Impact of maternal substance use on offspring neurobehavioral development

母亲物质使用对后代神经行为发育的影响

• 批准号: 10750254
• 负责人: RYAN H BOGDAN
• 金额: $ 643.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750254
• 关键词: Age Months; Alcohol consumption; Alcohols; Area; Attention deficit hyperactivity disorder; Axon; Behavior; Biological; Biological Assay; Brain; Brain imaging; Cannabis; Cells; Child; Child Development; Cognitive; Data; Development; Diffusion; Encephalitis; Environment; Exposure to; Geography; Immune; Immune signaling; Immune system; Impaired cognition; Inflammation; Interleukin-1 beta; Interleukin-6; Link; Macrophage; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Microglia; Mood Disorders; Morbidity - disease rate; Morphology; Mothers; National Institute of Drug Abuse; Negative Valence; Neonatal; Neurodevelopmental Disorder; Neurons; Neurotransmitters; Opioid; Outcome; Patients; Phenotype; Placenta; Play; Pregnancy; Protocols documentation; Public Health; Research; Risk; Role; Sampling; Serotonergic System; Serotonin; Signal Transduction; Site; Statistical Models; Surface; T-Lymphocyte; TNF gene; Testing; Therapeutic; Thick; Umbilical Cord Blood; United States; United States National Institutes of Health; analytical method; autism spectrum disorder; behavior measurement; behavioral outcome; cognitive system; cytokine; experimental study; fetal; fetal substance exposure; high risk; immune activation; in utero; indexing; insight; intrauterine environment; marijuana use; maternal opioid use; migration; monocyte; multidisciplinary; neonatal brain; neurobehavioral; neurodevelopment; neuroinflammation; neuropsychiatry; novel; offspring; opioid use; postnatal; prenatal; prenatal exposure; screening; sex; spectrograph; substance use; synaptogenesis; targeted treatment

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.

怀孕的药物使用是一个重大的公共卫生问题，与不良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。但是，物质物质使用的机制导致后代神经发育的发病率在很大程度上尚不清楚。新兴的证据突出了物质免疫失调作为一种合理的机制，因为使用阿片类药物，大麻和酒精与免疫激活有关，随后对lopenal免疫和血清素系统之间的动态相互作用产生了影响。我们的研究的目标是确定母体物质使用对母体免疫激活和后代神经行为的发育轨迹的影响，并确定胎盘在介导这些关联中的作用。这项研究资本借鉴了25个站点NIH/NIDA健康的大脑和儿童发展研究（HBCD），这是最大的（〜7500个母亲/儿童二元组）长期美国对孕产妇高风险暴露后早期脑和儿童发育结果的长期研究，包括药物使用。它是NIH的一部分，有助于长期结束成瘾（治愈）倡议，以加快美国阿片类药物公共卫生危机的科学解决方案。 NIH HEL HEAL Initiative Bolsters跨NIH的研究，以改善滥用和成瘾的治疗方法。我们提议通过进行遗产免疫药物，以及400位地理上不同的HBCD部位的400名怀孕者中的位置和脐带血免疫和5-羟色胺分析来弥合遗产物质使用和已知不良儿童结局之间的机械差距。这些生物学措施将与由0-15个月大的核心HBCD研究收集的母体表型，儿童脑成像和行为测量有关。这里提出的完整研究将在HBCD核心方案中没有产前环境和产后结果之间建立生物学联系。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来量化母体炎症和免疫激活（AIM 1）。我们将定义使用母体物质对置换和胎儿免疫激活以及胎儿阶段性血清信号传导的影响（AIM 2）。最后，我们将通过应用于现有HBCD MRI数据的新分析方法评估，将物质物质使用与新生儿神经炎症联系起来。 （目标3）。使用统计模型，我们将估计母亲 - 狂热免疫激活，血清素信号失调以及新生儿脑感染的失调，观察到物质使用与早期儿童行为结果之间的关联。这些目的的完成将提供新的机械洞察力，以了解母体物质使用对母体，占地去和胎儿免疫激活的影响，并有助于阐明位置免疫调节的影响，并改变血清素信号对儿童神经发育发育的影响。结果将指导筛查和治疗策略，以减轻孕产妇使用物质的不利变化影响。