The Development of a Multifactorial Mouse Model of Maternal Immune Activation for study of Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders (NDDs) like autism, Tourette’s, ADHD, and intellectual disability are rising globally and typically emerge in early childhood. Their origins reflect complex gene–environment interactions during prenatal and early postnatal development. Maternal stress, infection, and poor diet can induce chronic inflammation, supporting the maternal immune activation (MIA) hypothesis — where sustained inflammation disrupts foetal brain and immune development, increasing NDD risk. While animal MIA models help explore these links, most rely on single environmental triggers, limiting their ability to reflect the multifactorial nature of NDDs.

This thesis addresses this gap by exploring the influence of multiple environmental exposures – from preconception through prenatal, neonatal and the postnatal period. Specifically, this longitudinal animal study investigates the combined impact of intermittent social instability stress (SIS) exposure and chronic high fat diet (HFD) consumption on maternal physiology and reproductive outcomes. Secondary to this, I explore the influence of postnatal immune challenge using poly(I:C) (PIC) against this background of maternal stress, on offspring neurodevelopmental outcomes.

In summary, the findings presented in this thesis demonstrate that compounded moderate inflammatory factors can significantly deviate the normal trajectory of brain development. Further, pathological alterations in male offspring are reflected not only in the central nervous system, but also in the periphery. These findings underscore how the timing and cumulative effects of these exposures differentially influence neurodevelopmental trajectories between males and females; and provide a novel experimental model to continue further study into the environmental contributions underlying the pathogenesis of NDDs.