Prematurity Reprograms Cerebellar Development and Long-Term Behavior

Preterm survivors often develop motor and socio-cognitive impairments, yet mechanisms remain limited because prematurity arises from diverse combinations of perinatal insults. Here, we use a mouse model with experiment-controlled timing and sequence of maternal immune activation (MIA) and neonatal hypoxia (Hx), two of the most consequential prematurity-associated insults. We show that these insults remodel the developing cerebellum through distinct processes. Hx arrests granule cell maturation and reduces presynaptic excitatory input to Purkinje cells, whereas MIA perturbs granule cell migration and Purkinje dendritic development. Sequential MIA followed by Hx results in progressive neuronal mitochondrial damage and a reprogrammed circuit state. Behavioral phenotyping links these circuit states to alterations in motor-learning and coordination, translating into divergent sensorimotor organization during social investigation. These results identify developmental sequencing following preterm-birth insults as a determinant of cerebellar resilience, providing a mechanistic framework for heterogeneity in neurodevelopmental outcomes after preterm birth.