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  Funded PhD - Determining the genetic and circadian basis of bipolar disorder


   School of Physiology, Pharmacology & Neuroscience

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  Prof J Hodge, Dr Alice French  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

This project will be part of the University of Bristol - University of Kent Cotutelle Programme. It will be jointly supervised by Prof James Hodge (http://www.bristol.ac.uk/phys-pharm-neuro/people-new/hodge/) and Dr Alice French at the University of Bristol, and by Prof Gurprit Lall at University of Kent. The candidate will be expected to spend about equal time at each institution (the first two years at UoB, then two years at UoK) and, upon successful completion of their studies, they will receive a dual award issued by University of Bristol and University of Kent.

About the project

Circadian rhythms and sleep are evolutionarily conserved from fruit flies (Drosophila) through to mammals and are fundamental as well as vital to biology and health (Jagannath et al., 2017). Bipolar disorder is highly heritable with recent genomic studies identifying a conserved set of underlying genes that are also implicated in circadian rhythm and sleep regulation. These genes (clock, CACNA1C, GSK-Beta) are highly connected and evolutionarily conserved between flies, mice and human, including their response to mood stabilizing drugs (e.g., lithium and valproate), which can be studied in animal models and human cells (Dokucu et al., 2005; Franklin and Dwyer, 2021; Logan and McClung, 2016; McCarthy et al., 2016; McCarthy et al., 2012). In this project, both fly and mouse models mutant for these genes associated with bipolar disorder will be characterised for circadian rhythms under different light conditions. In parallel we measure the effect on sleep including measuring sleep stages and sleep deprivation, using standard biochemical and behavioural assays set up in our labs (Buhl et al., 2019; Buhl et al., 2022; French et al., 2021; Lalic et al., 2020).

To measure behavioural changes related to mood in these different flies, circadian and sleep states, we will use an affective bias assay we have developed for Drosophila (Deakin et al., 2018). We will validate the model by attempting rescue of behavioural deficits by feeding the flies lithium, valproate and other drugs predicted to correct the molecular defects (Dokucu et al., 2005). Translating results to mammals using multi-disciplinary circadian and disease modelling experiments in mice (Lall et al., 2012; Logan and McClung, 2016) and to humans through our active involvement in UK collaborative research networks (https://www.circadianmentalhealth.org/ and https://www.bioclocks.uk/). This PhD project will involve training and use of molecular genetics (generation of new CRISPR transgenic models), genetics, behaviour (e.g. circadian rhythms, sleep and measures of affect), clock neuron and superchiasmatic nucleus electrophysiology, computational modelling, confocal imaging, optogenetics, period-luciferase imaging and pharmacology in fly and mouse models.

How to apply

The application deadline is Sunday 12/05/24 at midnight.

Applicants must submit an application via the University of Bristol application portal: Physiology, Pharmacology and Neuroscience | Study at Bristol | University of Bristol . Please read the Admissions Statement, then click on "Apply Now" and select the programme "Physiology, Pharmacology and Neuroscience (PhD)". In the application, funding section, please indicate "UoB - Kent Cotutelle".

Enquiries

For questions about the project, please contact the project supervisor, Prof. Hodge, by emailing the Faculty of Life Sciences PGR Admin Team - [Email Address Removed]

If you require assistance with your application on the portal, please email the Faculty of Life Sciences PGR Admin Team - [Email Address Removed]


Biological Sciences (4) Mathematics (25) Medicine (26) Psychology (31)

Funding Notes

The University of Bristol - University of Kent Cotutelle is available for a 4-year PhD, for UK students, with a September 2024 start.
The studentship duration is four years, and it includes an annual stipend set at the current UKRI recommendation of £19,237.  
Tuition fees and research costs are fully supported by the studentship, as well as an allowance for paid sick leave and parental leave, in addition to 5 weeks of paid leave each year.

References

Buhl, E., et al (2019). Alzheimer's disease-associated tau alters Drosophila circadian activity, sleep and clock neuron electrophysiology. Neurobiol Dis 130, 104507.
Buhl, E., et al (2022). Effects of Eph/ephrin signalling and human Alzheimer's disease-associated EphA1 on Drosophila behaviour and neurophysiology. Neurobiol Dis 170, 105752.
Dokucu, M.E., et al (2005). Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila. Neuropsychopharmacology 30, 2216-2224.
Franklin, C., and Dwyer, D.S. (2021). Candidate risk genes for bipolar disorder are highly conserved during evolution and highly interconnected. Bipolar Disord 23, 400-408.
French, A.S., et al (2021). Sensory processing during sleep in Drosophila melanogaster. Nature 598, 479-482.
Jagannath, A., et al (2017). The genetics of circadian rhythms, sleep and health. Hum Mol Genet 26, R128-r138.
Lalic, T., et al (2020). TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses. Nat Commun 11, 4614.
Lall, G.S., et al (2012). Circadian entrainment and its role in depression: a mechanistic review. J Neural Transm 119, 1085-1096.
Logan, R.W., and McClung, C.A. (2016). Animal models of bipolar mania: The past, present and future. Neuroscience 321, 163-188.
McCarthy, M.J., L et al (2016). Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms. Neuropharmacology 101, 439-448.
McCarthy, M.J., et al (2012). A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response. PLoS One 7, e32091.

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