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

耶鲁大学中心代表了一个由五项相互关联的研究组成的多学科研究计划 致力于促进对ASD早期神经生物学的理解的项目和四个核心。这项建议 汇集了来自发育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，以识别分子、细胞和神经 自闭症从产前到儿童期的相关机制。我们的调查集中在两个队列中 患有自闭症儿童的年幼兄弟姐妹，由于家庭因素，他们患上自闭症的风险很高 障碍：在产前和围产期招募的前瞻性队列，并跟踪观察24个月，以及 HR兄弟姐妹，通过我们过去的研究，他们在24个月大时特征良好，将年满12岁 在耶鲁王牌的一生中。这些队列使我们能够搜索ASD的神经特征 胎儿、新生儿和学龄期，以及检查各种风险的连接体 ASD在男性和女性中都存在。虽然ASD的神经和行为标记物已报道在6- 一个月大的婴儿后来被诊断出患有ASD，据我们所知，这是对这两个胎儿的第一次调查 ASD中的新生儿功能连接性。新出现的数据表明，男性，但不是女性，ASD受试者 证明了神经网络的重大变化，而且--第一次--拟议的研究将 不仅确定ASD中连接性的变化，而且确定胎儿/新生儿性别对这些变化的影响 改变。由于最近的研究表明，在发育中的大脑中，神经可塑性跨越了第二秒和 在妊娠晚期，了解与ASD相关的因素是否在 这一相同的时间框架，并了解任何可能明显的性别差异，即使在那个年纪。这个 IPSC衍生的有机体系统模拟人类胎儿发育，使我们能够研究神经生物学风险 和保护性因素，在这一时期发挥独特的作用，并可能使发现特定于患者的 神经元或干细胞生物标记物可以用来预测ASD的风险或弹性。耶鲁王牌 AIMS依赖于应用尖端方法来分析连接体、胎儿和新生儿 高分辨率双光子成像IPSC方法用于神经发育的成像建模 方法，ASD早期标志物的开发，研究早期注意和学习，新的预测性 将大脑组织与行为联系起来的模型，以及整合数据光谱的统计方法 通过打字来解决这些目标。联合项目的结果有很大的潜力来确定新的 出生时的诊断和预后标志物，识别风险的神经、细胞和分子基础和 ASD的保护机制，并阐明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.