Brain Development and Behaviour in Developmentally Vitamin D-Deficient Mice

Lauren Harms (2011). Brain Development and Behaviour in Developmentally Vitamin D-Deficient Mice PhD Thesis, Queensland Brain Institute, The University of Queensland.

       
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Author Lauren Harms
Thesis Title Brain Development and Behaviour in Developmentally Vitamin D-Deficient Mice
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2011-06
Thesis type PhD Thesis
Supervisor Dr Thomas Burne
Assoc Prof Darryl Eyles
Total pages 273
Total colour pages 2
Total black and white pages 271
Language eng
Subjects 11 Medical and Health Sciences
Abstract/Summary Schizophrenia is a debilitating neuropsychiatric disorder associated with a wide range of genetic and environmental risk factors. Based on epidemiological evidence, maternal vitamin D deficiency has been proposed as an environmental risk factor for schizophrenia. Recent findings showed that low levels of vitamin D at birth were associated with an approximate two-fold increase in the risk of developing schizophrenia in later life (McGrath et al., 2010). Moreover, a rat model of developmental vitamin D (DVD) deficiency exhibited neuroanatomical and behavioural phenotypes analogous to schizophrenia (Eyles et al., 2009b), further supporting the biological plausibility of the epidemiological link between DVD deficiency and schizophrenia. Studies in a mouse model of DVD deficiency revealed that brain development and adult behaviour were affected by DVD deficiency in a strain-dependent manner (Harms et al., 2008; de Abreu et al., 2010). To further explore the effects of DVD deficiency on the mouse brain and to facilitate potential future genetic studies into DVD deficiency, the aim of the current thesis was to examine the effects of DVD deficiency in mice by assessing gene expression, cell proliferation and brain morphology in neonatal mice, as well as comprehensively assessing behaviour and brain morphology in DVD- deficient adult mice. DVD deficiency in C57BL/6J mice resulted in early changes in forebrain gene expression. Compared to brains from control mice, some 700 genes were differentially expressed in the brains of DVD-deficient neonates, the vast majority of which were down regulated. Pathways analysis of the genes that were down regulated revealed that the reelin and neuregulin signalling pathways were altered. Both of these pathways play an important role in brain development and have been implicated in schizophrenia. These changes in gene expression were not associated with alterations in the proportion of proliferating cells in DVD-deficient whole forebrain samples. However, there were changes in neonatal brain morphology, such that C57BL/6J female DVD-deficient neonatal mice had a smaller hippocampus compared to female controls. Adult C57BL/6J male DVD-deficient mice had smaller lateral ventricles compared to controls, which may have been compressed by the enlarged striatum seen in these DVD-deficient mice. The behaviour of adult DVD-deficient mice was examined in multiple tests used to model the positive, negative and cognitive symptoms of schizophrenia. Compared to controls, C57BL/6J DVD- deficient mice were hyper-explorative of novel stimuli in the hole-board test. Furthermore, male C57BL/6J DVD-deficient mice had altered patterns of locomotion in a test of pseudo-home cage activity; exhibiting lower activity levels at certain times of the day. Male DVD-deficient mice also made more perseverative responses in a continuous performance test of attention, potentially indicating compulsive behaviour and impaired response inhibition in these mice. The combined results from the studies in this thesis demonstrate that DVD deficiency in the mouse was associated with specific neurodevelopmental and behavioural changes. The alterations in gene expression in the reelin and neuregulin pathways in developing mice may suggest a possible mechanism by which DVD deficiency affects the risk of developing schizophrenia in human populations. The behavioural studies indicate that DVD deficiency affects systems involved in novelty-seeking and compulsive behaviours and also affects dopamine-related behaviour in a strain- dependent manner. Ultimately, these results highlight the importance of vitamin D signalling in the developing mammalian brain and present the DVD-deficient mouse as a platform for further investigation of vitamin D, neurodevelopment and schizophrenia.
Keyword Vitamin D
brain
development
Schizophrenia
Animal Model
C57bl/6j
129X1/SvJ
Additional Notes Colour pages: 77 and 87 Landscape pages: 60, 87, 100, 102, 103, 105, 112, 147, 149, 175, 178, 179

 
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