Wood, Ruth; (2022) A role for detailed assessment of hippocampal function in studies of Alzheimer’s Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The hippocampus is one of the first cortical regions to exhibit Alzheimer’s Disease (AD) pathology. The spatially-related firing of hippocampal place cells provides the cellular basis for spatial memory, and this is impaired relatively early in AD, yet few studies examine place cell activity in AD mouse models. Furthermore, current spatial navigation paradigms for rodents are not suited to tracking the progressive impairment seen in AD. This project aimed to address these gaps; the results provide initial support for the hypothesis that AD pathology disrupts hippocampal function which manifests as altered place cell activity and spatial behaviour. Chapter 3 outlines experiments validating a novel behavioural test of hippocampal function, the ‘Honeycomb Maze’, specifically designed to overcome the limitations of other tasks. Wild-type rats and mice rapidly learnt to navigate to a hidden goal, and a lesion study demonstrated the key contribution made by the hippocampus. Task difficulty was scalable through altering maze parameters, with difficult choices exhibiting a greater reliance on hippocampal processing. The findings suggest the Honeycomb Maze provides a reliable means of assessing hippocampal function in rodents and is well suited for application to studies of AD. Chapter 4 provides an in-depth characterisation of hippocampal pyramidal cell activity in an APP knock-in model of AD. Electrophysiological recordings were performed in the left CA1 subregion of four 15-month-old, freely moving, APPNL-G-F mice and four age-matched wild-type controls. Significantly fewer APPNL-G-F pyramidal cells exhibited spatial firing, and deficits were present in rate and temporal coding of spatial information. APPNL-G-F spatial cells had lower spatial information content, larger place fields, reduced phase-locking to the theta rhythm of the local field potential, and a reduction in theta phase precession. Despite the small sample size, a positive correlation was identified between amyloid β plaque burden and pyramidal cell spatial information in APPNL-G-F mice.

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