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A non-human primate model of dorsolateral prefrontal cortex dysfunction in schizophrenia https://doi.org/10.17863/CAM.114452 https://doi.org/10.17863/CAM.114452 Hodgson, Amy Clarke, Hannah Spatial working memory (SWM) impairment is a key cognitive symptom of schizophrenia, for which no effective treatment currently exists. In order to develop new treatments, we must better understand how these deficits arise from structural and functional changes within the neural circuits supporting SWM, principally the dorsolateral prefrontal cortex (dlPFC). One of these changes in schizophrenia is a loss of perineuronal nets (PNNs), extracellular matrix structures that serve to protect and support the function of neurons, within the dlPFC (Mauney et al., 2013). Our aim was to use a marmoset model to investigate how degrading PNNs in the dlPFC affected SWM, as well as additional behaviours, cognitive functions, and brain function relevant to schizophrenia. In Chapter 3, I describe the development and validation of a SWM task for marmosets that is dependent on the dlPFC and prevents the use of mediating strategies. In Chapter 4 I present preliminary data demonstrating that while PNN degradation alone does not appear to affect baseline working memory performance, it modulates the effect of drug infusions into the dlPFC, suggesting that PNN loss may affect the function of this region. In Chapter 5, data is presented demonstrating a lack of prosocial behaviour in a food-sharing task, and that this is not changed by dlPFC PNN degradation. In Chapter 6, I demonstrate that marmosets show novel object recognition memory at both 5-minute and 24-hour delays, but PNN degradation in the dlPFC impairs recognition memory. In Chapter 7 we used F-DOPA PET imaging to explore the effect of dlPFC PNN degradation on dopamine synthesis, and find evidence for an increase in the caudate body, suggesting this manipulation may induce striatal dopamine dysregulation. These implications of these results are discussed in Chapter 8 and future research directions are suggested. In summary, these results suggest that a loss of PNNs in the dlPFC can recreate some of the cognitive and neural changes in schizophrenia. This model may therefore allow for further exploration of how PNN loss relates to symptoms of schizophrenia, as well as testing of novel treatments. University of Cambridge 2024-07-30 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/377722 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1b72024c-8542-4b03-80e0-f64baa1c02ee/download 0ce6d1f9a287d5742a2949daed90d9ab https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/80575bf1-cd40-4fd9-acb9-6e461df7d2f0/download 87eda9de84448d1f82354d60eee3eb5f https://creativecommons.org/licenses/by-nc/4.0/ Neuroscience Schizophrenia Prefrontal cortex Working memory Primate Perineuronal net