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 ...