Examining Hippocampal Activity During Behaviour in a Mouse Model of Alzheimer’s Disease

Abstract

Although Alzheimer’s disease was first identified in 1906 by Alois Alzheimer the extensive pathophysiology that produces the disease is still poorly understood. It is a neurodegenerative disorder characterised by a marked reduction in the volume of the cerebral cortex and hippocampus, which produces general mental decline including memory loss and confusion, inability to create new memories, behavioural changes, and eventual death. Therefore, the primary aim of this project was to investigate neuronal calcium network dynamics responsible for memory deficits with simultaneous behavioural in transgenic mice [APPswe/PS1dE9] through the utilisation of head-mountable miniaturised microscopes. To image activity in the hippocampus mice were virally injected with the calcium activity reporter (GCaMP7) into the CA1, a GRIN lens was implanted superiorly for optical access, and a baseplate was secured to the skull to allow the future attachment of a miniscope. Male transgenic and non-transgenic littermate mice aged 15-17 months underwent open field, y-maze, and novel object recognition behaviour tests. These cognitive assessments query anxiety and fear (time spent in the exterior region and freezing in open field), short-term spatial memory (alternations in y-maze and novel object location), and short-term and long-term object memory (novel object recognition). Neuronal dynamics were simultaneously recorded through in vivo miniscope imaging of GCaMP7 expressing hippocampal CA1 neurons. Neuronal dynamics (mean amplitude, frequency, spike width, participation, and location specific firing) were examined, correlated with behaviour, and compared across genotypes. When examining two separate cohorts there were significant phenotypical differences between transgenic and wildtype regarding ambulation, open field anxiety and freezing, ymaze and novel object location short-term spatial memory measures, and novel object shortterm and long-term object memory measures. There were also significant differences between genotypes in mean spike width and participation – with aged transgenic mice exhibiting neuronal hyperactivity. Additionally, when staining for amyloid-β plaques (a hallmark histology marker) were witnessed in the transgenic hippocampus and cortex but not wildtype. This project in conjunction with previous work has established a protocol that permits queries into the underlying neuropathology to link behavioural deficits to neuronal changes.