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Critical period and network tuning

Supervisor: Dr Matthias Landgraf

 

Project summary:

As nervous systems develop, networks 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, causing propensity for seizures and neuro-developmental psychiatric disorders. The critical periods are universal and that of the Drosophila motor system has the hallmarks of mammalian critical periods: activity disturbances during this short 2-hour plasticity window lead to permanently unstable, seizure-prone networks.

How these periods of high plasticity are developmental regulated and genetically specified remains incompletely understood. Excitingly, we identified specific developmental phenomena of glial cells and neurons that demarcate the critical period of the Drosophila motor network. We also identified reactive oxygen species (ROS) as novel signals required for neural plasticity, and find ROS also critical for network tuning.

We can now investigate the cellular and molecular mechanisms that regulate onset and termination of the critical period. And we will ask how neuronal connections are impacted acutely and permanently by disturbances during the critical period. Together these approaches might help devise strategies for re-opening critical periods and promoting correction of developmental errors.  

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 in 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). Super-resolution imaging methods, such as expansion microscopy and ‘GRASP’ will allow quantitative imaging of synapses.

References:

1.     Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Morarach K, Sweeney ST and Landgraf M. (2017). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity.  Preprint  bioRxiv 081968.  DOI: dx.doi.org/10.1101/081968     

2.     Giachello, C. N. G. and Baines, R. A. (2015). Inappropriate Neural Activity during a Sensitive Period in Embryogenesis Results in Persistent Seizure-like Behavior. Curr Biol 25, 2964–2968.

3.     Zwart, M. F. et al. Selective Inhibition Mediates the Sequential Recruitment of Motor Pools. Neuron (2016). doi:10.1016/j.neuron.2016.06.031

4.    Couton L., Mauss A.S., Yunusov T., Diegelmann S., Evers JF., Landgraf M. Development of connectivity in a motoneuronal network in Drosophila larvae. Curr Biol. 25:568-76 (2015).  doi: 10.1016/j.cub.2014.12.056.

5.         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