The Impact of Maternal Obesity and Poor Antenatal Nutrition on Offspring RDoC Dimensions and Risk for Neurodevelopmental Disorders

母亲肥胖和产前营养不良对后代 RDoC 维度和神经发育障碍风险的影响

• 批准号: 10407484
• 负责人: JOEL T NIGG
• 金额: $ 68.92万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407484
• 关键词: 3-Dimensional; Address; Age-Months; Animal Model; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Birth; Blood; Blood Circulation; Brain; Buffers; Caregivers; Child; Child Mental Health; Coupled; Development; Diet; Dimensions; Environment; Essential Amino Acids; Exposure to; Fetal Development; Gestational Diabetes; Glucose; Goals; Healthcare; Hormonal; Hormones; Human; Human Development; Hypertension; Impaired cognition; Impairment; Incidence; Infant; Infant Behavior; Inflammation; Inflammatory; Insulin; Intake; Justice; Kynurenine; Learning; Leptin; Life; Link; Measurement; Mediator of activation protein; Mental disorders; Metabolic; Metabolic hormone; Modeling; Negative Valence; Neurodevelopmental Disorder; Neurotransmitters; Nutrient; Nutritional; Obesity; Omega-3 Fatty Acids; Outcome; Pathway interactions; Positive Valence; Pregnancy; Proteins; Psychopathology; Research Domain Criteria; Risk; Route; Saturated Fatty Acids; Serotonin; Shapes; Social Processes; Symptoms; System; Temperament; Testing; Time; Toddler; Translating; Tryptophan; Unhealthy Diet; Up-Regulation; Validation; Work; antenatal; cognitive control; cognitive system; cytokine; design; epidemiology study; experience; family burden; human data; human study; in utero; maternal obesity; mother nutrition; negative affect; nonhuman primate; novel; novel strategies; nutrition; offspring; postnatal; prenatal; prenatal exposure; prevent; programs; prospective; social

PROJECT SUMMARY The goal of this proposal, is to discover prenatal determinants of post-natal behavioral precursors, emerging in the first 36 months after birth, of neurodevelopmental and psychiatric disorders. Epidemiological studies have demonstrated an association between developmental exposure to maternal obesity, gestational diabetes, and hypertension and increased incidence of neurodevelopmental disorders; however, the mechanisms for this association remain largely unknown. Our own work, using non-human primate models, demonstrates causal effects on offspring temperament, operating via changes in inflammation and neurotransmitter synthesis and relate behaviorally to negative valence, supporting the timeliness of a more focused, prospective human study to isolate potential mechanisms. From the RDoC perspective, we therefore prioritize the negative valence domain, which our conceptual framework also places as central to developmental risk in very early life. We also secondarily consider key modulating domains, including positive valence, social processes, and cognitive systems. Working from a liability x experience model, and considering emerging concepts of developmental programming, we highlight two powerful but insufficiently understood environmental inputs in early development: maternal obesity and poor antenatal nutrition. We hypothesize that maternal obesity and poor nutrition alter the in-utero milieu that offspring are exposed to during fetal development resulting in increased exposure to inflammatory factors. Those, in turn, alter brain development (not directly evaluated here) and ultimately behavior (which we study carefully). The overarching hypothesis is that increased exposure to inflammatory factors during fetal development predicts alterations in infant negative valence, shaping a cascade of behavioral development that increases the outcomes related to ADHD, irritability, and behavioral risk for psychiatric disorder. To address this hypothesis, a powerful yet novel combination of a well-established infant/toddler behavioral characterization is coupled with detailed measurements of the nutritional, metabolic, inflammatory, and hormonal profile of the in-utero environment. We also examine selected postnatal moderators and other relevant RDoC-dimensions, in line with our model. Aim 1 evaluates the extent to which in humans' developmental exposure to maternal obesity and/or poor maternal nutrition predicts offspring infant and toddler behavior, in particular negative affectivity. Aim 2 examines changes in the in-utero environment induced by maternal obesity and poor nutrition and tests the hypothesis that increased exposure to inflammation during development underlies the behavioral changes in the offspring. Aim 3 examines the hypothesis that the programming of offspring behavior via maternal obesity-induced inflammation is moderated by the nutrients and hormones that offspring are exposed to during fetal development. Results will clarify mechanistic routes to psychopathology.

项目摘要 该提议的目的是发现产后行为前体的产前决定因素，在前36位出现 出生后的几个月，神经发育和精神疾病。流行病学研究表明 发育性暴露于孕产妇肥胖，妊娠糖尿病和高血压之间 神经发育障碍的发病率；但是，这种关联的机制在很大程度上仍然未知。我们的 使用非人类灵长类动物模型，自己的作品表现出对后代气质的因果影响，通过 炎症和神经递质合成的变化，并在行为上与负相关，支持 一项更集中，前瞻性人类研究的及时性，以隔离潜在机制。从RDOC的角度来看，我们 因此优先考虑负价域，我们的概念框架也将其视为发展的核心 在很早的生活中冒险。其次，我们还考虑关键调节领域，包括积极价，社会过程， 和认知系统。从责任X体验模型中工作，并考虑新兴的发展概念 编程，我们重点介绍了两个强大但不足以了解早期发展的环境意见： 产妇肥胖和产前营养不良。我们假设孕产妇肥胖和营养不良改变了utero 胎儿发育过程中后代暴露的环境导致暴露于炎症因素。 这些反过来又改变了大脑发育（在此不直接评估）并最终（我们仔细研究）。 总体假设是，在胎儿发育期间，增加对炎症因素的暴露预测 婴儿负面价的改变，塑造了一系列行为发展，从而增加了与 多动症，易怒和精神疾病的行为风险。为了解决这一假设，一个有力但新颖的 建立良好的婴儿/幼儿行为表征的结合与详细测量 UTERO环境的营养，代谢，炎症和激素谱。我们还检查选定的 与我们的模型一致的产后主持人和其他相关的RDOC维度。目标1评估 人类对孕产妇肥胖和/或孕产妇营养不良的发育暴露预测了后代婴儿和幼儿 行为，特别是负面的情感。 AIM 2检查母体引起的UTERO内环境的变化 肥胖和营养不良，并检验了以下假设，即发育过程中炎症的暴露增加了 后代的行为变化。 AIM 3检查了以下假设，即后代行为通过 母体肥胖引起的炎症是由后代暴露于期间的营养和激素调节的 胎儿发育。结果将阐明心理病理学的机理途径。