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Understanding how altered GABA signalling in the brain's master clock contributes to circadian rhythm disruption in Alzheimer's disease


   Faculty of Biology, Medicine and Health


About the Project

Our circadian clock is one of the most important timing systems in our body, ensuring that neuronal activity throughout our CNS is appropriately aligned with our homeostatic, physiological, and behavioural needs across the day. This includes the timing in our sleep-wake cycle and brain toxin clearance, such amyloid-Beta (AB). Disruption to this daily rhythm can lead to severe health consequences, including premature ageing and mental health disorders. 

Circadian rhythm disruption is a common symptom of Alzheimer’s disease (AD). Recent knowledge has identified that circadian disruptions often occur early in the course of AD and may precede the development of cognitive symptoms. The sleep–wake cycle regulates pathogenic AB peptide and tau levels in the brain, and manipulating the sleep-wake cycle can influence AD-related pathology. Indeed, the circadian system plays a key role in the neurodegenerative process of AD.

The mammalian master circadian clock is found in the suprachiasmatic nucleus (SCN), where the activity of clock genes produces daily excitability rhythms in SCN neurons, causing them to be more active during the day than at night. This rhythm in clock and electrical activity is vital for clock function, promoting well-being and health, but blunts in ageing and AD.

 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, the applicant will receive training in state-of-the-art in vivo and in vitro electrophysiology, imaging, optogenetic, and sophisticated behavioural measurements and computational analysis, using several animal models.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.  Candidates with experience in chronobiology and/or Alzheimer’s disease or with an interest in neurophysiology are encouraged to apply. Experience with in vivo neuroscience techniques, having a Home Office license for animal work and some experience of coding (e.g., Matlab/Python) is an advantage.

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Neuroscience.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website View Website

References

D. DeWoskin, J. Myung, M.D. Belle, H.D. Piggins, T. Takumi, and D.B. Forger (2015). Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping. Proceedings of the National Academy of Science. USA; 112: E3911-E3919.
M.D. Belle, A.T. Hughes, D.A. Bechtold, P. Cunningham, M. Pierucci, D. Burdakov, and H.D Piggins. (2014). Acute suppressive and long-term phase modulation actions of orexin on the mammalian circadian clock. Journal of Neuroscience; 34: 3607-3621.
Storchi R, Milosavljevic, N., Allen, A. E., Zippo, A. G., Agnihotri, A., Cootes, T. F., & Lucas, R. J. (2020). A high-dimensional quantification of mouse defensive behaviours reveals enhanced diversity and stimulus specificity. Current Biology, 30(23), 4619-4630
Milosavljevic N.*, Storchi R.*, Eleftheriou C., Colins A., Petersen R. and Lucas R. (2018) Photoreceptive retinal ganglion cells control the information rate of the optic nerve. PNAS, 115(50):E11817-E11826
Davis K, Fox S and Gigg J. (2014) Increased hippocampal excitability in the 3xTgAD model for Alzheimer’s disease in vivo. PLos One, DOI: 10.1371/journal.pone.0091203
Davis, K., Eacott, M., Easton, A. and Gigg, J. (2013) Episodic-like what-where-which occasion memory is sensitive to AD pathological accumulation and normal ageing processes in mouse. Behav. Brain Res. 254:73-82

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