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Magnetic resonance imaging of mouse models of de and dysmyelination

Best, Lawrence MJ; (2020) Magnetic resonance imaging of mouse models of de and dysmyelination. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Oligodendrocytes are the myelinating cells of the central nervous system, ensheathing axons and enabling rapid conduction of nerve impulses. Demyelination involves loss of functional myelin around one or a group of axons. Various diseases are caused by demyelination, with multiple sclerosis (MS) being the most common. While MS is caused by demyelination, inflammation is an important determinant of progression to its progressive form. There are still many questions about demyelination, including the role that inflammation plays in its development and progression. Diffusion weighted magnetic resonance imaging (DWMRI) is widely used to study myelinated axon tracts. However, the cellular changes that cause alterations to the DWMRI signal are not well understood. To investigate the changes that occur as a result of aberrant myelination and their effect on DWMRI, three demyelinating mouse models and one dysmyelinating model were characterised histologically before undergoing DWMRI. To assess the role of inflammation in demyelination and subsequent remyelination, microglia were depleted or inhibited pharmacologically in the Sox10iCreERT2:Myrf(fl/fl) genetic model and changes in phenotype and histology were quantified. My histological studies of de-or dys-myelinating models showed an inflammatory reaction involving resident microglial cells always accompanied acute demyelination. When the severity of demyelination reached a certain critical threshold, infiltration of peripherally-derived macrophages was triggered, precipitating rapid worsening of the physical phenotype. DWMRI signal was relatively insensitive to demyelination per se, at the signal to noise ratio and resolution in this study, however, I found evidence that the presence of actively phagocytosing immune cells had a major effect on DWMRI signal. Pharmacological depletion of microglia caused a worsening of demyelination in the Sox10iCreERT2:Myrf(fl/fl) model, indicating an overall beneficial effect of microglia during the initial stages of demyelination. However, the effect of microglial activation was variable, depending on when microglial depletion was initiated relative to the time course of demyelination.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Magnetic resonance imaging of mouse models of de and dysmyelination
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10110160
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