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.

妊娠期药物使用是一个公共健康问题，与显着的不良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、注意力缺陷多动障碍和情绪障碍。然而，母体药物使用导致后代的机制。神经发育发病率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可能的机制，因为阿片类药物、大麻和酒精的使用与免疫激活有关，从而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，并确定胎盘在调节这些关联中的作用。本研究利用了 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/儿童二人组）长期研究，研究母亲高风险暴露（包括物质使用）后的早期大脑和儿童发育结果。这是 NIH 帮助消除成瘾长期 (HEAL) 计划的一部分，旨在加快国家阿片类药物公共卫生危机的科学解决方案。 NIH HEAL 计划支持 NIH 的研究，以改善阿片类药物滥用和成瘾的治疗。通过对 4 个不同地理区域的 400 例妊娠进行孕产妇免疫分析以及胎盘和脐带血免疫和血清素分析，了解孕产妇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指标将与 0-15 个月龄核心 HBCD 研究收集的母亲表型、儿童大脑成像和行为指标相关联，此处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。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引起的母体炎症和免疫激活（目标 1）。在最后，我们将通过应用于现有 HBCD MRI 数据的新分析方法来评估母体物质使用与新生儿神经炎症之间的关系（目标 3）。将估计母胎免疫激活、血清素信号失调和新生儿脑部炎症在多大程度上介导物质使用和儿童早期行为结果之间观察到的关联。这些目标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传导对儿童神经发育发病率的影响。结果将指导缓解的筛查和治疗策略。母体物质使用的不利跨代影响。