Understanding how altered GABA signalling in the brain’s master clock contributes to circadian rhythm disruption in Alzheimer’s disease. PhD in Medical Studies (MRC GW4 BioMed DTP) Ref: 3650
About the award
Dr Mino Belle, Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter
Dr James Hodge, Faculty of Life Sciences, University of Bristol
Dr Jon Brown College of Medicine and Health, University of Exeter
Prof Krasimira Tsaneva-Atanasova, College of Engineering, Mathematics and Physical Sciences, University of Exeter
Our daily or circadian body clock is one of the most important timing systems in our body, ensuring that the neuronal activity throughout our CNS is appropriately aligned with our homeostatic, physiological and behavioural needs across the day. These needs include the timing in our sleep-wake cycle, peak cognition ability, and optimum brain toxin clearance, such amyloid-B (AB). Disruption of this daily rhythm can lead to severe health consequences, which include premature ageing and mental health disorders.
Indeed, circadian rhythm disruption is a common symptom of Alzheimer’s disease (AD) and recent knowledge has identified that circadian disruptions often occur early in the course of the disease and may precede the development of cognitive symptoms. The sleep-wake cycle regulates the levels of pathogenic amyloid-B peptide and tau in the brain, and manipulating the sleep-wake cycle can influence AD-related pathology in mouse models. Indeed, the circadian system has long been identified as having a role in the neurodegenerative process of AD.
In mammals, the master circadian clock is found in a region of the hypothalamus called the suprachiasmatic nucleus (SCN). In the SCN, the activity of clock genes produces daily excitability rhythms in SCN neurons, making them fire at higher rates during the day with high intracellular calcium and less active at night with low intracellular calcium. This daily rhythm in clock and electrical activity is well-conserved between Drosophila and mammals, and is vital for clock function, promoting well-being, cognition, and health, but blunts in ageing and AD in both models. GABA is the main neurotransmitter in the SCN and is critical for the generation of circadian rhythms. Remarkably, although GABAergic signalling in the SCN is critical for our sense of daily rhythm, and is affected during AD, the mechanisms governing how GABA signals regulate SCN electrical and intracellular calcium activity remain poorly understood. Here, we will investigate when and how GABA signalling regulates SCN neurophysiology, clock gene rhythms, and behaviour in healthy and AD-mice. To achieve this, we are combining some state-of-the-art electrophysiology, imaging, and optogenetic methods, with circadian clock activity-reporting transgenic mouse models (Period1-Venus mouse without or containing human AB or Tau), and sophisticated behavioural measurements and mathematical analysis.
In order to understand the impact of AD on brain-wide clock function, which is possible in the fly but difficult in mice, we will perform appropriate clock and calcium imaging studies in healthy Drosophila and AD-fly models throughout their lifespan. The hope is to appropriately combine our knowledge from both organisms to understand how a deficient and weakened master circadian clock contributes to AD pathology, and identify key GABAergic mechanisms and therapeutic targets. These targets will be initially screened in Drosophila to restore clock function in aged and AD flies, and see if it also rescues sleep and memory loss, neurodegeneration, and shortened lifespan. This will then be translating to mammals.
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.
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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|