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）：已知催产素可以调节社会行为，压力反应性，心理健康，心血管和免疫系统，部分是通过中央和自主神经系统中的行动。初步研究表明，在早期生命中暴露于外源合成催产素可能会对依赖内源性催产素的行为，神经系统和基因产生长期的表观遗传作用。拟议的翻译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的行为，内分泌，自主神经和表观遗传学后果。尽管整个人体的许多系统可能受催产素的影响，但我们最初将集中在已知对内源性催产素敏感的神经过程和遗传途径上，包括催产素和相关肽，精氨酸加压素（AVP）的基因表达，以及这些对这些的所选受体的表达。使用一系列相互关联的项目，我们将检查（a）在出生过程中暴露于合成催产素（pitocin）的后果，通常用于诱导或增强以后诱导或增强，以及（b）通过暴露于催产素拮抗剂（OTA）来阻止催产素受体，用于减慢生物的生育过程。该提案的具体目的是：（1）开发一种旨在建模和研究人类出生性干扰的特征的翻译动物范式，（2）检验以下假设：与出生相关的功能性存在或不存在神经肽的存在或不存在，将影响对后代的行为和大脑的影响，并影响氧气/AVP的行为和大脑。 途径（包括肽及其受体的基因），（3）获得可能受到出生相关干预措施影响的神经机制的更深入了解，（4）识别催产素和其他与出生有关的干预措施的特定表观遗传后果。男性和女性都将进行测试，从而使我们能够研究与出生有关的影响的假设 干预可能是性二态的。这些研究还将检验以下假设：催产素受体（OXTR）最初基于DNA的甲基化的表观遗传机制，可以通过出生经验转化表观遗传组。此处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，并改善了优化出生结果的方法。这项研究的数据还将告知人们对社会和情感行为正常发育生物学的当前理解，并将有助于评估通常用于操纵人类出生过程的治疗婴儿的后果。这些研究还将增加我们对神经，自主神经，内分泌和表观遗传机制的基本理解，这些机制是基本的哺乳动物行为，包括社会行为，情绪调节以及指示焦虑和抑郁的行为。这里使用的动物模型将是草原沃尔（Prairie Vole），它具有类似人类的自主神经系统，一个以高度的社会性和所有父母行为为特征的社会系统，长期持久的成对纽带和高水平的催产素措施在以后的生活中采取的索引，包括（a）社会行为的索引，包括他们的社会和情绪的措施，包括内分泌和替代（b）内分泌的替代（b）替代（b）替代（MR）（MR）（MR）。 PCR，（c）通过射电遥测测量的自主神经系统功能，并由迷走传出途径介导的心率和心律变化索引，（D）通过功能磁成像（FMRI）对社交提示的响应以及（e）测量详细信息的响应，通过功能磁成像（FMRI）来衡量的神经激活和电路的变化，以此来衡量。催产素途径中基因的甲基化，例如Oxtr。 相关性：目前对出生干预的婴儿的后果，尤其是暴露于合成催产素（pitocin）或干扰内源性催产素的药物的影响仍然很大程度上是未知的。现在，每年在美国分娩的430万妇女中，大多数妇女中的大部分通常都暴露于皮托素，通常是为了促进劳动或防止产后出血。此外，正在开发药物以防止早产，这会影响8个儿童中的1个，每年成本262亿美元。但是，这些疗法是否对婴儿产生有害后果，尚未系统地研究。拟议的研究使用啮齿动物模型来检查这些与出生有关的干预措施的后代的后果，并了解其机制。