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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)

  • Full or part time
  • Application Deadline
    Monday, November 25, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Supervisory team:
Dr Mino Belle, Institute of Biomedical and Clinical Science, Medical School, 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

Circadian rhythm times our sleep and its disruption can exacerbate Alzheimer’s disease (AD) pathology. The brain’s master clock uses GABA for circadian timekeeping. GABA activity is affected in AD, but the effect on clock function is unknown. We will study how GABA drives excitability in healthy and AD mouse clock neurons, to restore clock function and improve quality of life.

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.

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.

Funding Notes

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: View Website

This project is in competition with 88 other projects across the partnership; up to 18 studentships in total will be available.

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