Wu, Claire; (2020) Disruption of large-scale neuronal activity patterns in Alzheimer’s disease models. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The overexpression and aggregation of tau is observed in a class of neurodegenerative diseases termed tauopathies. Individuals with tauopathy, and animal models of tauopathy, show a loss of behavioural and cognitive function, but the neural underpinnings of these symptoms are poorly understood. We investigated changes in neural function in in the Tg4510 model of tauopathy in primary visual cortex (V1) - an area where the relationship between stimulus features, single unit responses, and the circuits and mechanisms underlying them, is relatively well characterised - and in CA1. We conducted chronic awake head-fixed recordings in V1 of 5-6.5 month old mice, presenting a variety of visual stimuli, including drifting grating stimuli that varied across feature dimensions such as orientation, contrast, or size. Mice were also trained to run in a virtual reality environment, either closed loop, open loop (playback) or in the dark. Tau+ and Tau- mice displayed clear differences in the oscillatory local field potentials in V1 and CA1, notably Tau+ mice showed a large decrease in high frequency power as well as minor changes in stimulus-evoked power and power in relation to running speed. Single unit responses in V1 of Tau+ mice were also altered. Tau+ mice showed greater orientation selectivity and suppression following orientation adaptation, and improved contrast tuning, but worse selectivity in response to sparse noise stimuli. Responses to other stimulus features, such as spatial frequency and size, were unchanged between the two groups. In conclusion, tauopathy in the Tg4510 mouse shows clear effects on information processing in the visual cortex and in CA1. This was not through a non-selective decrease in responsiveness, but instead enhanced some types of processing, such as orientation selectivity, while disrupting others such as responses to sparse noise. These selective effects on neural function may reflect selective patterns of tauopathy on different cell classes or brain areas.

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