Anatomy and Neuroscience - Theses
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ItemInvestigating oligodendrocyte population expansion in the central nervous system( 2022)The myelin sheath is an essential component of central nervous system (CNS) health, without which neuronal function is compromised. Oligodendrocytes are the myelinating cells of the CNS and are produced throughout life through the division and differentiation of oligodendrocyte precursor cells, or OPCs. Interestingly, the processes driving oligodendrocyte production appear distinct between humans and mice. Human OPCs divide quickly and stop dividing with age. There is little oligodendrocyte addition to human white matter tracts in adulthood, and few pre-existing oligodendrocytes are replaced by new cells. By contrast, murine OPCs divide slowly, continue generating new oligodendrocytes in adulthood, and evidence suggests oligodendrocyte replacement is high in adult murine white matter. For these reasons, the relevance of using mice to study human conditions in which oligodendrocytes and myelin are compromised–such as multiple sclerosis (MS)–has recently been questioned. This presents a fundamental hurdle to performing translatable basic research into demyelinating diseases like MS. Oligodendrocyte addition is also required to facilitate new learning, in a phenomenon known as ‘adaptive myelination’. Therefore, distinct oligodendrocyte production dynamics in the human versus the mouse challenges whether studies of murine learning are of clinical relevance to the human. This has severe implications for pre-clinical animal studies which attempt to mitigate the effects of cognitive decline. In this thesis, I use novel techniques to show that both human and mouse OPCs divide quickly and stop dividing with age. I show humans and mice have similar profiles of oligodendrocyte integration over life, and that oligodendrocyte replacement is low in mice as it is in humans. I mount the argument that previous distinctions between human and mice are primarily driven by a tendency to use relatively young mice to assess ‘adult’ white matter change, in conjunction with a tendency to use density-based metrics, rather than measuring total numbers of oligodendroglia. Finally, I investigate whether oligodendrocyte production or survival alters in two established murine models of adaptive myelination: social isolation and environmental enrichment. I find that juvenile social isolation does not alter the course of oligodendrocyte production nor survival in the prefrontal cortex, but that juvenile environmental enrichment transiently increases oligodendrocyte survival. Consistent with recent studies, this suggests that environmental interventions have an exciting potential to promote more efficient modes of oligodendrocyte addition in the CNS. Importantly, this thesis realigns mouse and human oligodendrocyte growth systems to provide credence to the translatability of mouse studies. While the number of oligodendrocytes may be plastic in juvenile development, there is little ability for extensive cellular remodelling in adulthood. This brings forth important questions such as: are there limits to adaptive myelination with ageing? Are there limits to myelin repair? As the human population experiences an increase in the average lifespan, investigating such questions will become key to our ability to therapeutically target white matter repair in neurodegenerative conditions, or preserve cognitive function in age-related cognitive decline.