Anatomy and Neuroscience - Theses
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ItemThe effects of stress on the onset and progression of Huntington's disease in a transgenic mouse model( 2014)Huntington’s disease (HD) is a neurodegenerative disorder largely governed by genetics. The cause of the disease is a fully penetrant gene mutation, inherited by autosomal dominant transmission. The length of this mutation also predicts the age of disease onset, which can range from childhood to late adulthood. Work from our lab on the R6/1 transgenic mouse model of HD was the first to show that environmental factors can alter symptom progression. Environmental enrichment and voluntary wheel running delayed or ameliorated the triad of motor, affective and cognitive dysfunctions in HD mice. Recent clinical studies also suggest that lifestyle factors can affect the age of onset. Currently, there are no treatments to slow or change the course of HD so environmental interventions may offer a feasible approach to extend the symptom-free years in HD gene-positive individuals. There is evidence to suggest that the stress response is abnormal in HD mice and patients. The present study is the first to investigate the impact of stressors on the onset and progression in an animal model of HD. We used an acute (Chapter 3) and two chronic stress paradigms (Chapters 4 and 6) to assess the impact on characteristic symptoms of HD. We also extended the phenotyping of R6/1 HD mice to include behaviours of ethological relevance (Chapter 5). All 3 stress protocols were able modify various functions in R6/1 HD mice, notably accelerating cognitive decline and further impairing olfactory deficits. This work contributes data for sex differences in the HD phenotype and to the general stress literature. Importantly, we show that stress is not only able to modulate specific behaviours in HD mice, but that the gene mutation may confer a susceptibility to the negative effects of stress. Therefore, behavioural management therapy in combination with other lifestyle changes may help manage the course of the disease in gene positive individuals.