Intrinsic gestational timing governs human cerebellar development after preterm birth

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Abstract
Intrinsic programs shape brain maturation; however, which of these programs are perturbed by prematurity as well as 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. Using 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, which indicate lineage-specific developmental asynchrony. Thus, prematurity constitutes biologically displaced maturation, in which infants of equivalent postmenstrual age occupy divergent developmental states.
Funding Information
  • National Institutes of Health (R37NS109478)
  • National Institutes of Health (Child Health Research Career Development Award (CHRCDA))
  • National Institutes of Health (1R21NS135088)
  • Raynor Cerebellum Project
  • American SIDS Institute
  • Children’s National Board of Visitors’ Grant
  • DC-IDDRC (P50HD105328)

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