Abstract
Epidemiological research has identified that exposure to maternal immune activation (MIA) confers substantial risk for later diagnosis of schizophrenia in offspring. As a result, extensive translational research has been dedicated to elucidating the pathophysiology mediating symptomology. Current evidence suggests that the time at which insult occurs during gestation may result in differing profiles of pathological outcomes, necessitating increased research into the time specific impact of MIA on psychiatric disease. To this end, the present thesis examined the impact of GD10 and GD18 MIA in rats (polyriboinosinic-polyribocytidilic acid; 4mg/kg; n = 80) using a range of operant tasks, in conjunction with statistical modelling and microbiological assay. Prepulse inhibition (PPI) assessment found that MIA did not impact the acoustic startle response.
The first stream of experiments investigated the cognitive bases of temporal perception abnormalities in the MIA model. Using a temporal bisection task, we established that MIA rats were significantly underestimating elapsed durations, corresponding to a subjective quickening of time. Following this, a simple two choice discrimination paradigm was manipulated to assay sustained attention and working memory maintenance abilities, although MIA was not found to have incited pathology in either of these metrics. Correlation analyses revealed a strong relationship between attention and timing measures, indicating that a sustained attention deficit was mediating abnormal temporal perception in MIA rats. Working memory maintenance was not found to predict timing behaviour.
The second stream of experiments investigated the impact of MIA on goal-directed decision making. Using a contingency degradation task, we found that MIA did not impair sensitivity to action-outcome contingency. Additionally, exposure to MIA was not found to impact risk-based decision making during a probabilistic discounting task. Western blot assay of MAPK expression in prefrontal cortex was not systematically impacted by MIA, however a novel correlation between MAPK levels and PPI performance was found in MIAs, but not controls, providing preliminary evidence for MAPK as a biomarker for MIA incited pathology. In addition, MAPK levels were found to predict performance on the contingency degradation task irrespective of treatment, ultimately suggesting that higher MAPK levels had a detrimental impact on sensitivity to action-outcome contingency.
In all, pathologies identified in this research are commensurate with clinical findings in schizophrenia. Results are interpreted within a dopamine framework of pathology. Moreover, while results did not find a time-specific impact of MIA on behaviour and microbiology, they did support the idea that the first trimester of pregnancy is a particular phase of vulnerability for immune mediated insult. Collectively, these outcomes support the conceptualisation of MIA as a considerable disease primer for the development of schizophrenia. Findings have implications for future translational research, as well as public health approaches in a New Zealand context.