White matter (WM) makes up a critical component of the CNS, composed primarily of myelinated axons. Herein, axons and the myelin sheath form a dynamic and communicative axo-glial unit which acts to regulate and support axonal function. The myelin sheath not only electrically insulates axons allowing for rapid and efficient axonal conduction and complex neuronal circuitry but also supports axonal viability. The loss or dysregulation of the myelin sheath is detrimental to axons as well as overall brain function. Furthermore, this is a key hallmark, not only, of classical WM diseases including multiple sclerosis but also is observed in brain ageing and dementias including Alzheimer’s disease. Where, it is considered a key driver of cognitive impairment and disability. Thus, the need to have robust and reliable means of modelling WM pathology is critical, not only to determine how WM specifically responds to pathology but furthermore to identify therapeutic targets and agents that act to preserve WM integrity. The results of which could have widespread clinical implications and benefits. This thesis will examine this concept in two very distinct models; one utilising acute ex-vivo modelling, the other chronic and in-vivo, predominately these models will be assessed both functionally using electrophysiology and structurally using microscopy. Although unrelated, the observations made in these models will hopefully give insights into some critical considerations and the potential future of modelling WM pathology. As well as identifying new potential therapeutics which may be successful in the preservation of WM clinically.

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