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: 10176597
• 负责人: JOEL T NIGG
• 金额: $ 76.05万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176597
• 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 这项建议的目的是发现产前决定因素的产后行为的前兆，出现在前36 出生后几个月，神经发育和精神疾病。流行病学研究表明， 母体肥胖、妊娠期糖尿病和高血压与发育性暴露之间的关系 神经发育障碍的发病率;然而，这种关联的机制在很大程度上仍然未知。我们 自己的工作，使用非人类灵长类动物模型，演示了因果关系对后代气质的影响，通过 炎症和神经递质合成的变化，并在行为上与负效价相关，支持 及时进行更有针对性的前瞻性人体研究，以分离潜在机制。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作为发展的核心 生命早期的风险我们还其次考虑了关键的调节域，包括积极效价，社会过程， 和认知系统。从责任x经验模式出发，并考虑到新出现的发展 规划，我们强调两个强大的，但不充分理解的环境投入在早期发展： 产妇肥胖和产前营养不良。我们假设母亲的肥胖和营养不良改变了子宫内的 在胎儿发育过程中后代暴露于导致增加的炎症因子暴露的环境。 这些反过来又会改变大脑发育（这里没有直接评估），最终改变行为（我们仔细研究）。 最重要的假设是，在胎儿发育过程中，炎症因子的暴露增加预示着 婴儿负效价的改变，形成了一系列的行为发展，增加了与以下相关的结果： 注意力缺陷多动障碍、易怒和精神障碍的行为风险。为了解决这个假设，一个强大而新颖的 一个完善的婴儿/幼儿行为特征的组合与详细的测量相结合， 子宫内环境的营养、代谢、炎症和激素概况。我们还检查了选定的 出生后的主持人和其他相关的RDoC维度，符合我们的模型。目标1评估了在何种程度上， 人类发育暴露于母亲肥胖和/或母亲营养不良可预测后代婴儿和幼儿 行为，特别是消极情感。目的2：研究母体妊娠引起的子宫内环境的变化。 肥胖和营养不良，并测试假设，增加暴露于炎症在发展过程中的基础 后代的行为变化。目的3检验了这样一个假设，即后代行为的编程是通过 母亲肥胖引起的炎症是由后代在怀孕期间接触的营养素和激素调节的。 胎儿发育研究结果将阐明精神病理学的机制途径。