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Epigenetic and transcriptional mechanisms mediating neuronal plasticity ​

Supervisor: Dr Matthias Landgraf

Project summary:

Transient experiences during formative stages of nervous system development, called ‘critical periods’, can permanently impact on nervous system function. Extensively studied in mammalian sensory systems, e.g. optical dominance column formation, critical periods occur as networks become functional and transition to patterned activity. However, the mechanisms that lead to network adjustment during this critical period have remained largely elusive, nor do we understand how transient experience can have lasting effects on neuronal properties, akin to cellular specification.

The importance of critical periods for network development is perhaps most evocatively illustrated by studies around epileptic seizures: transient disturbances of the excitation:inhibition balance during the embryonic critical period has lasting effects, leading to seizure-prone networks. Conversely, the effects of seizure-causing mutations can be permanently rescued by transiently re-balancing activity levels during the critical period.

We discovered an explicit critical period that can be studied using a readily accessible synaptic connection between identified cells in the motor system of the fruitfly, Drosophila melanogaster. We have already identified sets of plasticity mechanisms regulated during this critical period. Excitingly, we find that these are marked by changes in gene expression and also by associated epigenetic chromatin marks.

What the student will be doing:

In this project you will use a combination of genetics, genomics, imaging and electrophysiology to characterise the how transient critical period experiences lead to lasting changes in gene expression via chromatin modifications. 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). Chromatin Accessibility profiling using Targeted DamID (CATaDa) will be used to quantify genome wide changes in chromatin conformation, with focus on candidate genes known to be associated with the plasticity pathways we have identified.

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.     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.         Aughey, G. N., Estacio-Gómez, A., Thomson, J., Yin, H., & Southall, T. D. (2018). CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo. eLife, 7, 6061. http://doi.org/10.7554/eLife.32341