The effects of environmental and microbiota manipulation on myelination in the YAC128 and BACHD models of Huntington disease

White matter (WM) deterioration is increasingly being recognised as a hallmark of Huntington disease (HD) and is correlated to disease severity. The research presented in this thesis employed environmental and microbiota manipulations as assays to interrogate white matter plasticity in two mouse models of Huntington disease (YAC128 and BACHD), as well as wild-type (WT) control animals. In the first study, we examined the effects of environmental enrichment on several HD specific behavioural traits, and on white matter characteristics in the posterior region of the corpus callosum (CC) in the YAC128 mouse and WT control. This was followed by a second study in which the same outcomes were explored in response to environmental deprivation through social isolation in identical mouse genotypes. Finally, we investigated the effects of microbiota manipulation on white matter in the anterior mid-body region of the CC and in the prefrontal cortex of the BACHD mouse and WT control, housed under germ-free and specific pathogen free conditions. White matter plasticity was examined using a range of techniques, including transmission electron microscopy, immunohistochemistry, and immunoblotting, while behavioural characteristics were evaluated using a battery of targeted tests. Our findings suggested that myelination in the CC region was affected by social deprivation in WT mice, but was relatively insensitive in YAC128 mice, however, both groups responded to enrichment in a similar manner. In contrast, a germ-free environment had complex effects in both WT and BACHD mice, including alterations in axonal diameter, myelin thickness, myelin related gene transcripts, as well as oligodendroglial cell populations. Thus, the work described herein provides further evidence that environmental and microbiota manipulations influence white matter plasticity in both the healthy and HD brain, and lay the foundation for future studies on potential therapeutic approaches in the latter.