Associative learning in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease defined by severe memory loss and the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The experiments presented in this thesis examined cognitive performance in a well-­‐characterised mouse model of AD, the APPswe/PS1dE9 (TG) mouse, at 4-­‐5 months old prior to extensive amyloid plaque deposition. The experiments employed were associative learning tasks, which are not often used to measure cognitive performance in classical neuroscience research into neurodegenerative disease. Chapter 1 looked at appetitive Pavlovian cue and context conditioning and extinction, and found some evidence of impaired contextual discrimination during conditioning. Cue conditioning and extinction was found to be intact in the TG mouse model. Chapter 2 looked at appetitive Pavlovian delay and trace conditioning before examining the ability to time the arrival of the unconditioned stimulus (US). No genotype differences were found during delay or trace conditioning; however, TG mice were impaired (lost precision) in their ability to time the arrival of the US during test trials. Chapter 3 examined recognition memory performance, via the spontaneous novel object recognition (sNOR), relative recency (RR) and context priming (CP) tasks, interpreting the results in terms of Wagner’s SOP model of memory. No genotype differences were found in the sNOR or RR tasks, supporting intact stimulus-­‐generated priming; however, evidence from Bonardi et al. (2016) and non-­‐significant trends in the CP task supported impaired retrieval-generated priming. Chapter 4 looked at the levels of neuro-­‐inflammation (microglia) in the cortex, hippocampus and striatum to assess the possible early contribution of inflammation on the development of AD. This chapter reported greater levels of microglia in the hippocampus and striatum of TG mice compared to wild types. Greater microglia clusters were also seen in the cortex and hippocampus of TG mice compared to wild types. The results from this thesis show evidence of impaired cognitive performance, prior to extensive plaque deposition, in associative learning tasks that are not routinely employed in neuroscience research. Further work is required in these learning tasks to establish whether they could be effectively used to diagnose AD at an early stage