Impact of maternal substance use on offspring neurobehavioral development

怀孕期间药物使用是一个重大的公共卫生问题，并与不良的后代神经发育和行为结果相关，包括认知功能障碍、自闭症谱系障碍、注意缺陷多动障碍和情绪障碍。然而，母体物质使用导致后代神经发育疾病的机制在很大程度上仍然未知。新出现的证据强调母体免疫失调是一种合理的机制，因为阿片类药物、大麻和酒精的使用与免疫激活有关，随后对胎盘免疫系统和血清素系统之间的动态相互作用产生影响。我们的研究目的是确定母体物质使用对母体免疫激活和后代神经行为发育轨迹的影响，并确定胎盘在介导这些关联中的作用。这项研究利用了25个站点的NIH/NIDA健康大脑和儿童发育研究（HBCD），这是美国最大的（约7500对母亲/儿童）长期研究，研究了母亲高风险暴露（包括物质使用）后的早期大脑和儿童发育结果。这是美国国立卫生研究院帮助结束长期成瘾（HEAL）计划的一部分，该计划旨在加速科学解决全国阿片类药物公共卫生危机。NIH HEAL倡议支持NIH的研究，以改善阿片类药物滥用和成瘾的治疗。我们建议通过对4个地理位置不同的HBCD地点的400例妊娠进行母体免疫分析、胎盘和脐带血免疫和血清素分析，弥合母体物质使用与已知不良儿童结局之间的机制差距。这些生物学测量将与母体表型、儿童脑成像和从0-15个月大的核心HBCD研究收集的行为测量相关联。本文提出的补充研究将在产前环境和产后结果之间建立生物学联系，这是HBCD核心方案中所缺乏的。我们的多学科团队将通过研究母体细胞因子、T细胞和单核细胞来量化母体物质使用暴露引起的母体炎症和免疫激活（Aim 1）。我们将确定母体物质使用对胎盘和胎儿免疫激活和胎胎盘血清素信号的影响（目的2）。最后，我们将通过一种应用于现有HBCD MRI数据的新型分析方法，将母体物质使用与新生儿神经炎症联系起来。(3)为目标。使用统计模型，我们将估计母婴免疫激活、血清素信号失调和新生儿脑部炎症介导物质使用与儿童早期行为结果之间的关联的程度。这些目的的完成将为母体物质使用对母体、胎盘和胎儿免疫激活的影响提供新的机制见解，并有助于阐明胎盘免疫失调和血清素信号改变对儿童神经发育疾病的影响。结果将指导筛选和治疗策略，以减轻母体物质使用的不良跨代影响。

Substance use in pregnancy is a significant public health problem and is associated with adverse offspring neurodevelopmental and behavioral outcomes, including cognitive dysfunction, autism spectrum disorder, attention deficit hyperactivity disorder, and mood disorders. However, the mechanisms by which maternal substance use results in offspring neurodevelopmental morbidity remain largely unknown. Emerging evidence highlights maternal immune dysregulation as a plausible mechanism because the use of opioids, cannabis, and alcohol has been associated with immune activation, with subsequent effects on the dynamic interaction between the placental immune and serotonin system. Our study’s objectives are to determine the impact of maternal substance use on maternal immune activation and offspring neurobehavioral developmental trajectories, and to define the placenta’s role in mediating these associations. This study capitalizes on the 25-site NIH/NIDA HEALthy Brain and Child Development study (HBCD), the largest (~7500 mother/child dyads) long-term United States study of early brain and child development outcomes after maternal high-risk exposures, including substance use. It is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL initiative bolsters research across NIH to improve treatment for opioid misuse and addiction. We propose to bridge the mechanistic gap between maternal substance use and known adverse child outcomes, by performing maternal immune profiling, and placental and cord blood immune and serotonin profiling in 400 pregnancies across 4 geographically diverse HBCD sites. These biological measures will be linked to maternal phenotyping, child brain imaging, and behavioral measures collected by the core HBCD study from 0-15 months of age. The complementary studies proposed here will create a biological link between the prenatal environment and postnatal outcomes that is absent from the HBCD core protocol. Our multidisciplinary team will quantify maternal inflammation and immune activation induced by exposure to maternal substance use through studies of maternal cytokines, T cells and monocytes (Aim 1). We will define the impact of maternal substance use on placental and fetal immune activation and fetoplacental serotonin signaling (Aim 2). Lastly, we will link maternal substance use to neonatal neuroinflammation, as assessed by a novel analytic method applied to existing HBCD MRI data. (Aim 3). Using statistical modeling, we will estimate the extent to which maternal-fetal immune activation, dysregulated serotonin signaling, and neonatal brain inflammation mediate observed associations between substance use and early child behavioral outcomes. Completion of these Aims will provide new mechanistic insights into the impact of maternal substance use on maternal, placental, and fetal immune activation, and help elucidate the influence of placental immune dysregulation and altered serotonin signaling on child neurodevelopmental morbidity. Results will guide screening and therapeutic strategies to mitigate adverse transgenerational impacts of maternal substance use.