Maternal adversity, inflammation, and neurodevelopment: How intergenerational processes perpetuate disadvantage in a low-resource setting

资助赠款或项目的摘要或摘要 超过50%的美国儿童至少有一次不良童年经历(ACE)；在巴西- 我们的网站对于建议的工作--这个比率更高。拥有更大王牌的孩子在- ADHD/外化障碍[优势比(OR)1.5-6.8]以及物质使用障碍的风险增加 (OR2.3-7.7)、危险性行为和性传播疾病(OR1.7-8.1)。此外，王牌合二为一 这一代人被证明会给下一代人带来精神障碍的风险。然而，这些机制 潜在的血管紧张素转换酶相关的代际影响尚不清楚，这大大限制了预防工作。 这个项目将研究母亲的ACEs与儿童大脑行为发展的关系，重点是认知- 与外化和冲动相关的条件有关的情绪控制和相关神经回路。我们将测试 母体产前炎症作为这些代际影响的关键途径的作用尚未得到充分研究。 暴露于高水平母亲白介素6(IL-6)和C反应蛋白(CRP)的婴儿表现出非典型的连接性 前额叶、顶叶和岛叶皮质与认知控制有关。临床前研究表明 母体血管紧张素转换酶和相关炎症通过改变 促炎基因(如II-6、II-1β、肿瘤坏死因子-α)。 我们的建议是基于CUIMC/NYSPI和 S圣保罗联邦大学专注于高度暴露于ACES的贫困社区 外化和冲动相关障碍的比率升高。在我们最近完成的婴儿核磁共振试验中 在S圣保罗的研究(n=44；2-4周大的婴儿)我们发现，母亲的A级，增加 产前母体炎症(CRP)和认知控制亚组中功能连接性减弱 婴儿的性激素水平。在这里，我们的目标是建立在这些发现的基础上，并测试一个机械模型，假设(I) ACE引起母体炎症标志物的增加，以及(Ii)在妊娠期间，母体炎症 改变胎盘基因调控，从而改变婴儿的大脑发育。识别神经发育 对于特定于产前炎症的影响，我们将测量和调整其他对胎儿/胎儿的影响。 FANT神经发育包括母亲情绪、感知压力(自我报告)、妊娠晚期母亲低血压 丘脑-垂体-肾上腺轴活动(头发皮质醇水平)、家庭环境和后代遗传易感性 (GWAS-ADHD的多基因风险，认知控制能力减弱的指标)。我们将招收580名孕妇 女性[低A值(0或1)的290人；高A值(2或以上)的n=290人]，并跟随她们的后代24岁 月份。证实ACE的代际效应将极大地影响目前对ETI的认识-- 冲动和认知控制不良相关的障碍，拓宽了降低风险的时间框架- 查明诱发因素，并找出新的预防途径--特别是与资源匮乏的环境有关的预防。

SUMMARY OR ABSTRACT OF THE FUNDED GRANT OR PROJECT Over 50% of US children are exposed to at least one Adverse Childhood Experience (ACE); in Brazil — our site for the proposed work — this rate is even higher. Children with greater ACEs are at significantly in- creased risk for ADHD/externalizing disorders [Odds ratio (OR) 1.5-6.8], as well as substance use disorders (OR2.3 - 7.7), risky sexual behaviors and sexually transmitted diseases (OR 1.7-8.1). Moreover, ACEs in one generation have been shown to confer risk for psychiatric dysfunction onto the next. However, the mechanisms underlying ACE-related intergenerational effects are unclear, significantly limiting prevention efforts. This project will study maternal ACEs in relation to child brain-behavior development focusing on cogni- tive control and related neural circuits implicated in externalizing and impulsivity-related conditions. We will test the role of maternal prenatal inflammation as a key understudied pathway for these intergenerational effects. Infants exposed to high maternal interleukin-6 (IL-6) and C-reactive protein (CRP) show atypical connectivity within prefrontal temporoparietal, and insular cortices related to cognitive control. Preclinical research suggests that maternal ACEs and related inflammation confer these neurodevelopment effects by altering expression of pro-inflammatory genes (e.g. II-6, II-1β, TNF-α). Our proposal is a collaborative effort based on a fruitful partnership between CUIMC/NYSPI and the Federal University of São Paulo (UNIFESP) focused on impoverished communities highly exposed to ACEs with elevated rates of externalizing and impulsivity-related disorders. In our recently completed pilot infant MRI study in São Paulo (n=44; 2-4 week old infants) we found associations between maternal ACEs, increased prenatal maternal inflammation (CRP), and diminished functional connectivity within cognitive control sub- strates in infants. Here, we aim to build on these findings and test a mechanistic model hypothesizing that (i) ACEs give rise to increased maternal inflammatory markers and (ii) during gestation, maternal inflammation alters placental gene regulation and, consequently, infant brain development. To identify neurodevelopment effects specific to prenatal inflammation, we will measure and adjust for other perinatal influences on fetal/in- fant neurodevelopment including maternal mood, perceived stress (self-report), third trimester maternal hypo- thalamic-pituitary-adrenal axis activity (hair cortisol levels), home environment, and offspring genetic liability (poly-genetic risk from GWAS-ADHD, a proxy for diminished cognitive control). We will enroll 580 pregnant women [n=290 with low ACEs (0 or 1); n=290 with high ACEs (2 or more)] and follow their offspring for 24 months. Substantiating intergenerational effects of ACEs will dramatically impact current knowledge of the eti- ologies of impulsivity and disorders related to poor cognitive control, broaden the time frame for curtailing risk- inducing factors, and identify new avenues for prevention — especially relevant to low-resourced settings.