Non-motor symptoms in the aav-α-synuclein rat model of Parkinson’s disease: exercise as a therapeutic intervention

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Dolan, Erin
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University College Cork
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Parkinson’s disease (PD) is no longer primarily classified as a motor disorder due to the emergence of a number of non-motor symptoms (NMS) of the disease. These NMS are highly prevalent and greatly affect the quality of life of patients with PD. Thus, an animal model that replicates these symptoms is greatly needed to enhance the translational impact of preclinical research. The AAV-α-synuclein rat model is the only animal model to date that has been shown to robustly and consistently reproduce the primary neuropathological and behavioural features of PD. However, there has been little research on the ability of the model to replicate NMS of the disease. Moreover, this model is most commonly employed unilaterally, which can confound cognitive testing due to contralateral functional compensation. Thus, the aim of this thesis was to use an AAV2/6 viral vector overexpressing human wild-type α-synuclein to characterise NMS of PD, exploring behavioural phenotypes of both unilaterally- and bilaterally-administered αsynuclein. Furthermore, it set out to explore whether voluntary exercise could ameliorate motor and NMS in this PD model, including if exercise could protect against hippocampal-associated cognitive deficits by modulating adult hippocampal neurogenesis. We demonstrated that unilateral and bilateral administration of AAV-αsynuclein induced distinct patterns of nigrostriatal degeneration and associated motor dysfunction. Overexpression of AAV-α-synuclein was used to model NMS associated with PD, including deficits in hippocampalassociated tasks. This was coupled with α-synuclein-positive immunostaining in the dentate gyrus of the hippocampus, confirming the propagation of the protein throughout distinct regions of the brain. Bilateral intranigral administration of AAV-α-synuclein was found to induce motor dysfunction and a significant loss of nigral dopaminergic neurons, neither of which were rescued by voluntary running. Overexpression of α-synuclein also resulted in significant impairment on a neurogenesis-dependent pattern separation task, as well as anxiety-like behaviours on both the open field and the elevated plus maze. Voluntary running improved performance on the pattern separation task only. This was substantiated by an effect on hippocampal neurogenesis levels in the dorsal, and not ventral, dentate gyrus, suggesting that the functional effects on pattern separation were mediated by increasing neurogenesis.
Parkinson's disease , Alpha-synuclein , Non-motor symptoms , Exercise
Dolan, E. 2017. Non-motor symptoms in the aav-α-synuclein rat model of Parkinson’s disease: exercise as a therapeutic intervention. PhD Thesis, University College Cork.