Cellular, molecular, and functional imaging approaches to understanding early neurodevelopment in autism

耶鲁大学中心是一个多学科的研究项目，包括五个相互关联的研究， 项目和四个核心致力于推进对ASD早期神经生物学的理解。该提案 汇集了来自发展精神病理学和神经生物学领域的专家团队， 遗传学，神经学，放射学，神经科学和统计学，以确定分子，细胞和神经 从产前阶段到儿童期与ASD相关的机制。我们的调查集中在两组 ASD儿童的弟弟妹妹，由于家庭因素，他们处于发展的高风险（HR）， 疾病：一个前瞻性队列在产前和围产期招募，随访24个月， 通过我们过去的研究，在24个月时特征良好的HR兄弟姐妹将达到12岁 在耶鲁大学ACE的生命中。这些队列使我们能够在自闭症期间寻找ASD的神经特征。 胎儿，新生儿和学龄期，以及检查整个风险谱的连接体， 男性和女性的ASD。虽然ASD的神经和行为标志物已在6- 一个月大的婴儿后来被诊断为ASD，据我们所知， 和新生儿功能连接的研究进展新的数据表明，男性，而不是女性，ASD受试者 证明了神经网络的重大改变，而且-第一次-拟议的研究将 不仅要确定ASD中连接的变化，还要确定胎儿/新生儿性别对这些变化的影响。 变化由于最近的研究表明，大脑发育中的神经可塑性跨越了晚一秒， 在妊娠的第三个三个月，有必要了解与ASD相关的因素是否正在发展， 这同样的时间框架，并了解任何性别差异，可能是明显的，甚至在早期的年龄。的 iPSC衍生的类器官系统模拟人类胎儿发育，使我们能够研究神经生物学风险 和保护因素，在这一时期发挥独特的作用，并可能使患者特异性的发现， 神经元或干细胞生物标志物，可用作ASD风险或恢复力的预测因子。耶鲁ACE 目的依赖于应用尖端的方法来分析连接体，胎儿和新生儿 使用iPSC方法和高分辨率双光子成像对神经发育进行成像建模 方法，ASD早期标志物的开发，研究早期注意力和学习，新的预测 将大脑组织与行为联系起来的模型，以及整合数据谱的统计方法 来实现这些目标。来自联合项目的结果具有很大的潜力，以确定新的 出生时的诊断和预后标志物，识别风险的神经，细胞和分子基础， ASD的保护机制，阐明ASD性别差异的神经基础。

The Yale Center represents a multidisciplinary research program consisting of five inter-related research projects and four cores dedicated to advancing understanding of early neurobiology of ASD. The proposal brings together a team of experts from the fields of developmental psychopathology and neurobiology, genetics, neurology, radiology, neuroscience, and statistics to identify the molecular, cellular, and neural mechanisms related to ASD from prenatal stages to childhood. We focus our investigation on two cohorts of younger siblings of children with ASD who, due to familial factors, are at high risk (HR) for developing the disorder: a prospective cohort recruited pre- and perinatally and followed through 24 months, and a cohort of HR siblings who was well-characterized at 24 months through our past studies and will reach the age of 12 years during the life of the Yale ACE. These cohorts enable our search for neural signatures of ASD during fetal, neonatal, and school-age periods, as well as to examine the connectome across the spectrum of risk for ASD both in males and females. Although neural and behavioral markers of ASD have been reported in 6- month-old infants later diagnosed with ASD, to our best knowledge, this is the first investigation into both fetal and neonatal functional connectivity in ASD. Emerging data suggest that male, but not female, ASD subjects demonstrate significant alterations in neural networks, and – for the first time – the proposed studies will identify not only the changes in connectivity in ASD but also the impact of fetal/neonatal sex upon these changes. Since recent studies demonstrate neuroplasticity in the developing brain across the late second and third trimesters of gestation, it is essential to understand if the factors associated with ASD are developing in this same time frame and to understand any sex differences that may be apparent even at that early age. The iPSC derived organoid system models human fetal development, allowing us to investigate neurobiological risk and protective factors that play a unique role in this period and may enable the discovery of patient-specific neuronal or stem cell biomarkers that could be used as predictors of risk or resilience in ASD. The Yale ACE aims rely on application of cutting-edge approaches to the analysis the connectome, fetal and neonatal imaging modeling neural development using the iPSC methodology with high resolution dual photon imaging approaches, the development of early markers for ASD, studying early attention and learning, novel predictive models relating brain organization to behavior, and statistical approaches for integrating the spectrum of data types across to address these aims. Results from the combined projects have a great potential to identify novel diagnostic and prognostic markers at the time of birth, identify neural, cellular, and molecular bases of risk and protective mechanisms in ASD, and clarify neural bases of sex differences in ASD.