Project 3: Neurodevelopment in an NHP MIA model

项目 3：NHP MIA 模型中的神经发育

• 批准号: 10378733
• 负责人: Melissa Dawn Bauman
• 金额: $ 108.68万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378733
• 关键词: Acute; Address; Age-Months; Animal Model; Animals; Autopsy; Bacterial Infections; Behavior; Behavioral; Biological Assay; Biological Markers; Biological Models; Biopsy; Birth; Blood specimen; Brain; Child; Clinical; Cognitive; Collaborations; Data; Development; Diagnosis; Disease; Environment; Etiology; Evaluation; Exhibits; Exposure to; Female; Fetal Tissues; Gene Expression; Goals; Growth; Heterogeneity; Human; Immune; Immune system; Impairment; Infection; Inflammatory; Knowledge; Lead; Link; Macaca mulatta; Measurement; Measures; Mental disorders; Modeling; Monkeys; Motivation; Mus; Neurodevelopmental Disorder; Neuroimmunomodulation; Outcome; Outcome Measure; Peripheral; Phenotype; Physiology; Population; Pre-Clinical Model; Predictive Factor; Predisposition; Pregnancy; Primates; Risk; Risk Factors; Rodent; Sampling; Schizophrenia; Sex Differences; Social Behavior; Structure; Systems Development; Time; TimeLine; Tissue Sample; Tissues; Virus Diseases; Woman; behavioral outcome; behavioral phenotyping; brain tissue; cell type; cognitive control; cohort; computer framework; cytokine; epidemiology study; experience; fetal; fetal blood; gray matter; human disease; immune activation; immune function; indexing; inflammatory marker; insight; male; neurobehavioral; neurodevelopment; neuroimaging; nonhuman primate; offspring; patient population; postnatal; postnatal period; prenatal; prepuberty; resilience; response; sex; social; success; tissue archive; young adult

PROJECT SUMMARY – PROJECT 3 Epidemiological studies have implicated maternal infection in the etiology of psychiatric and neurodevelopmen- tal disorders, such as schizophrenia (SZ). Animal models of maternal immune activation (MIA) further support the link by demonstrating that experimental activation of the maternal immune system induces changes in offspring brain and behavioral development in domains relevant to human neurodevelopmental disease. However, critical gaps in knowledge persist related to two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal infection and (ii) susceptible pregnancies lead to multiple distinct disorders in offspring. We have recently extended the results of the rodent MIA model into a species more closely related to humans – the rhesus monkey. Compared with rodents, nonhuman primate (NHPs) are more similar to humans in placental structure and physiology, gestational timelines, brain develop- ment, immune ontogeny, neuroanatomical organization, and behavioral complexity. The NHP thus provides a translationally relevant model system to systematically examine issues related to MIA risk, resilience and phenotypic heterogeneity. Results to date indicate that MIA-exposed male monkeys exhibit immune alterations in the early postnatal period, followed by reductions in frontal grey matter as early as 6 months of age and sub- tle impairments in social behavior and cognitive processing that emerge prior to 18 months of age. These early developmental changes in MIA-exposed NHPs provide an opportunity to identify translationally relevant factors that predict susceptibility or resilience to prenatal immune challenge, and to explore for the first time the impact of MIA in female NHP offspring. In this project we will (i) quantify the acute maternal-placental-fetal response to prenatal immune challenge and determine the relationship with subsequent changes in NHP neurobehavioral development; (ii) determine the impact of MIA on species-typical social and cognitive developmental milestones in male and female NHP offspring; and (iii) characterize long-lasting changes in dynamic cellular immune function, peripheral inflammatory markers, and brain cytokines in NHP offspring. Our project directly addresses the central hypothesis and all 3 aims of this Conte Center and leverages the unique features of the NHP model to bridge the gap between rodent MIA models and patient populations. Results from this project will provide unprecedented insight into MIA-induced changes in the primate maternal-placental-fetal environment in collaboration with Project 1. Our comprehensive assessment of NHP behavior is translationally aligned with Project 2 rodent studies and Project 5 human studies, resulting in an overarching computational framework that will bridge the species. The same NHPs that undergo behavioral phenotyping will participate in longitudinal neuroimaging (Project 5) followed by characterization of brain cytokines and changes in gene expression (Project 4). If successful, our project will identify translational biomarkers to predict which pregnan- cies are most vulnerable, thus providing a means to mitigate the deleterious effects of MIA during pregnancy.

项目摘要 - 项目3 流行病学研究已经在精神病和神经发育者的病因学中实施了母体感染。 TAL疾病，例如精神分裂症（SZ）。母体免疫激活（MIA）的动物模型进一步支持 通过证明母体免疫系统的实验激活引起的链接会引起变化 与人类神经发育疾病有关的领域的大脑和行为发展。 但是，知识的关键差距持续与此风险因素的两个最重要方面有关 人类疾病：（i）大多数怀孕对孕产妇感染有弹性，（ii）易感性怀孕导致 后代多种不同的疾病。我们最近将啮齿动物MIA模型的结果扩展到了 物种与人类（恒河猴）更紧密相关。与啮齿动物相比 （NHP）在占地结构和生理学，妊娠时间表，大脑发育中更与人类更相似 预测，免疫本体发育，神经解剖组织和行为复杂性。因此，NHP提供了 翻译相关的模型系统，以系统地检查与MIA风险，韧性和 表型异质性。迄今为止的结果表明，暴露于MIA的雄性猴子暴露了免疫改变 在产后早期，随后在6个月大的时候减少额叶灰质和 在18个月大之前出现的社会行为和认知处理的损害。这些早 暴露于MIA的NHP的发展变化提供了一个机会来识别翻译相关的因素 这可以预测对产前免疫挑战的敏感性或韧性，并首次探索影响 女性NHP后代的MIA。在这个项目中，我们将（i）量化对 产前免疫挑战并确定与随后NHP神经行为变化的关系 发展; （ii）确定MIA对物种典型的社会和认知发展的影响 男性和女性NHP后代的里程碑； （iii）表征动态细胞的持久变化 NHP后代中的免疫功能，周围炎症标记和脑细胞因子。我们的项目直接 解决了中心假设和该孔戴中心的所有3个目标，并利用了该中心的独特特征 NHP模型弥合啮齿动物MIA模型和患者种群之间的差距。该项目的结果 将为MIA引起的初级植物 - 定位 - 狂欢的变化提供前所未有的洞察力 与项目1合作的环境。我们对NHP行为的全面评估是翻译的 与项目2啮齿动物研究和项目5人类研究一致，导致了总体计算 将桥接物种的框架。经历行为表型的同一NHP将参与 纵向神经影像学（项目5），然后表征脑细胞因子和基因的变化 表达式（项目4）。如果成功，我们的项目将确定转化生物标志物，以预测哪种怀孕 - CIE是最脆弱的，因此提供了一种减轻怀孕期间MIA的有害影响的手段。