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

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dc.contributor.advisor Sullivan, Aideen M. en
dc.contributor.advisor Nolan, Yvonne M. en Dolan, Erin 2018-08-20T11:11:10Z 2018-08-20T11:11:10Z 2017 2017
dc.identifier.citation 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. en
dc.identifier.endpage 267 en
dc.description.abstract 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. en
dc.description.sponsorship Clinical and Translational Research Scholarship en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2017, Erin Dolan. en
dc.rights.uri en
dc.subject Parkinson's disease en
dc.subject Alpha-synuclein en
dc.subject Non-motor symptoms en
dc.subject Exercise en
dc.title Non-motor symptoms in the aav-α-synuclein rat model of Parkinson’s disease: exercise as a therapeutic intervention en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD en
dc.internal.availability Full text available en Not applicable en
dc.description.version Accepted Version
dc.contributor.funder Molecular Medicine Ireland en
dc.description.status Not peer reviewed en Anatomy and Neuroscience en
dc.check.type No Embargo Required
dc.check.reason Not applicable en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Embargo not applicable (If you have not submitted an e-thesis or do not want to request an embargo) en
dc.internal.conferring Autumn 2017 en

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