Florey Department of Neuroscience and Mental Health - Theses
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ItemUtilising touchscreen technology for preclinical modelling of cognition in brain disorders( 2014)Schizophrenia is a debilitating disease that affects an estimate of 1% of the global population1,2. Cognitive disability, among many other factors, make this disease one of the highest ranking psychiatric disorders on the World Health Organisation’s global burden of disease3. Cognitive impairment affects approximately 70% of schizophrenic patients and is negatively correlated with the ability to live as a functional member in a community 4,5. While treatments exist to abate the positive and negative symptoms, effective therapeutics are yet to be developed for the treatment of cognitive impairment6,7. Glutamate signalling is important for the mechanisms underlying cognition8-10, while disruption to glutamate signalling has been implicated in the development of schizophrenia11,12. Metabotropic glutamate receptor 5 (mGluR5) is found in areas associated with cognition and modulates synaptic plasticity by up-regulating N-Methyl-D-aspartate (NMDA) receptor activity13. It too has been associated with schizophrenia though a genetic linkage study14. The mGluR5 knockout (KO) mouse has been used as a model of schizophrenia as is displays many endophenotypes of the disease9,15-17. Similarly, environmental factors contribute to the morbidity of schizophrenia2,18-21, and environmental enrichment in the mGluR5 KO mouse has therapeutic effects on cognition17. In a bid to improve the translation of findings between rodent studies and clinical trials, the touchscreen automated testing battery has been developed. This battery can be used to test a wide variety of cognitive functions using reward-based operant conditioning. The data presented in this thesis utilises this technology to assess visual discrimination, reversal learning and paired-associates learning in mGluR5 KO mice. Here we demonstrate that mGluR5 KO mice have selective impairments in all three of these tasks, a result which is likely due to altered modulation of NMDA receptors in brain regions such as the hippocampus, cortex and striatum. Interestingly, in this case the application of environmental enrichment was not therapeutic, although a replication study with optimised design will be required to test this definitively. The utilisation of touchscreen technology and more sophisticated mouse models, will facilitate the development of new therapeutics for the treatment of cognitive impairment in schizophrenia. This thesis provides a foundation for future touchscreen-based testing in the mGluR5 KO mouse. This protocol warrants further investigation, as does the potential, novel impulsive phenotype in our model.