Abstract
Prenatal immune insults have been shown to increase the offspring’s risk of developing schizophrenia. Based on this knowledge, a maternal immune activation (MIA) rat model of the disorder has been developed, where pregnant dams are injected with Poly I:C, a viral mimetic. Chapter 1 provides an introduction to this and other topics covered in the following thesis.
In chapter 2 pre-pulse inhibition (PPI) testing is described. Contrary to previous studies, no significant overall group difference was seen as a result of prenatal treatment. There was, however, a trend was observed in the expected direction, showing MIA animals to have a decreased %PPI response in comparison to saline treated animals, with this difference proving significant at 80dB, a middle range pre-pulse amplitude, which have been shown to elucidate group differences most clearly.
After the completion of PPI testing, animals underwent four consecutive days of treatment with Saline or the specific serotonin reuptake inhibitor Fluoxetine (Flx). A four week delay was used after drug treatment as we were interested in the effect of a time delay that corresponds to the treatment lag observed with antidepressants. Three different memory tasks followed.
In chapter 3, performance on two different Novel Object Displacement Tasks, a task relying on object recognition and location memory, is described. The first variation involved exposing animals to an environment with four objects, and after a 3.5-4 hour delay re- exposing animals to the environment, where the position of two objects had been swapped. In the second variation a similar procedure was used, but the environment only contained two objects, with one object displaced before re-exposure. Unexpectedly, no effect of prenatal treatment was observed. There was, however, a significant effect of drug treatment, showing that Flx treated animals spent less time around displaced objects than controls, suggesting a decrement in object-place memory.
One of the cognitive symptoms observed in schizophrenia is decreased flexibility in several tasks, including reversal learning. Therefore, chapter 4 describes performance on a reversal Y-maze task. While no differences were seen among treatment groups during training, an effect of prenatal treatment became apparent during reversal learning. It was found that MIA animals required significantly more trials to reach reversal criterion than saline treated rats. This contrasts previous data which demonstrated that MIA animals were quicker to reach reversal criterion. It is discussed that a major difference in the current study to previous ones was reward valence, with the current experiment using appetitive and previous using aversive motivating. This suggests that differences may be due to deficits in reward processing. No significant main effect or interaction of Flx treatment was observed.
Lastly, chapter 5 is dedicated to discussing the experiments, their limitations and potential implications. The behavioural memory studies presented here hint at an interesting relationship between prenatal immune insults and Flx treatment with time delays before testing in consideration of antidepressant treatment lag. Further research in this area may have huge implications in our understanding of these topics and underlying brain mechanisms, which would have immense therapeutic value.