Establishing a novel cognitive task in rats of relevance to schizophrenia

Abstract

The most debilitating symptoms for patients with neuropsychiatric disorders, such as schizophrenia, are often cognitive deficits; yet they remain largely untreated by current medications. In preclinical animal models, the techniques used to measure cognitive deficits need to be improved to enhance our ability to screen novel drug targets and gain a better understanding of the neurobiological correlates of cognitive dysfunction. Therefore, the aim of this thesis was to develop and test a new high throughput cognitive task in rodents. I have designed a novel Signal Detection Task (SDT) for this purpose.The first aim in developing the SDT was to compare alternative tasks (such as the 5-choice serial reaction time task) and address limitations including the extensive training time required and the lack of control over body position during stimulus presentation.Experiments were then selected to assess the face, construct and predictive validity of the SDT for measuring attentional deficits relevant to schizophrenia. Specifically, I determined if the effects of genetic, environmental, neurobiological and pharmacological manipulations could be detected in rats using this task. The SDT was conducted in rat operant chambers with a series of task variants to probe different components of performance, such as increasing detection difficulty and distraction. Briefly, the studies conducted compared strains (genetics), housing conditions (environment), the impact of a prefrontal cortical lesion (neurobiology) and the effects of amphetamine (pharmacology) on task performance. My findings indicate a relatively short training period was required for rats to perform the SDT with a high level of accuracy compared to other tasks; task acquisition was shown to be dependent on interactions between genetics and environment; prefrontal cortical lesions did not alter baseline performance but impaired attention during distraction and low dose amphetamine significantly improved accuracy. I demonstrated for the first time that the procognitive effects of amphetamine were dependent on baseline attentional performance. In addition, I found that individual variation in baseline performance was related to dopamine metabolism in the striatum.The research outlined in this thesis presents a novel tool for researchers exploring the cognitive phenotype of animal models relevant to neuropsychiatric disorders and for exploring the neurobiology of attention, including mechanisms of action for procognitive medication.ii Declaration by authorThis thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis.