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Nuclear hormone rhythms in the brain


Project Description

Much of our behaviour and physiology is driven rhythmically by internal circadian clocks, and disruption of these rhythms (e.g. during aging, chronic shift work, 24hr lifestyle) contributes to decreased cognitive performance, and also many human disease pathologies (such as obesity, cancer, depression). Within the brain, clocks are strongly implicated in coordination of neural processes including synthesis of new neurones, and synaptic plasticity in learning and memory circuits. Genetic targeting of clocks in different tissues has demonstrated that the clock not only provides timing information, but is also critical to normal organ function (e.g. glucose homeostasis in the liver). However, to date, very few studies have attempted to target clock-gene function in the brain, or link specific timing circuits to learning, memory and diurnal behaviour, including regulation of sleep.

This project will therefore break new ground, by examining how specific elements of the circadian clockwork contribute to behaviour and brain function. The focus will be on Rev-erb and Rev-erb. Using genetic techniques in transgenic mice, we aim to suppress activity of these genes in timing and learning centres of the brain (suprachiasmatic nucleus and hippocampus). The latter structure is crucial for regulation of a key stress and metabolic hormone (corticosteroid), so the student will also explore whether loss of hippocampal timers leads to altered metabolism. Studies will centre on in vivo whole animal physiology, use of a range of behavioural assays for learning and memory, assessment of circadian physiological and behavioural rhythms, and complimented by use of genetic and biochemical methods.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

• Bechtold DA, Loudon AS (2013) Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci. 36(2):74-82.
• Li J, Hand LE, Meng QJ, Loudon AS, Bechtold DA (2011) GPR50 Interacts with TIP60 to Modulate Glucocorticoid Receptor Signalling. PLoS One 6(8):e23725.
• Bechtold DA, Gibbs JE, Loudon AS. (2010) Circadian dysfunction in disease. Trends Pharmacol Sci 31(5):191-8.
• Meng QJ*, Maywood ES*, Bechtold DA*, Lu WQ, Li J, Gibbs JE, Chesham J, Rajamohan F, Knafels F, Ohren JF, Walton KM, Wager TT, Hastings MH, Loudon AS. (2010) Entrainment of disrupted circadian behavior through inhibition of CK1 enzymes. PNAS 107(34):15240-5

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