Sex-specific trajectories of adolescent brain maturation and sensorimotor gating after maternal influenza infection in mice

<title>Abstract</title> <p>Maternal infection during pregnancy is increasingly recognised as a risk factor for neurodevelopmental disorders, yet how a clinically relevant viral insult reshapes brain maturation remains poorly defined. Here, we used a live influenza A virus model of maternal immune activation (MIA) to examine whether prenatal infection alters offspring brain development across adolescence. Pregnant mice were infected at embryonic day 12, and offspring underwent longitudinal high-field MRI at 5, 8, 11 and 14 weeks, followed by prepulse inhibition (PPI) testing as a measure of sensorimotor gating. Maternal influenza exposure produced sex- and age-dependent alterations in brain maturation. Atlas-based volumetry identified FDR-corrected sex- and age-dependent treatment-related effects in the hippocampal CA1 region, while tensor-based morphometry revealed dynamic structural changes across sensory cortices, insula, hippocampus and thalamus. Network analyses further showed disrupted inter-regional structural coordination, particularly in males during early–mid adolescence. Despite partial normalisation of network architecture by late adolescence, influenza-exposed offspring displayed impaired PPI. Partial least squares regression linked these behavioural deficits to altered developmental trajectories in somatosensory cortex, medulla and pons. These findings show that maternal influenza infection does not simply produce static brain abnormalities but alters the trajectory and coordination of adolescent brain maturation in a sex-, region- and circuit-specific manner with long-term behavioural consequences. This work identifies developmental windows and neural systems that may guide future strategies to prevent or reverse infection-associated neurodevelopmental vulnerability.</p>