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

基金资助的赠款或项目摘要 超过50%的美国儿童暴露于至少一种不良童年经历（ACE）;在巴西- 我们的网站为拟议的工作-这一速度甚至更高。有较大ACE的儿童在- ADHD/外化障碍的风险增加[比值比（OR）1.5-6.8]，以及物质使用障碍 （OR 2.3 - 7.7）、危险性行为和性传播疾病（OR 1.7-8.1）。此外，ACE在一个 已经证明，一代人的精神障碍风险会传递给下一代。然而，机制 潜在的ACE相关代际影响尚不清楚，严重限制了预防工作。 该项目将研究母亲ACE与儿童大脑行为发育的关系，重点是认知功能， 主动控制和相关的神经回路牵连外化和冲动相关的条件。我们将测试 母体产前炎症作为这些代际影响的关键未充分研究的途径的作用。 暴露于高母体白细胞介素-6（IL-6）和C反应蛋白（CRP）的婴儿表现出非典型连接 前额叶颞顶和岛叶皮层与认知控制有关。临床前研究表明 母体ACE和相关炎症通过改变 促炎基因（如II-6、II-1β、TNF-α）。 我们的建议是基于CUIMC/NYSPI与 圣保罗联邦大学（UESP）关注高度暴露于ACE的贫困社区 外化和冲动相关疾病的发病率升高。在我们最近完成的婴儿核磁共振试验中， 在圣保罗的一项研究（n=44; 2-4周大的婴儿）中，我们发现母体ACE之间的关联， 产前母体炎症（CRP），以及认知控制亚组内功能连接减少， 在婴儿身上留下痕迹。在这里，我们的目标是建立在这些发现和测试的机制模型假设（i） ACE引起母体炎症标志物增加，以及（ii）妊娠期间，母体炎症 改变了胎盘的基因调控，从而影响了婴儿的大脑发育。来识别神经发育 产前炎症的特定影响，我们将测量和调整其他围产期对胎儿/新生儿的影响。 胎儿神经发育，包括母亲情绪，感知压力（自我报告），孕晚期母亲低血糖， 丘脑-垂体-肾上腺轴活动（毛发皮质醇水平）、家庭环境和后代遗传倾向 （来自GWAS-ADHD的多基因风险，这是认知控制能力下降的代表）。我们将招募580名孕妇 女性[n=290例低ACE（0或1）; n=290例高ACE（2或更多）]并随访其后代24 个月ACE的代际效应将极大地影响目前对ETI的认识， 与认知控制能力差有关的冲动和疾病，扩大了减少风险的时间框架- 我们需要了解各种诱发因素，并确定新的预防途径-特别是与资源匮乏的环境相关的途径。

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.