Elsevier

NeuroImage

Volume 52, Issue 1, 1 August 2010, Pages 1-8
NeuroImage

Supplement
Voxel-based analysis of postnatal white matter microstructure in mice exposed to immune challenge in early or late pregnancy

https://doi.org/10.1016/j.neuroimage.2010.04.015Get rights and content

Abstract

Maternal infection during prenatal life is a risk factor for neurodevelopmental disorders, including schizophrenia and autism, in the offspring. We and others have reported white mater microstructure abnormalities in prefrontal–striato-temporal networks in these disorders. In addition we have shown that early rather than late maternal immune challenge in the mouse model precipitates ventricular volume change and impairs sensorimotor gating similar to that found in schizophrenia. However, it is not known whether the timing of maternal infection has a differential impact upon white matter microstructural indices. Therefore this study directly tested the effect of early or late gestation maternal immune activation on post-natal white matter microstructure in the mouse. The viral mimic PolyI:C was administered on day 9 or day 17 of gestation. In-vivo diffusion tensor imaging (DTI) was carried out when the offspring reached adulthood. We describe a novel application of voxel-based analysis to evaluate fractional anisotrophy (FA). In addition we conducted a preliminary immunohistochemical exploration of the oligodendrocyte marker, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), to determine whether differences in myelination might contribute to any changes in FA observed. Our results provide experimental evidence that prenatal exposure to inflammation elicits widespread differences in FA throughout fronto-striatal–limbic circuits compared to control saline exposure. Moreover, FA changes were more extensive in the group exposed earliest in gestation.

Introduction

Evidence from multiple directions supports a consensus view that schizophrenia and related disorders including autism have onset early in neurodevelopment (Bailey et al., 1998, Beckmann, 1999, Bullmore et al., 1998, Bunney et al., 1995, McAlonan et al., 2005, Murray, 1994, Murray et al., 1992, Pilowsky et al., 1993). We have previously reported diffusion tensor imaging (DTI) data supporting white matter microstructure anomalies in these conditions (Cheung et al., 2009, Cheung et al., 2008). This likely contributes to the differences in functional connectivity consistently observed during higher-order cognitive processing in schizophrenia and autism compared to typically developing individuals (Demirci et al., 2009, Foucher et al., 2005, Just et al., 2007, Koshino et al., 2005, Schlosser et al., 2003, Zhou et al., 2007).

Epidemiological studies implicate maternal infection during prenatal life as a strong risk factor for neurodevelopmental disorders in the offspring (Brown, 2006, Chess, 1971, O'Callaghan et al., 1991, Sham et al., 1992, Takei et al., 1995). This has established a platform for the development of rodent models in which maternal infection precipitates a behavioural phenotype with features similar to those found in schizophrenia and/or autism spectrum (Fatemi et al., 2005, Fatemi et al., 2008a, Shi et al., 2003). It appears that non-specific activation of the maternal immune response (MIA) using viral analogues is sufficient to bring about behavioural phenotypic change in the offspring (Meyer et al., 2005, Meyer et al., 2006, Meyer et al., 2007, Patterson, 2002, Watanabe et al., 2004) and that early gestational exposure triggers more extensive behavioural and neuroanatomical sequelae than later exposure (Li et al., 2009, Meyer et al., 2007).

There is preliminary data to support a link between prenatal inflammatory exposure in late gestation and changes in white matter markers in offspring (Fatemi et al., 2008b), however the latter study was restricted to pre-selected regions of interest (ROI) and examined only a late gestational exposure. Given the crucial role of timing in determining phenotypic outcome (Li et al., 2009, Meyer et al., 2007), we examined white matter FA in adult mice following exposure in early gestation, day 9 (GD9) and late pregnancy (GD17) time points. Schizophrenia and autism spectrum disorders are complex and unlikely to be explained by any single, well-circumscribed lesion. Therefore, in order not to restrict our analysis to predefined ROIs, we planned to exploit voxel-wise analysis techniques (VBM) used in the human literature to explore FA in mouse brain in-vivo. From the clinical literature we predicted widespread involvement of white matter tracks, especially in front-striatal–limbic circuits and the corpus callosum (Cheung et al., 2009, Cheung et al., 2008, Ellison-Wright and Bullmore, 2009). We expected that FA anomalies would be more extensive in the early exposed group. In addition we conducted a preliminary immunohistochemical exploration of the oligodendrocyte marker 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) to determine whether myelination processes might contribute to any changes in FA observed.

Section snippets

Animals

Timed pregnant female C57BL6/N mice were supplied by The University of Hong Kong, Laboratory Animal Unit, (LAU) for a study approved by the Committee on the Use of Live Animals in Teaching and Research at The University of Hong Kong. Prenatal treatment comprised either saline control or a 5-ml/kg injection volume of 5 mg/kg PolyI:C (potassium salt, Sigma Aldrich) administered via the tail vein on GD9 or GD17. Offspring were weaned and sexed at postnatal day 21. Three to 4 male littermates were

VBM

Voxel-wise analysis indicated widespread regions of significantly lower and higher FA in GD9 and GD17 PolyI:C exposed animals relative to controls. As can be seen in Table 1 and Fig. 1, FA was lower in both GD9 and GD17 polyI:C exposed mice compared to controls in the left amygdala and cerebral peduncles and right fimbria. There were additional regions of lower FA in the GD 9 group including anterior cingulate, ventral striatum and external capsule. In contrast GD17 polyI:C animals had lower FA

Discussion

The present study yields direct experimental evidence that prenatal exposure to maternal inflammation disrupts white matter microstructure across a number of critical brain circuits. In either early or late gestation, MIA elicited widespread bidirectional changes in FA throughout fronto-striatal–limbic circuits. Regions with lower FA were more extensive in the early exposed group. In both groups there were regions with increased FA but again, these were more extensive in the early exposed

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