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.