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.

项目概要 该提案的目标是发现产后行为前兆的产前决定因素，这些因素出现在前 36 种行为中。 出生后几个月出现神经发育和精神疾病。流行病学研究表明 母亲肥胖、妊娠期糖尿病和高血压的发育暴露与​​增加之间的关联 神经发育障碍的发生率；然而，这种关联的机制仍然很大程度上未知。我们的 自己的工作，使用非人类灵长类动物模型，展示了对后代气质的因果影响，通过操作 炎症和神经递质合成的变化，并在行为上与负价相关，支持 及时进行更有针对性的前瞻性人体研究，以隔离潜在的机制。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作为发展的核心 生命早期的风险。我们还其次考虑关键的调节领域，包括正价、社会过程、 和认知系统。从责任 x 经验模型出发，并考虑新兴的发展概念 在编程中，我们强调了早期开发中两个强大但尚未充分理解的环境输入： 产妇肥胖和产前营养不良。我们假设母亲肥胖和营养不良会改变子宫内的发育 后代在胎儿发育过程中所接触的环境，导致炎症因子的暴露增加。 这些反过来又会改变大脑发育（此处未直接评估）并最终改变行为（我们仔细研究）。 总体假设是，胎儿发育过程中接触炎症因子的增加预示着 婴儿负价的改变，形成一系列行为发展，增加与以下相关的结果 多动症、烦躁和精神疾病的行为风险。为了解决这个假设，一个强大而新颖的 将完善的婴儿/幼儿行为特征与详细的测量相结合 子宫内环境的营养、代谢、炎症和激素特征。我们还检查选定的 产后调节因素和其他相关的 RDoC 维度，与我们的模型一致。目标 1 评估在多大程度上 人类发育中母亲肥胖和/或母亲营养不良可预测后代婴儿和幼儿 行为，特别是负面情绪。目标 2 检查母体引起的子宫内环境的变化 肥胖和营养不良，并检验了发育过程中炎症暴露增加的假设 后代的行为变化。目标 3 检验了以下假设：后代行为的编程是通过 母亲肥胖引起的炎症可以通过后代在怀孕期间接触到的营养物质和激素来缓解 胎儿发育。结果将阐明精神病理学的机制途径。