Entorhinal cortex dysfunction in rodent models of dementia
Thesis or dissertation
University of Exeter
Reason for embargo
Standard embargo period (18 months) for publishing papers from thesis.
As both the major input and output of the hippocampal formation, the entorhinal cortex (EC) occupies a pivotal position in the medial temporal lobe. The discovery of grid cells in the medial entorhinal cortex (mEC) has led to this region being widely implicated in spatial information processing. Importantly, the EC is also the first area affected by dementia pathology, with neurons appearing particularly susceptible to degeneration. Despite this, little is known about how pathology affects the functional output of mEC neurons, either in their ability to coordinate firing to produce network oscillations, or to represent information regarding the external environment. This thesis will use electrophysiological techniques to examine how dementia pathology contributes to the breakdown of mEC neuronal networks using the rTg4510 mouse model of tauopathy. The first 2 results chapters will show how the anatomical organisation along the dorso-ventral axis of the mEC has profound influence on the network activity that can be observed both in brain slices and awake-behaving mice. It will further show how deficits in network activity in rTg4510 mice occur differentially across this axis, with dorsal mEC appearing more vulnerable to changes in oscillatory function than ventral. The third results chapter will begin to explore the relationship between global network activity and the external environment, showing that rTg4510 mice display clear deficits in the relationship between oscillation properties and locomotor activity. Finally, the underlying basis for these changes will be examined, through the recording of single-unit activity in these mice. It will show a decreased tendency for mEC neurons to display firing rates modulated by running speed, as well as an almost complete breakdown of grid cell periodicity after periods of tau overexpression. Understanding how dementia pathology produces changes to neuronal function and ultimately cognition is key for understanding and treating the disease. This thesis will therefore provide novel insights into the dysfunction of the EC during dementia pathology.
PhD in Medical Studies