Establishing Early Brain Signatures associated with Maternal Immune Activation Exposure

建立与母体免疫激活暴露相关的早期大脑特征

基本信息

批准号：
10570905
负责人：
Christoph Juchem
金额：
$ 107.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-11 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570905
关键词：
2019-nCoV Age Age Months Anterior Area Astrocytes Behavior Behavioral Behavioral Paradigm Biochemical Biological Biomedical Engineering Blood Brain Brain Mapping Brain region Cells Child Clinical Cross-Sectional Studies Data Data Collection Data Science Development Diagnosis Discipline of obstetrics Dorsal Exposure to Fetus Functional Imaging Future Goals Growth Gynecology Head circumference Health Human IL17 gene IL8 gene Immune Immunoglobulin G Immunologic Markers Infant Infection Inflammation Inflammatory Influenza Insula of Reil Interleukin-1 beta Interleukin-6 Knowledge Learning Disabilities Left Level of Evidence Life Link MRI Scans Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maps Maternal-fetal medicine Measures Medical Mental Health Services Mental disorders Metabolic Modification Motor National Institute of Mental Health Neonatal Neurosciences Newborn Infant Normal Statistical Distribution Pathway interactions Perinatal Physiological Pilot Projects Placenta Population Pregnancy Pregnant Women Premature Infant Process Property Psychoneuroimmunology Psychosocial Stress Public Health Reporting Research Research Domain Criteria Risk Rodent Schizophrenia School-Age Population Science Signal Transduction Spottings Stimulus Stress Structure System TNF gene Temperament Third Pregnancy Trimester Time Training Umbilical Cord Blood Variant Work autism spectrum disorder behavioral health behavioral phenotyping behavioral response brain behavior cognitive control cohort early childhood early detection biomarkers emotion regulation endophenotype epidemiology study experience fetal fetal reactivity imaging science immune activation in vivo indexing individual variation infancy interest longitudinal, prospective study metabolic profile myoinositol neonatal period neonate neural neurobehavior neuron development offspring pathogen postnatal preclinical study prenatal prenatal exposure psychiatric symptom psychologic public health relevance recruit response

项目摘要

While 1 in 5 children are at risk for psychiatric disorders, only 1 in 20 young children receive mental health care. There remains a gap in knowledge of early causes and precursor symptoms of psychiatric disorders; therefore, many children are not identified as at risk until school age, when a diagnosis can reliably be made. Prenatal maternal immune activation (MIA) from infection, stress, medical conditions, and environmental pathogens has been associated with offspring risk of psychiatric disorders. There remains a gap in our knowledge of the early brain and behavioral antecedents of this risk. Preclinical studies suggest that MIA may lead to biochemical changes in the developing brain that disrupt brain-behavior functional associations. We propose to examine whether prenatal exposure to MIA leads to metabolic and functional modifications in the developing brain and analogous behavioral phenotypes in human offspring. Our prior work demonstrated that MIA (interleukin-6; IL- 6) was associated with functional connectivity of the salience network (SAN), a network integral for emotion regulation, in neonates. Extending this, we will conduct longitudinal magnetic resonance imaging (MRI) scans in fetuses, neonates, and infants to determine if the alterations in the SAN originate in the fetal period and map developmental trajectories of the SAN in early life. In tandem, we plan to collect longitudinal magnetic resonance spectroscopy (MRS), which provides mechanistic information about the metabolic and cellular properties that may correspond to disruptions of SAN functional activity. Our pilot data suggests that MIA is associated with myo-inositol, an indicator of astroglial cell activation, in the newborn brain. Our central hypothesis is that MIA, evidenced by levels of inflammation (primary: IL-6) and infection (primary: Total immunoglobulin G), is associated with brain connectivity and metabolites in the SAN and behavioral reactivity from the fetal to infancy periods. One hundred and seventy-five pregnant women-fetal dyads will participate in this study from 12 weeks gestation to 9 months postnatal life. The pregnant women will have blood draws and psychological assessments at three timepoints and fetal physiologic assessment and MRI at 33-36 weeks. The infants will participate in MRI (2-6 weeks and 4 months postnatally) and observer-based behavioral paradigms at 4- and 9-months of age. Our proposal uses a collaborative science approach, bringing together perinatal-developmental neuroscience (Marisa Spann), psychoneuroimmunology (Staci Bilbo), maternal-fetal medicine (Mirella Mourad), and quantitatively trained biomedical engineers in the areas of developmental functional imaging and data science (Dustin Scheinost) and MRS (Christoph Juchem). This proposal is significant because it will provide mechanistic and system levels information about the rapidly developing brain that map on to an important behavioral system, emotion regulation. This research has the potential to reveal trajectories of behavioral health in early childhood and present approaches to detect early markers of psychiatric risk.

虽然五分之一的儿童面临精神疾病的风险，但只有二十分之一的幼儿接受心理保健。对精神疾病的早期原因和先兆症状的了解仍然存在差距；所以，许多儿童直到学龄时才被确定为处于危险之中，此时可以做出可靠的诊断。产前感染、压力、医疗状况和环境病原体引起的母体免疫激活（MIA）与后代患精神疾病的风险有关。我们对早期的认识仍然存在差距这种风险的大脑和行为前因。临床前研究表明 MIA 可能导致生化发育中的大脑发生变化，破坏大脑与行为功能的关联。我们建议审查产前暴露于 MIA 是否会导致发育中大脑的代谢和功能改变人类后代的类似行为表型。我们之前的工作表明 MIA（白细胞介素 6；IL- 6）与显着网络（SAN）的功能连接相关，显着网络是情感的网络组成部分新生儿的调节。扩展这一点，我们将在以下区域进行纵向磁共振成像（MRI）扫描：胎儿、新生儿和婴儿以确定 SAN 的改变是否起源于胎儿期并绘制地图早期生活中 SAN 的发展轨迹。与此同时，我们计划收集纵向磁共振光谱学 (MRS)，提供有关代谢和细胞特性的机械信息可能对应于 SAN 功能活动的中断。我们的试点数据表明 MIA 与肌醇是新生儿大脑中星形胶质细胞激活的指标。我们的中心假设是 MIA，通过炎症（主要：IL-6）和感染（主要：总免疫球蛋白 G）水平证明，相关性 SAN 中的大脑连接和代谢以及从胎儿到婴儿期的行为反应。一百七十五名孕妇-胎儿二人组将从妊娠 12 周开始参与这项研究至产后 9 个月的生活。孕妇将在三点进行抽血和心理评估 33-36 周时的时间点、胎儿生理评估和 MRI。婴儿将参加 MRI（2-6 出生后几周和 4 个月）以及 4 个月和 9 个月大时基于观察者的行为范式。我们的该提案采用协作科学方法，将围产期发育神经科学结合在一起（Marisa Spann）、心理神经免疫学（Staci Bilbo）、母胎医学（Mirella Mourad）和在发育功能成像和数据科学领域接受过定量培训的生物医学工程师（达斯汀·沙伊诺斯特）和 MRS（克里斯托夫·尤赫姆）。该提案意义重大，因为它将提供机制以及有关快速发育的大脑的系统级信息映射到重要的行为系统，情绪调节。这项研究有可能揭示幼儿期行为健康的轨迹并提出检测精神风险早期标志的方法。