The neural circuit basis of spatial memory loss in Alzheimer’s disease. PhD in Medical Studies (MRC GW4 BioMed DTP) Ref: 3649
About the award
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
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.
This studentship is funded through GW4 BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£15,009 for 2019/20, updated each year) for 3.5 years.
For further information relating to the funding please see the main MRC GW4 BioMed website
This project is in competition with a number of other projects across the partnership; up to 18 studentships in total will be available.
Eligibility and Residency Requirements
To be eligible for a full award (fees and stipend) from a Research Council, a UK or EU student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship.
An EU student who has not been resident in the UK for at least 3 years prior to the start of the studentship is generally eligible for a fees-only award from the Research Council: to be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU; in the same way as UK students must be ordinarily resident in the UK.
For our regular recruiting round, the Doctoral Training Partnership has additional funding from the partner universities to support a limited number of EU students who do not meet the UK residency requirements, so long as they meet the criteria for a fees-only award: these studentship will therefore be fully funded (fees and stipend).
For full details on eligibility, please refer to the MRC GW4 BioMed website
Students with 'International' status are unfortunately not eligible to apply.
If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.
Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).
For further information regarding data protection for the Application Process and if you become a student on one of the Programmes please click here
For an overview of the MRC GW4 BioMed progamme, please see the website www.gw4biomed.ac.uk
In addition to those with traditional biomedical or psychology backgrounds, the DTP welcomes students from non-medical backgrounds, especially in areas of computing, mathematics and the physical sciences, and can fund additional training, including Masters to assist discipline conversion. Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Applicants with a Lower Second Class degree will be considered if they also have a Master’s degree or have significant relevant non-academic experience.
If English is not your first language you will need to have achieved at least 6.5 in IELTS (and no less than 6.5 in any section) by the start of the programme.
How to apply
Applications Open on 29 September and close at 17:00 on Monday 25 November 2019
You will need to complete an application to the GW4 BioMed MRC DTP for an 'offer of funding'
Applying for an 'offer of funding'
Please complete the application form at https://www.gw4biomed.ac.uk/doctoral-students/ by 5pm Monday 25 November 2019.
The Research Theme Panels will complete the shortlisting and will aim to inform applicants by Thursday, 19 December 2019. If you are shortlisted you will need to:
- contact the lead supervisor of you chosen project in which you are interested, to arrange an informal interview (which can be in person, by telephone or by Skype) between 3 and 15 January 2020. Please note that interview expenses will not be available for candidates to attend these meetings.
- attend a formal interview, with a panel of four academics which will take place in Cardiff on 21 and 22 January 2020.
For further details of the application process please see the following web page www.gw4biomed.ac.uk/doctoral-students/
You do NOT need to apply to the University of Exeter at this stage - only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Exeter.
|Application deadline:||25th November 2019|
|Value:||Stipend matching UK Research Council National Minimum (£15,009 p.a. for 2019/20, updated each year) plus UK/EU tuition fees|
|Duration of award:||per year|
|Contact: PGR Recruitmentemail@example.com|