Early or Late Gestational Exposure to Maternal Immune Activation Alters Neurodevelopmental Trajectories in Mice: An Integrated Neuroimaging, Behavioral, and Transcriptional Study

Abstract

BackgroundExposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear. MethodsWe characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing. ResultsEarly MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation. ConclusionsLeveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.