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

• 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
• 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

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.

每5个儿童中就有1个有精神障碍的风险，但只有1/20的幼儿接受心理健康护理。 对精神疾病的早期原因和先兆症状的认识仍然存在差距；因此， 许多儿童直到学龄期才被确定为有风险，到了学龄期才能可靠地做出诊断。产前 来自感染、压力、医疗条件和环境病原体的母体免疫激活(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。 大脑和行为是这种风险的前因。临床前研究表明MIA可能导致生化 大脑发育过程中扰乱大脑行为功能联系的变化。我们建议研究 产前暴露于MIA是否会导致发育中大脑的代谢和功能改变 人类后代中类似的行为表型。我们先前的工作表明，MIA(白介素6；白介素6) 6)与显著网络(SAN)的功能连通性有关，SAN是情绪的整体网络 调节，在新生儿中。在此基础上，我们将在 胎儿、新生儿和婴儿以确定窦房结的改变是否起源于胎儿期和MAP 早期生命中桑人的发展轨迹。同时，我们计划收集纵向磁共振 光谱学(MRS)，它提供关于代谢和细胞属性的机械信息， 可能对应于SAN功能活动的中断。我们的试验数据表明，MIA与 肌醇，一种星形胶质细胞激活的指标，在新生儿的大脑中。我们的中心假设是MIA， 炎症(主要：IL-6)和感染(主要：总免疫球蛋白G)的水平证明， 与大脑连通性和代谢物在窦房结和行为反应从胎儿到婴儿时期。 175名孕妇-胎儿双胞胎将从怀孕12周开始参与这项研究 至9个月的产后寿命。孕妇将在三点进行抽血和心理评估。 33-36周的时间点和胎儿生理评估及MRI检查。婴儿将参加核磁共振(2-6 出生后4周和4个月)和4个月和9个月龄时基于观察者的行为范式。我们的 Proposal使用协作科学的方法，将围产期发育神经科学结合在一起 (玛丽莎·斯潘)，精神神经免疫学(斯塔西·比尔博)，母胎医学(米雷拉·穆拉德)，以及 在发展功能成像和数据科学领域接受过量化培训的生物医学工程师 (Dustin Scheinost)和夫人(Christoph Juchim)。这项提议意义重大，因为它将提供机械的 以及关于快速发展的大脑的系统层次信息，这些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儿童早期行为健康的轨迹 并提出了检测精神风险的早期标志物的方法。