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Optical investigation of individual synaptic contacts during network remodelling

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

Non-academic partner: Cairn Research

PhD Project Title: Optical investigation of individual synaptic contacts during network remodelling

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 synapses can shape the activity of neuronal networks without causing destabilization.

The project will focus on the pre- and postsynaptic mechanisms regulating neurotransmitter release at small central synapses in the mammalian central nervous system. As part, of the project a novel approach to single vesicle live imaging will be developed in collaboration with our industrial partners (Cairn Research) and Dr Lowe (Department of Chemistry, University of Leicester).

By combining optical and electrophysiological recordings of cortical neurons in acute slices, we will study the relationship between release probability and postsynaptic structure and function. We will induce spike-timing dependent plasticity (STDP) while labelling vesicles with phosphorescent compounds, compatible with lifetime imaging, using Cairn Research fast switching LED-based illumination systems. This approach will allow us to test the hypothesis that, while pre- and postsynaptic neurons work synergistically to strengthen or weaken their connection, changes at individual synaptic contacts are heavily influenced by spine morphology and position on the dendrite. Preliminary observations indicate that contacts with high synaptic weights (large postsynaptic currents) are less likely to induce increases in release probability at their presynaptic terminal after long term potentiation. The project will build on these observations and expand the study to STDP-induced long-term depression. Using Phosphorescence Lifetime Imaging (PLIM) and structured illumination microscopy, we will monitor simultaneously a number of presynaptic terminals to investigate the effect of network-level plasticity on individual release sites. Patch-clamp techniques will be employed to record activity and label a postsynaptic neuron, while axons connecting onto this target will be stimulated, once for vesicles loading with phosphorescent compounds and a second time to study vesicular release and its modulation after hebbian plasticity. The successful candidate will produce software to make full use of Cairn Research structured illumination system for applications such as super-resolution live imaging and photostimulation. Independent methods, based on styryl dye (FM1-43FX) photoconversion for electron microscopy, will be used in parallel to validate this newly developed methodology.

We welcome applications from candidates with a background in physics, engineering, computer science, neuroscience or biological sciences.

Closing date for applications: 2nd March 2018

Interview dates: TBC

Check eligibilty and apply