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Impact of synaptic remodelling on neuronal network activity

Principal Supervisor: Vincenzo Marra - Department of Neuroscience, Psychology and Behaviour

Co-supervisor: Prof Ian Forsythe

PhD project title: Impact of synaptic remodelling on neuronal network activity

University of Registration: University of Leicester

Project outline:

Information transmission in the nervous system relies on synaptic connections between neurons. While the strength of these connections is constantly changing through activity-dependent plasticity, the output of large neuronal networks is reliable over time. This project will investigate how plastic changes at individual identified synapses can shape the activity of large neuronal networks without causing destabilization them. Thalamocortical connections in layer 4 of the A1 auditory cortex are key mediators of information transmission and this region is already under investigation in collaboration with Professor Forsythe. The auditory cortex is a robust model of synaptic plasticity and will allow investigation of key signalling pathways, including cholinergic and nitrergic pathways and is amenable to direct physiological and behavioural manipulation.

Network wide structural changes caused by activity-dependent plasticity will be studied while manipulating neuronal firing in the thalamus using optogenetic tools. The number and distribution of thalamocortical connections will be studied in intact cortical circuits using CLARITY and compared with key presynaptic and postsynaptic markers. This recently developed technique, combined with confocal imaging, will allow the visualization of the synaptic terminals originating from neurons transfected with Channelrhodopsin in the thalamus.

Functional changes in neuronal activity will be monitored in acute cortical slices. Optogenetic stimulation and electrophysiological investigation (using current and voltage-clamp) will be combined with labelling of synaptic vesicles to study changes in synaptic strength and release probability. Labelled synaptic vesicles will be studied at the fluorescence and ultrastructural level using a novel approach for correlative light and electron microscopy that is well-established in the lab.

The project integrates the two main lines of research in the lab, bridging the gap between the cellular study or release probability and the systems level approach to the study of neuronal networks. The student will receive training in a wide range of cutting-edge techniques with particular focus on the use of computational tools for the analysis of large datasets.

References:

  1. Marra V., Burden J.J., Thorpe J.R., Smith I., Smith S.L., Häusser M., Branco T., Staras K. A preferentially segregated recycling vesicle pool of limited size supports neurotransmission in native central synapses. Neuron. 2012 Nov 8;76(3):579-89.
  2. Steinert J.R., Robinson S.W., Tong H., Haustein M.D., Kopp-Scheinpflug C., Forsythe I.D. Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability. Neuron. 2011 July 28;71(2-3):291-305.
  3. Ratnayaka A.*, Marra V.*, Branco T., Staras K. Extrasynaptic vesicle recycling in mature hippocampal neurons. Nat Commun. 2011 Nov 8;2:531.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Live confocal imaging of synaptic vesicles and calcium signals
  • CLARITY
  • Optogenetics
  • Whole-cell patch clamp
  • Extracellular recordings
  • Brain slice preparation
  • Correlative Light and Electron Microscopy (CLEM)
  • Interfacing experimental data with computational modelling

Contact: Dr Vincenzo Marra, University of Leicester