Dr M Belle, Dr J Brown, Prof Krasi Tsaneva-Atanasova, Prof J Hodge
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
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 oursleep-wake cycle, peak cognition ability, and optimum brain toxin clearance, such amyloid-Beta (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 ABpeptide 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 key 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 computational analysis. 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 then be screened in Drosophila to restore clock function in aged and AD flies, and see if it rescues sleep and memory loss, neurodegeneration, and shortened lifespan. This will then be translated to mammals.
Funding Notes
A GW4 BioMed MRC DTP studentship includes full tuition fees at the UK/Home rate, a stipend at the minimum UKRI rate, a Research & Training Support Grant (RTSG) valued between £2-5k per year and £300 annual travel and conference grant based on a 3.5-year, full-time studentship.
These funding arrangements will be adjusted pro-rata for part-time studentships.
Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities