Sex-Dependent and Dynamic Brain Structural Mri Changes in Mice Following Influenza a Virus Maternal Immune Activation

Background Maternal infections or inflammatory insults during pregnancy, can significantly impact brain development in the offspring, and have been associated with later neurodevelopmental disorders, including schizophrenia. Preclinical maternal immune activation (MIA) models provide valuable tools to explore factors affecting neurodevelopment under controlled environments. Unlike previous studies that used synthetic viral mimetics like poly(I:C), live influenza A virus (IAV) was utilized to induce MIA (IAV-MIA), providing a more ‘real-world’ model. We used MRI to examine brain changes at multiple time points during brain development (from early adolescence at week 5, to adulthood at week 14 postnatally) to assess the impact of IAV-MIA. We also examined associations with sensorimotor-gating deficits. Aims & Objectives We hypothesised that: (i) prenatal IAV-MIA alters trajectories of brain development during adolescence; and (ii) the most perturbed trajectories predict sensorimotor-gating deficits, a schizophrenia-relevant behaviour. Method Pregnant C57BL/6 dams received intranasal HKx31 (H3N2) virus or PBS at embryonic day 12. Offspring (n=6-8/sex/group) underwent longitudinal 9.4 T T2* MRI at 5, 8, 11, and 14 weeks. Atlas-based segmentation yielded regional volumes; tensor-based morphometry (TBM) provided voxel-wise Jacobian maps. Linear mixed-effects models tested MIA×Age×Sex interactions. Graph-theoretical metrics quantified reorganisation of volume-correlation networks. At 14.5 weeks, sensorimotor-gating deficits were assessed by prepulse inhibition (PPI) and linked to developmental trajectory parameters by partial-least-squares regression. Results Brain structural trajectory change was highly significant in the CA1 area of hippocampus (p<0.0003) in the atlas-based analysis. TBM showed IAV-MIA-dependent age effects with greater sex-related deviations among males than females in various regions. Male MIA networks showed marked reorganisation between 5-8 weeks (Jaccard similarity ↓ 64%, p=0.034) and increased global closeness (↑30%, p=0.032), whereas female changes were subtler and earlier. PPI was reduced in MIA offspring (F(1,28)=5.26, p=0.030). PLS linked PPI deficits to intercept and quadratic terms of somatosensory cortex, pons and medulla trajectories (Component 1, p=0.0009). Discussion & Conclusions IAV-MIA induces dynamic, sex-dependent structural disruption, with adolescence (week 8) emerging as a male-vulnerable window. Coupling of specific volumetric trajectories with impaired PPI highlights candidate macroscopic biomarkers and developmental periods as potential targets for intervention in schizophrenia-relevant circuitry.