Project 3: Neurodevelopment in an NHP MIA model

项目摘要--项目3 流行病学研究表明，母体感染与精神和神经发育的病因有关-- 精神障碍，如精神分裂症(SZ)。母体免疫激活(MIA)的动物模型进一步支持 这一联系是通过证明母体免疫系统的实验性激活导致 与人类神经发育疾病相关领域的子代大脑和行为发育。 然而，与这一风险因素的两个最重要方面有关的知识差距仍然存在 人类疾病：(一)大多数怀孕对产妇感染有抵抗力；(二)易感妊娠导致 在后代中有多种明显的疾病。我们最近将啮齿动物MIA模型的结果扩展到 与人类关系更近的物种--恒河猴。与啮齿动物相比，非人灵长类 (NHP)在胎盘结构和生理、妊娠时间线、大脑发育方面与人类更相似- 情绪、免疫个体发育、神经解剖组织和行为复杂性。因此，国家卫生计划提供了一个 翻译相关的模型系统，系统地检查与MIA风险、复原力和 表型异质性。到目前为止的结果表明，暴露于MIA的雄性猴子表现出免疫变化 在出生后早期，紧随其后的是6个月龄时额叶灰质的减少和亚 在18个月之前出现的社交行为和认知处理方面的障碍。这些早期的 暴露于MIA的NHP的发育变化为识别翻译相关因素提供了机会 预测对产前免疫挑战的易感性或弹性，并首次探索其影响 在雌性NHP后代中发现MIA。在这个项目中，我们将(I)量化孕妇-胎盘-胎儿的急性反应 产前免疫挑战及其与NHP神经行为后续变化的关系 发展；(2)确定MIA对物种的影响--典型的社会和认知发展 男性和女性NHP后代的里程碑；以及(Iii)表征动态细胞的长期变化 NHP子代的免疫功能、外周炎症标志物和脑细胞因子。我们的项目直接 阐述了Conte中心的中心假设和所有3个目标，并利用了 NHP模型，以弥合啮齿动物MIA模型和患者群体之间的差距。本项目的成果 将提供前所未有的洞察MIA诱导的灵长类母体-胎盘-胎儿的变化 与项目1合作的环境。我们对NHP行为的全面评估是翻译过来的 与项目2啮齿动物研究和项目5人类研究保持一致，导致总体计算 这个框架将在物种之间架起桥梁。接受行为表型鉴定的相同的NHP将参与 纵向神经成像(项目5)，随后描述脑细胞因子和基因变化 表达(项目4)。如果成功，我们的项目将识别翻译生物标记物来预测哪个孕妇- CIES是最脆弱的，因此提供了一种手段来减轻怀孕期间MIA的有害影响。

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.