these treatments have detrimental consequences for the infant has not been systematically studied. The proposed studies use a rodent model to examine the consequences for the offspring of these birth-related interventions, and to understand their mechanisms.

描述（由申请人提供）：众所周知，催产素可以部分通过中枢和自主神经系统的作用来调节社会行为、应激反应、心理健康、心血管和免疫系统。初步研究表明，生命早期接触外源性合成催产素会对依赖内源性催产素的行为、神经系统和基因产生持久的表观遗传影响。拟议的转化研究将提供第一个专门用于测试与出生过程相关的催产素暴露的行为、内分泌、自主和表观遗传后果的动物模型。尽管全身的许多系统可能都受到催产素的影响，但我们首先将重点关注已知对内源性催产素敏感的神经过程和遗传途径，包括催产素和相关肽、精氨酸加压素 (AVP) 的基因表达，并为其中每一个选择受体。通过一系列相互关联的项目，我们将检查 (a) 出生期间接触合成催产素（Pitocin）（通常用于以后诱导或增强）的后果，以及 (b) 通过接触催产素拮抗剂 (OTA) 来阻断催产素受体，用于减缓分娩过程。该提案的具体目标是：(1) 开发一种转化动物范式，旨在模拟和研究人类生育干预的选定特征，(2) 检验神经肽、催产素的功能存在或不存在与催产素相关的假设。出生会影响后代的行为和大脑，对催产素/AVP产生影响 途径（包括肽及其受体的基因），（3）深入了解可能受出生相关干预措施影响的神经机制，以及（4）确定催产素和其他出生相关干预措施的特定表观遗传后果。男性和女性都将接受测试，使我们能够检验以下假设：出生相关的影响 干预可能是性别二态性的。这些研究还将检验以下假设：表观遗传机制最初基于催产素受体 (OXTR) 的 DNA 甲基化，允许表观基因组因出生经历而发生转变。这里描述的新开发的范例可用于发现出生干预的表观遗传后果，并改进优化出生结果的方法。这项研究的数据还将有助于目前对社会和情感行为的正常发育生物学的理解，并将有助于评估通常用于操纵人类出生过程的治疗对婴儿的影响。这些研究还将增进我们对哺乳动物基本行为（包括社交行为、情绪调节以及焦虑和抑郁行为）背后的神经、自主、内分泌和表观遗传机制的基本了解。这里使用的动物模型将是草原田鼠，它具有类似人类的自主神经系统、以高水平的社会性和所有亲代行为为特征的社会系统、持久的配对关系和高水平的催产素。晚年生活包括以下指标：(a) 社交和情绪行为，(b) 内分泌变化，包括使用 PCR 测量内源性催产素和 AVP 及其受体的基因表达 (mRNA)，(c) 测量的自主神经系统功能通过无线电遥测，并以心率和迷走神经传出通路介导的心率节律变化为索引，(d) 通过功能磁成像 (fMRI) 测量的神经激活和电路变化，以响应社交线索，以及 (e) 测量通过对催产素途径中基因（例如 OXTR）的 CpG DNA 甲基化进行详细分析，对后代基因组进行表观遗传修饰。 相关性：目前，出生干预对婴儿的影响，特别是接触合成催产素（Pitocin）或干扰内源性催产素的药物的影响仍然很大程度上未知。美国每年有 430 万分娩妇女，其中大多数现在都接触催产素，通常是为了促进分娩或预防产后出血。此外，正在开发预防早产的药物，该药物影响八分之一的儿童，每年花费 262 亿美元。然而，这些治疗是否对婴儿产生有害后果尚未得到系统研究。拟议的研究使用啮齿动物模型来检查这些与出生相关的干预措施对后代的影响，并了解其机制。