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Investigating the influence of myelin plasticity on neural circuit function

Primary Supervisor: Dr Daniel Fulton, Institute of Inflammation and Ageing, University of Birmingham

Secondary Supervisor: Dr Vincenzo Marra, Department of Neuroscience, Psychology and Behaviour, University of Leicester

PhD project title: Investigating the influence of myelin plasticity on neural circuit function

University of Registration: University of Birmingham

Project outline:

Oligodendrocytes (OL) wrap axons in myelin, an insulting material whose formation in tightly compacted spirals increases the speed of action potentials by up to 10-fold. Traditionally, myelination has been viewed as a static process regulated by the diameter of axons, and remaining unchanged once formed. Recent work has overturned this view by showing that numerous parameters associated with myelination, including OL differentiation and myelin sheath length, are altered when neuronal activity is reduced1,2. This is significant since myelin sheath length is positively linked to axonal conduction velocity (longer sheaths/faster conduction). The implication of these new discoveries are: (1) activity- dependent myelination allows axons to fine-tune their conduction speeds by altering the length of their myelin sheaths; and (2) this phenomenon will contribute to neural plasticity by influencing coincidence detection at the synapse3.

State of the art: Based on the above, activity-dependent myelination is positioned to influence fundamental properties of neural circuit function such as information encoding, yet to date there has been no attempt to investigate the influence of activity-dependent myelination on neural circuit function. This joint project between The Fulton and Marra labs will seek fundamental knowledge on this important question by using quantitative electrophysiological and optical imaging techniques to measure neural network activity in circuits subjected to alterations in myelination.

Scientific approach: The student will use transgenic brain slice cultures where myelination can be visualised and modulated in living tissues, and neural circuit activity recorded using multi-electrode array (MEA) electrophysiology and optical recordings. MEA recordings will allow circuit responses to be recorded following time-locked stimulation, while optical measurements from patch-clamped neurons provides the means to measure conduction velocities in individual myelinated axons. OL-myelination will be reduced pharmacologically by targeting neuronal activity, or increased by incubating brain slices in conditioned medium isolated from activated microglial cultures. Comparison of recordings under differing culture conditions will allow changes in myelination to be linked to alterations in circuit function.

Training plan: The student will be based in the Fulton lab at the University of Birmingham (UoB) where they will learn to generate forebrain slice cultures isolated from fluorescent OL reporter mice, monitor myelination via imaging of the OL reporter during slice cultivation, and quantify myelination in fixed slices by immunofluorescent assays. The student will also learn to culture microglia and stimulate them to produce pro-myelination factors, and to use this conditioned medium, or pharmacological treatments targeting neuronal activity1, to experimental increase and decrease OL myelination respectively.

Having acquired these fundamental skills the student will work at the Marra lab at the University of Leicester to learn electrophysiological and optical imaging methods for the analysis of cortical neural circuit function in forebrain slice cultures (~ 8 months). The student will also learn to analyse and interpret this circuit activity data. After this training the student will return to UoB to to study cortical circuit function in forebrain slice cultures subjected to alterations in myelination (increased by microglial conditioned medium/ decreased pharmacologically). Alterations in myelination will be confirmed in living slices through imaging of the OL reporter, and recordings of cortical activity obtained using the skills developed in the Marra lab.

References:

  • Fannon J, Tarmier W & Fulton D (2015) Glia 36: 6937-48. 63:1021-1035. https://doi.org/10.1002/glia.227.
  • Toth E, Rassul SM, Berry M & Fulton D (2019) BioRxiv [Preprint] doi: https://doi.org/10.1101/750083.
  • Fields D (2015) Nat Rev Neurosci 16:756-767.
BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour

Techniques that will be undertaken during the project:
  1. Organotypic brain slice cultures
  2. Qualitative and quantitative Long-term live imaging of OL differentiation and myelination using PLP-dsRED OL reporter brain slice cultures
  3. Quantitative Immunofluoresence
  4. Quantitative electrophysiological measures of single neurons
  5. Quantitative electrophysiological measurements from neural circuits / networks
  6. Quantitative optical imaging of neural activity (calcium / voltage / vesicular neurotransmitter release)

Contact: Dr Daniel Fulton, University of Birmingham