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Specification of neuronal function by metabolic reactive oxygen species

Supervisor: Prof Matthias Landgraf

Project summary

How do transient experiences leave a permanent impact on the nervous system? As nervous systems develop, they undergo a period of heightened plasticity, called ‘critical period’, which facilitates tuning of connections between nerve cells. Errors that occur during this critical period lead to permanent mis-adjustment, thought the cause of seizures and neuro-developmental psychiatric disorders. Critical periods are universal phenomena. Now the mechanisms by which these mediate specification of neuronal properties need to be investigated.

Excitingly, having taken advantage of a clearly defined critical period in Drosophila, we identified metabolic reactive oxygen species (ROS) as instructive signals for neural and network properties. For example, changing metabolic ROS during the critical period permanently impacts on the epigenetic landscape and gene expression, including neurotransmitter receptors. We can now use this system to investigate the signalling pathways and molecular mechanisms through which metabolic ROS mediate changes during nervous system development.

What the student will be doing

In this project you will use a combination of genetics, imaging and electrophysiology to characterise the developmental events around the critical period. Behavioural assays include larval crawling and electroshock. A combination of semi-intact preparations (for pharmacological manipulations) or intact animals (manipulated using thermo- and opto-genetics) will be used to study changes in neuronal structure and function (using functional imaging and electrophysiology).

References

1. Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Giachello, CNG, Morarach K, Baines RA, Sweeney ST and Landgraf M. (2018). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity. eLife, 7. http://doi.org/10.7554/eLife.39393

2. Oswald, M. C. W., Garnham, N., Sweeney, S. T., & Landgraf, M. (2018). Regulation of neuronal development and function by ROS. FEBS Letters. http://doi.org/10.1002/1873-3468.12972

3. Dhawan S, Myers P, Bailey DMD, Ostrovsky AD, Evers JF, Landgraf M (2021). Reactive Oxygen Species Mediate Activity-Regulated Dendritic Plasticity Through NADPH Oxidase and Aquaporin Regulation. Front Cell Neurosci. 15:641802. doi: 10.3389/fncel.2021.641802. 4. Zhao J, et al. (2021). Metabolic remodelling during early mouse embryo development. Nat Metab. 10:1372-1384. doi: 10.1038/s42255-021-00464-x.