Dr Jonathan Witton, College of Medicine and Health, University of Exeter
Dr Michael Ashby, Faculty of Life Sciences, University of Bristol
Dr Jonathan Brown, College of Medicine and Health, University of Exeter
The loss of memories of places is an early symptom of Alzheimer’s disease (AD). These “spatial memories” are generated by networks of space coding neurons, called place cells, in a key brain structure for memory called the hippocampus. This project will use cutting-edge in vivo brain imaging to discover how place cells become disrupted in AD, and attempt to treat this using drugs that target AD pathology.
Aim: Determine the long-term trajectory across which Alzheimer’s disease (AD)-related pathology disrupts the brain’s spatial memory network in the hippocampus.
Background: One of the most debilitating symptoms of AD is memory loss. The hippocampus is a brain structure that is crucial for learning and memory. The hippocampus is particularly important for forming and recalling spatial memories, and this is known to be disrupted early in AD. The hippocampus contains interconnected networks of neurons that fire in specific places in an environment, called place cells, and these patterns of neural activity are thought to provide a substrate for spatial memories in the brain.
The hippocampus is one of the first brain regions to develop pathology in AD. A key type of this pathology is called tauopathy, which is formed from aggregates of misfolded tau protein. Tauopathy is known to drive neuronal dysfunction and degeneration, and the hippocampus is particularly vulnerable to tauopathy in AD. This suggests that a cause of spatial memory loss in AD is tauopathy disrupting networks of place cells in the hippocampus. Using a mouse model of taupoathy (rTg4510 mice), our lab has shown that spatial memory loss is associated with profound disruption of spatial coding by place cells in very advanced stages of the disease (Booth et al. J Neurosci. 2017). While it is therefore clear that tauopathy can disrupt spatial coding in the hippocampus, we don’t yet know how this deficit develops throughout the disease, or whether we can intervene by reducing tauopathy to preserve the function of the hippocampal network.
Experimental design: The student will study the long-term dynamics of hippocampal place coding in tauopathy using a state-of-art in vivo brain imaging technique in mice, called fluorescence micro-endoscopy.
We will use rTg4510 mice in which we have identified disrupted place cell activity in late-stage tauopathy. The student will use a novel (circa 2009), lightweight (<2 g) miniature microscope that can be mounted on the mouse’s head to perform Ca2+ imaging of up to hundreds of place cells in the hippocampus in rTg4510 and control mice. Imaging will be linked to the assessment of behaviour in maze-based navigation tasks. As the microscope can be removed and replaced to record from exactly the same cells across time, the student will track changes in the function of specific groups of place cells as deficits emerge throughout a period of prodromal tauopathy in rTg4510 mice (3-5 months). The ability to stably record from large neuronal populations across weeks is a unique advantage of our approach that cannot be achieved by other methods (e.g. electrophysiology). The large imaging data sets that will be generated (10-20 GB per experiment) will be analysed using computational analysis routines implemented in the Matlab programming environment.
Additionally, in vivo brain imaging will be integrated with pharmacology and ex vivo histology to determine whether reducing tauopathy can preserve hippocampal network function. The student will study the effects of knocking down the mutant tau transgene in rTg4510 mice and testing the repurposed putative AD drug trazodone.
Outcomes: The project will generate foundational understanding of the cellular and network processes underpinning the failure of hippocampal place coding and by extension spatial memory loss in AD, and determine whether reducing a key disease causing agent (tauopathy) can preserve hippocampal function as a route to treating AD.
To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl
by 5pm Friday 25 November 2019.