Project 3: Neurodevelopment in an NHP MIA model

项目概要-项目3 流行病学研究表明，母体感染与精神和神经发育有关， 言语障碍，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性激活诱导了 在与人类神经发育疾病相关的领域中的后代大脑和行为发育。 然而，在这一风险因素的两个最重要方面， 人类疾病：（一）大多数妊娠对母体感染有抵抗力，（二）易感妊娠导致 在后代身上发现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 与人类关系更近的物种--恒河猴。与啮齿类动物相比， （NHP）在胎盘结构和生理学，妊娠时间表，大脑发育方面与人类更相似- 智力、免疫个体发育、神经解剖学组织和行为复杂性。因此，NHP提供了一个 翻译相关模型系统，系统地检查与MIA风险、弹性和 表型异质性迄今为止的结果表明，MIA暴露的雄性猴子表现出免疫改变， 在出生后的早期，其次是减少额灰质早在6个月的年龄和亚 在18个月之前出现的社会行为和认知过程的轻微损伤。这些早期 暴露于MIA的NHP的发育变化提供了一个机会，以确定预防相关因素 预测对产前免疫挑战的易感性或恢复力，并首次探索 在NHP雌性后代中的MIA。在这个项目中，我们将（i）量化急性母-胎盘-胎儿反应， 产前免疫激发，并确定与随后的NHP神经行为变化的关系 （二）确定MIA对物种典型的社会和认知发展的影响 雄性和雌性NHP后代的里程碑;以及（iii）表征动态细胞内的长期变化 免疫功能，外周炎症标志物和脑细胞因子在NHP后代。我们的项目直接 解决了中心的假设和所有3个目标，这个孔蒂中心，并利用独特的功能， NHP模型，以弥合啮齿动物MIA模型和患者人群之间的差距。本项目的成果 将提供前所未有的深入了解MIA诱导的灵长类动物母体-胎盘-胎儿的变化 与项目1合作。我们对NHP行为的全面评估是谨慎的 与项目2啮齿动物研究和项目5人类研究一致，导致总体计算 一个可以连接物种的框架。接受行为表型分析的相同NHP将参与 纵向神经成像（项目5），然后表征脑细胞因子和基因变化， 表达式（项目4）。如果成功，我们的项目将确定翻译生物标志物，以预测哪一种生物标志物- 婴儿是最脆弱的，因此提供了一种手段，以减轻怀孕期间失踪的有害影响。

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.