Intrinsic Gestational Timing Governs Human Cerebellar Development After Preterm Birth

Abstract

Intrinsic programs shape brain maturation, yet which are perturbed by prematurity, and the molecular pathways involved remain unknown. The human cerebellum serves as a paradigm of extrauterine development; its accelerated growth and circuit formation align with the third trimester, a period disrupted by preterm delivery. Through multimodal datasets encompassing in vivo neuroimaging and neurodevelopmental outcomes with postmortem spatial-transcriptomic and histopathological profiling, we show that prematurity diverts the cerebellar developmental trajectory. Cerebellar growth and functional outcomes scaled with gestational age, despite modifying perinatal exposures. Spatially resolved developmental programs underlying macroscopic trajectories were marked by incomplete granule cell maturation and impaired Purkinje cell structural refinement, indicating lineage-specific developmental asynchrony. Thus, prematurity constitutes biologically displaced maturation, in which infants of equivalent post-menstrual age occupy divergent developmental states.