Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat

Abstract

Background: Environmental or genetic disturbances of early brain development are suggested to underlie the pathophysiology of several adult-onset neuropsychiatric disorders. We traced the developmental trajectories of brain structural and behavioral abnormalities from adolescence to young adulthood in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (poly-I:C) in pregnancy.

Methods: Pregnant rats were injected on gestational day 15 with poly-I:C (4 mg/kg) or saline. Volumes of lateral ventricles, hippocampus, striatum, and prefrontal cortex in male and female offspring were assessed longitudinally at postnatal days 35, 46, 56, 70, and 90 using in vivo magnetic resonance imaging. At parallel time windows, groups of offspring from the same litters underwent behavioral testing (latent inhibition and amphetamine-induced activity) and magnetic resonance imaging (cross-sectional assessment).

Results: The specific developmental trajectories of volumetric changes in both control and poly-I:C offspring were region-, age-, and sex-specific, but overall, poly-I:C offspring had smaller volumes of the hippocampus, striatum and prefrontal cortex, and larger ventricular volume. Structural pathology in different regions had different times of onset and was gradually accompanied by behavioral deficits, disrupted latent inhibition, and excessive amphetamine-induced activity. The onset of structural frontocortical and ventricular abnormalities and behavioral abnormalities was delayed in females. In both sexes, hippocampal and striatal volume reduction predated the appearance of behavioral abnormalities.

Conclusions: Prenatal insult interferes with postnatal brain maturation, which in turn may result in behavioral abnormalities.