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Title: Touchscreen assessment of motivation and reinforcement-related choice behaviour in mice
Author: Phillips, Benjamin
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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This dissertation describes the development and optimisation of a set of touchscreen tasks for the assessment of motivation and reinforcement processes in mice. Changes in motivational state and reinforcement sensitivity are characteristic of depressive symptoms in a number of neuropsychiatric and neurodegenerative conditions. However, the efficacy of current therapeutic strategies is limited. Thus, the development of methods for studying these processes is important both to facilitate investigation of underlying mechanisms and subsequently develop targeted therapeutics. Part 1 describes the optimisation and application of fixed and progressive ratio tasks for the assessment of motivational state in mice. First, a comparison of multiple reinforcers under fixed and progressive ratio schedules is described. Given the limitations of performance measures derived from performance across the entire session, these experiments are complemented by the use of response rate analysis, which reveals dissociations between standard measures and rate of responding. Next, these tasks are applied to a model of maternal high fat diet (hfd), revealing selective alterations in motivated behaviour. Finally, the motivational state of the TgR406W mouse model of frontotemporal dementia, a condition frequently characterised by depressive symptoms, is investigated. It is shown that the motivational state of TgR406W mice is age dependent, with apparent early apathy-like behaviour and a late disinhibition in responding. This is accompanied by deficits in attentional performance as measured by a 3-choice serial reaction time task. Thus, part 1 demonstrates the applicability of the battery of touchscreen tasks for assessment of motivation to diverse mouse models. Part 2 describes the development and validation of touchscreen tasks for the assessment of reinforcement-related choice in mice. First, it is demonstrated that C57BL/6 mice systematically discount a preferred reinforcer in a delay discounting procedure. Subsequently, choice behaviour is modified by systemic treatment of dopaminergic drugs and a reinforcer pre-feeding procedure. Next, procedures for the assessment of learning and choice, dependent on the integration of positive and negative feedback, are described. Specifically, the valence-probe visual-discrimination (VPVD) task is an adapted version of the standard visual discrimination with the addition of a probabilistic stimulus that is reinforced 50% of the time. This modification allows for assessment of the impact of positive and negative feedback on discrimination learning. In addition, a spatial within-session probabilistic reversal learning procedure was adapted for the touchscreen apparatus. The effect of serotonin 2C receptor manipulation on these tasks is presented. Serotonin 2C receptor antagonism is shown to disrupt discrimination learning and result in diminished sensitivity to positive feedback. Conversely, 2C receptor agonism results in changes in feedback sensitivity consistent with heightened sensitivity to positive feedback and diminished sensitivity to negative feedback. Taken together, these results show that these tasks can be used to interrogate reinforcement-related behavioural profiles in experimental mice. Finally, the implications of these tasks with respect to investigation of motivation, reinforcement sensitivity and adaptive decision-making in rodent models, and their relevance to MDD in humans is discussed.
Supervisor: Bussey, Timothy Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Touchscreen ; Mouse ; Operant ; Motivation ; Depression ; Reinforcement ; Learning ; Probabilistic