About the Project
Parkinson’s disease is caused by a dramatic loss of dopaminergic neurons from the midbrain. Typically the characteristic motor symptoms do not appear until more than 80% of the dopamine neurons projecting to the dorsal striatum have been lost. Little is known about how this loss of dopamine changes the computations of striatum. Consequently, we are lacking good answers to the most basic questions about the link between dopamine and motor control: Why does it take more than 80% loss? How do motor symptoms of akinesia and bradykinesia arise from this loss? And why those motor symptoms and not others? Understanding this link will let us understand how current treatments (L-DOPA and deep brain stimulation) work and identify potential new targets for intervention.
This project will pursue the hypothesis that chronic loss of dopamine causes the fragmentation of striatal processing of cortical input. The striatum supports neural populations coding for different actions, forming the basis for action selection. Animal model data has suggested that chronic dopamine loss causes the fragmentation of these populations, mixing together previously well-defined populations (Cho et al 2002). Computer models have shown that dopamine loss occurs in “voids” (Dreyer 2014) fragmenting the striatum into regions of low and high dopamine.
To test this hypothesis, the candidate will develop our existing large-scale model of the striatal network (Tomkins et al, 2014; Humphries et al, 2010) and combine it with a newly-developed model of dopamine-dependent plasticity at cortical synapses onto striatal neurons (Gurney et al, 2015). The project will then test aspects of the hypothesis: Does fragmentation occur via changes to network excitability or to plastic change to network inputs? Does fragmentation cause the breakdown of action selection and therefore the observed motor symptoms? And why is 80% loss of dopamine necessary for this to occur?
http://www.systemsneurophysiologylab.ls.manchester.ac.uk/
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form, full details on how to apply can be found on our website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mrc-dtp/.
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
Cho, J., Duke, D., Manzino, L., Sonsalla, P. K. & West, M. O. (2002) Dopamine depletion causes fragmented clustering of neurons in the sensorimotor striatum: evidence of lasting reorganization of corticostriatal input. Journal of Comparative Neurology, 452, 24-37
Dreyer, J. K. (2014) Three mechanisms by which striatal denervation causes breakdown of dopamine signaling. Journal of Neuroscience, 34, 12444-12456
Gurney, K. N., Humphries, M. D. & Redgrave, P. (2015) A New Framework for Cortico-Striatal Plasticity: Behavioural Theory Meets In Vitro Data at the Reinforcement-Action Interface. PLoS Biology, 13, e1002034
Humphries, M. D., Wood, R. & Gurney, K. (2010) Reconstructing the three dimensional GABAergic microcircuit of the striatum. PLoS Computational Biology, 6: e1001011.
Tomkins, A., Vasilaki, E., Beste, C., Gurney, K. & Humphries, M. (2014) Transient and steady-state selection in the striatal microcircuit. Frontiers in Computational Neuroscience, 7, 192