SupplementVoxel-based analysis of postnatal white matter microstructure in mice exposed to immune challenge in early or late pregnancy
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
References (79)
- et al.
An investigation of the Wnt-signalling pathway in the prefrontal cortex in schizophrenia, bipolar disorder and major depressive disorder
Schizophr. Res.
(2002) - et al.
Prenatal infection and cavum septum pellucidum in adult schizophrenia
Schizophr. Res.
(2009) - et al.
Does dysplasia cause anatomical dysconnectivity in schizophrenia?
Schizophr. Res.
(1998) - et al.
Wnt/Axin1/beta-catenin signaling regulates asymmetric nodal activation, elaboration, and concordance of CNS asymmetries
Neuron
(2007) - et al.
Selective neurotoxic effects of nicotine on axons in fasciculus retroflexus further support evidence that this a weak link in brain across multiple drugs of abuse
Neuropharmacology
(2000) - et al.
The arcuate fasciculus and the disconnection theme in language and aphasia: history and current state
Cortex
(2008) - et al.
A diffusion tensor imaging tractography atlas for virtual in vivo dissections
Cortex
(2008) - et al.
Virtual in vivo interactive dissection of white matter fasciculi in the human brain
Neuroimage
(2002) - et al.
Development of a high resolution three-dimensional surgical atlas of the murine head for strains 129 S1/SvImJ and C57Bl/6 J using magnetic resonance imaging and micro-computed tomography
Neuroscience
(2007) Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism
Curr. Opin. Neurobiol.
(1997)
Autism, amnesia, hippocampus, and learning
Neurosci. Biobehav. Rev.
Investigation of relationships between fMRI brain networks in the spectral domain using ICA and Granger causality reveals distinct differences between schizophrenia patients and healthy controls
Neuroimage
Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients
Neurobiol. Dis.
The effects of an early stressful life event on sensorimotor gating in adult rats
Schizophr. Res.
Meta-analysis of diffusion tensor imaging studies in schizophrenia
Schizophr. Res.
Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders
Schizophr. Res.
Functional integration in schizophrenia: too little or too much? Preliminary results on fMRI data
Neuroimage
Functional connectivity in an fMRI working memory task in high-functioning autism
Neuroimage
A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition
Neurosci. Biobehav. Rev.
To model a psychiatric disorder in animals: schizophrenia as a reality test
Neuropsychopharmacology
Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia
Neurosci. Biobehav. Rev.
Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology
Brain Behav. Immun.
Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice
Brain Behav. Immun.
Genes, viruses and neurodevelopmental schizophrenia
J. Psychiatry Res.
Schizophrenia: from developmental deviance to dopamine dysregulation
Eur. Neuropsychopharmacol.
Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic
Lancet
Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness
Curr. Opin. Neurobiol.
Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study
Biol. Psychiatry
Anatomical brain connectivity and positive symptoms of schizophrenia: a diffusion tensor imaging study
Psychiatry Res.
Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling
Neuroimage
Cerebral asymmetries in 12-week-old C57Bl/6 J mice measured by magnetic resonance imaging
Neuroimage
The fasciculus retroflexus controls the integrity of REM sleep by supporting the generation of hippocampal theta rhythm and rapid eye movements in rats
Brain Res. Bull.
Possible evolutionary origins of cognitive brain lateralization
Brain Res. Brain Res. Rev.
Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats
Neurosci. Res.
Functional disintegration in paranoid schizophrenia using resting-state fMRI
Schizophr. Res.
Distribution of choline acetyltransferase (ChAT) immunoreactivity in the central nervous system of a chondrostean, the siberian sturgeon (Acipenser baeri)
J. Comp. Neurol.
A clinicopathological study of autism
Brain
Are abnormalities of the Wnt signalling pathway present in schizophrenia?
Schizophr. Res.
Developmental malformations in cerebral structures of schizophrenic patients
Eur. Arch. Psychiatry Clin. Neurosci.
Cited by (52)
Neurodevelopmental insights into circuit dysconnectivity in schizophrenia
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryMaternal Immune Activation by Poly I:C as a preclinical Model for Neurodevelopmental Disorders: A focus on Autism and Schizophrenia
2020, Neuroscience and Biobehavioral ReviewsIncreased extracellular free-water in adult male rats following in utero exposure to maternal immune activation
2020, Brain, Behavior, and ImmunityCitation Excerpt :In vivo magnetic resonance imaging (MRI) applied to MIA rodent investigations showed that prenatal Poly-I:C exposure produced, in the adult offspring, hallmark structural brain changes associated with schizophrenia, including enlarged ventricles and smaller volumes of the striatum, hippocampus and prefrontal cortex (Crum et al., 2017; Li et al., 2009; Piontkewitz et al., 2010, 2011; Piontkewitz et al., 2009; Vernon et al., 2015). In addition, there are preliminary studies to indicate alterations in DTI-derived FA of juvenile (Fatemi et al., 2008) and adult (Li et al., 2010) mice exposed to maternal infection or immune activation, mimicking one of the most well-replicated findings in MRI studies of patients with schizophrenia. It is unknown however, whether white matter abnormalities in MIA-exposed rodents reflect excess free-water, resembling prior observations in FEP.
Hypersynchronicity in the default mode-like network in a neurodevelopmental animal model with relevance for schizophrenia
2019, Behavioural Brain ResearchCitation Excerpt :Fatemi and colleagues investigated fractional anisotropy (FA) in selected white matter structures of male mice prenatally exposed to human influenza virus and observed some alterations at different ages (ranging from birth to young adulthood), which were different depending on the exact timing of the prenatal immune challenge [14,15]. Only one study investigated FA throughout the entire brain of male adult mice exposed to Poly I:C during gestation and reported changes throughout fronto-striatal-limbic circuits, which were more pronounced when mice were exposed during early gestation [17]. Differences in nature and timing of the immune challenge, species and age of the offspring may explain the difference between our results and the results obtained in these studies.
Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study
2017, Brain, Behavior, and ImmunityCitation Excerpt :This can be informative for linking environmental or genetic disturbances with abnormalities of postnatal brain maturation and behaviour and mapping their cellular and molecular correlates (Piontkewitz et al., 2012a; Vernon et al., 2015; Hamburg et al., 2016; Richetto et al., 2016). Accordingly, cross-sectional MRI studies provide evidence for subtle, but enduring, brain structural abnormalities in the adult rodent brain following prenatal exposure to maternal immune activation (MIA) induced by polyriboinosinic-polyribocytidylic acid (POL) (Fatemi et al., 2008; Li et al., 2009, 2010; Richetto et al., 2016; Piontkewitz et al., 2011b, 2009). To date, only a single longitudinal in vivo MRI study has been performed to assess the trajectory of these changes from adolescence to adulthood (Piontkewitz et al., 2011a).
- 1
The first 2 authors contributed equally to the manuscript.