The effects of Advanced Paternal Age (APA) on behavioural and brain structural phenotypes in C57BL/6J mice.

Claire J Foldi (2012). The effects of Advanced Paternal Age (APA) on behavioural and brain structural phenotypes in C57BL/6J mice. PhD Thesis, Queensland Brain Institute, The University of Queensland.

       
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Author Claire J Foldi
Thesis Title The effects of Advanced Paternal Age (APA) on behavioural and brain structural phenotypes in C57BL/6J mice.
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2012-02
Thesis type PhD Thesis
Supervisor Dr Thomas HJ Burne
Assoc Prof Darryl W Eyles
Total colour pages 282
Total black and white pages 269
Language eng
Subjects 1109 Neurosciences
1701 Psychology
060801 Animal Behaviour
Abstract/Summary Advanced paternal age (APA) is associated with an increased risk of adverse health outcomes in offspring, including autism and schizophrenia. With respect to biological mechanisms for this association, most attention to date has focussed on the effects of aging on the integrity of germ cells. This is because there are many more germline cell divisions in the life history of a sperm relative to that of an oocyte. Each time these cells divide, the replication of the genome increases susceptibility to copy error mutations such that there is more opportunity for accumulation of copy error in germ cells from older fathers. Evidence also suggests that epigenetic patterning in the sperm from older men is altered. Rodent models provide an experimental platform to examine the association between APA and brain development. We have previously investigated structure-function relationships in the adult offspring of young (3 month-old; Control) and old (12-18 month-old; APA) C57Bl/6J sires. Mice underwent a comprehensive behavioural test battery and their brains were subsequently examined ex vivo using high resolution MRI (Foldi et al., 2010). Other APA models have been published with relevance to intermediate phenotypes related to neuropsychiatric disorders. All three existing mouse models vary in key features creating a lack of consistency with respect to behavioural phenotypes. Our published model showed increased anxiety-related and exploratory behaviours and a decrease in ventricular volume, which corresponded to an increase in rostral cortical volume. Another study demonstrated reduced social behaviour (Smith et al., 2009), while the third was associated with reductions in avoidance learning and locomotion (Garcia-Palomares et al., 2009b). In this thesis, I have carefully considered several potential modifers of APA effects in the mouse and probed the phenotypic instability by investigating the effects of breeding programme and APA sire age range on behavioural phenotypes in offspring. I have demonstrated that length of prenatal sire exposure does not contribute to offspring outcomes. We have also conducted a ‘proof of principle’ exploration of the genomic correlates of phenotypes by exploring the association between copy number variation (CNV) load and behavioural and neuroanatomical outcomes. Here, we show that particular CNV expansions, only found in APA mice, are correlated with changes in specific behavioural domains. In addition, increasing the APA sire age to 24 months was shown to be associated with increased anxiety-related behaviour in the offspring, and indicated that increasing APA sire age produced a more robust hypoexplorative phenotype. Thus, variation in CNV load and APA sire age could explain the phenotypic variability in APA mouse models. Ultimately, the results of these studies demonstrate that mouse models of APA are valuable for elucidating the mechanisms by which APA influences brain-related outcomes.
Keyword Paternal Age
Behaviour
Neuroanatomy
Schizophrenia
Autism
Animal models
C57BL/6J Mouse
Additional Notes Colour pages: 39, 143, 242-244, 246, 249, 256, 270, 273, 280-282 Landscape pages: 27, 39, 48, 53, 84, 88-91, 99, 107, 108, 116, 119, 120, 122, 124, 165, 184

 
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Created: Fri, 01 Jun 2012, 18:23:13 EST by Claire Foldi on behalf of Library - Information Access Service