Impact of maternal substance use on offspring neurobehavioral development

怀孕期间使用药物是一个重要的公共卫生问题，与不良的后代神经发育和行为结果有关，包括认知功能障碍，自闭症谱系障碍，注意力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，随后对胎盘免疫和血清素系统之间的动态相互作用产生影响。我们研究的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个地点的NIH/NIDA健康大脑和儿童发育研究（HBCD），这是美国最大的（约7500名母亲/儿童二对）关于母亲高风险暴露（包括物质使用）后早期大脑和儿童发育结果的长期研究。这是NIH帮助结束长期成瘾（HEAL）计划的一部分，旨在加速科学解决国家阿片类药物公共卫生危机。NIH HEAL计划支持整个NIH的研究，以改善阿片类药物滥用和成瘾的治疗。我们建议通过在4个地理位置不同的六溴环十二烷研究中心的400例妊娠中进行母体免疫分析以及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。这些生物测量将与核心六溴环十二烷研究收集的0-15个月龄的母体表型、儿童脑成像和行为测量相关联。此处提议的补充研究将在产前环境和产后结果之间建立六溴环十二烷核心议定书中没有的生物联系。我们的多学科团队将通过对母体细胞因子、T细胞和单核细胞的研究，量化暴露于母体物质使用诱导的母体炎症和免疫激活（目标1）。我们将定义母体物质使用对胎盘和胎儿免疫激活和胎儿胎盘5-羟色胺信号传导的影响（目的2）。最后，我们将通过应用于现有六溴环十二烷MRI数据的新分析方法评估，将母体物质使用与新生儿神经炎症联系起来。(Aim 3）。使用统计模型，我们将估计母胎免疫激活，5-羟色胺信号失调，新生儿脑炎症介导物质使用和早期儿童行为结果之间观察到的关联的程度。这些目标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5-羟色胺信号传导改变对儿童神经发育发病率的影响。研究结果将指导筛查和治疗策略，以减轻母体物质使用的不利跨代影响。

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.