Developmental Consequences of Birth Interventions

描述（由申请人提供）：催产素被认为调节社会行为、应激反应、心理健康、心血管和免疫系统，部分通过中枢和自主神经系统的作用。初步研究表明，在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分娩过程相关的催产素暴露的行为，内分泌，自主神经和表观遗传后果的动物模型。虽然体内的许多系统都可能受到催产素的影响，但我们将首先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、精氨酸抗利尿素（AVP）基因的表达，以及这些基因的选定受体。通过一系列相互关联的项目，我们将研究(a)在分娩期间暴露于合成催产素（Pitocin）的后果，通常用于诱导或增强后期，以及(b)暴露于催产素拮抗剂（OTA）来阻断催产素受体，用于减缓分娩过程。本提案的具体目标是：(1)建立一个可翻译的动物范例，用于模拟和研究人类出生干预的选定特征；(2)验证与出生相关的神经肽、催产素的功能存在或缺失将影响后代的行为和大脑，从而影响催产素/AVP的假设

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.