Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study

William R Crum,Stephen J Sawiak,Winfred Chege,Jonathan D Cooper,Steven C.R Williams,Anthony C Vernon

doi:10.1016/j.bbi.2016.12.008

Abstract

Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.

Highlights

Longitudinal magnetic resonance imaging (MRI) studies of typically developing individuals show that adolescence and early adulthood are dynamic and critical periods of brain maturation (Shaw et al, 2008; Sussman et al, 2016; Vijayakumar et al, 2016; Whitaker et al, 2016; Zhou et al, 2015; Sowell et al, 2001; Sowell et al, 2003)
Total brain volume increased with age at each post-natal timepoint, but did so comparably between SAL and polyribocytidylic acid (POL)-exposed litters treatment did not affect total brain volume, but led to a reduction in the absolute volume of (b) the lateral ventricles by PND180
Post-hoc testing of the interaction confirmed significantly smaller absolute lateral ventricles (LV) volume in POL litters compared to SAL at PND180 (Table 1; Fig. 1b)

Summary

Introduction

Longitudinal magnetic resonance imaging (MRI) studies of typically developing individuals show that adolescence and early adulthood are dynamic and critical periods of brain maturation (Shaw et al, 2008; Sussman et al, 2016; Vijayakumar et al, 2016; Whitaker et al, 2016; Zhou et al, 2015; Sowell et al, 2001; Sowell et al, 2003). Genetic or environmental risk factors is a potential susceptibility mechanism for the development of psychopathology in adult life, including schizophrenia (Millan et al, 2016; Insel, 2010; Rapoport et al, 2012) This is supported by data from longitudinal MRI studies of youth at high risk for psychosis (Cannon et al, 2015), youth with sub-threshold psychosis spectrum (PS) symptoms (Satterthwaite et al, 2016) and childhood onsetschizophrenia (COS) (Alexander-Bloch et al, 2014). These have established that structural and functional brain abnormalities similar to those observed in adult patients are already present early in life.

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