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.

项目总结 这项提议的目标是发现出生后行为先兆的产前决定因素，出现在前36个 出生后几个月，患有神经发育和精神障碍。流行病学研究表明， 孕期暴露于母体肥胖、妊娠期糖尿病和高血压之间的关系及其增加 神经发育障碍的发生率；然而，这种联系的机制在很大程度上仍然不清楚。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 炎症和神经递质合成的变化以及与负价相关的行为，支持 更有针对性、更具前瞻性的人体研究的及时性，以分离潜在的机制。从RDoC的角度来看，我们 因此，优先考虑负价领域，我们的概念框架也将其作为发展的核心 在很小的时候就有风险。我们还次要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，考虑新兴的发展概念 在编程中，我们重点介绍了早期开发中两个强大但未被充分理解的环境投入： 母亲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宫内发育。 子代在胎儿发育过程中暴露于的环境，导致暴露于炎症因子的增加。 这些反过来又改变了大脑的发育(这里没有直接评估)和最终的行为(我们仔细研究了这一点)。 最重要的假设是，胎儿发育期间暴露于炎性因子的增加预示着 婴儿负性情绪的改变，形成了一系列行为发展，从而增加了与 多动症、易怒和精神障碍的行为风险。为了解决这一假设，一个强大而又新颖的 良好的婴儿/幼儿行为特征与详细的测量相结合 宫内环境的营养、代谢、炎症和荷尔蒙状况。我们还检查了选定的 出生后主持人和其他相关的RDoC维度，与我们的模型一致。目标1评估在何种程度上 人类发育过程中暴露于母亲肥胖和/或母亲营养不良可预测后代婴儿和学步儿童 行为，尤其是消极的情感。目的2研究母体对子宫内环境的影响 肥胖和营养不良，并验证了在发育过程中暴露于炎症的增加是基础的假设 后代的行为变化。目标3检验了这样一种假设，即对后代行为的编程通过 母体肥胖引起的炎症被子代在肥胖期间接触的营养物质和激素所缓解 胎儿发育。结果将澄清通向精神病理学的机械路线。