Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice

Abstract

Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia. A previous study in mice suggested that the offspring of aged sires have altered locomotion and avoidance learning. The aim of the current study was to conduct a comprehensive behavioural screen in adult offspring of mice of APA. We also examined brain morphology in neonate and adult mice. The adult offspring of 12- to 18-month-old (APA) and 4-month-old (control) male C57BL/6J mice underwent a behavioural test battery comprising tests for locomotion, anxiety, exploration, social behaviour, learned helplessness and sensorimotor gating. The brains of these mice were collected at 3 months and imaged ex vivo using a 16.4 T MRI scanner to assess gross neuroanatomy. Neuroanatomy was also examined at birth in a separate cohort of animals. Overall, the APA mouse model was associated with subtle behavioural changes and altered cortical morphology. The behavioural phenotype of female APA mice included increased anxiety-related behaviour, increased exploration and decreased learned helplessness compared to control females. Male APA mice had thinner cortices at birth and increased cortical volume as adults. This animal model may assist in exploring the mechanism of action linking APA with disorders such as schizophrenia and autism.

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies

“…De novo germline mutations, epigenetic alterations and life course toxic exposure may partly explain the observed association. The evidence is substantial enough to justify a search for the underlying mechanisms in both human and animal models (55,56). …”

Paternal age and mental health of offspring

“…Another study comparably showed reduced capacity for passive-avoidance learning for offspring of older sires[41] and another found alterations in cortical growth, which are perhaps relevant to the behavioral findings[42]. Both schizophrenia and autism entail reduced learning ability, so these findings may be relevant to the mechanism linking later paternal age to these conditions[35, 43-45].…”

Deformation-based brain morphometry in rats

“…The ROI-based manual outlining of individual brain structures enables the estimation of absolute volumes but requires well-reasoned and time-consuming area demarcation, and the outlining protocols may not be compatible between different laboratories (Foldi et al, 2010;Hasegawa et al, 2010;Henke et al, 2008;Nagel et al, 2004;Sawiak et al, 2009a;Schubert et al, 2008Schubert et al, , 2009. Unfortunately, manual approaches fail if the volumes of selected structures differ partially by small amounts.…”