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Investigating the role of dopamine in cognitive impairments in a rat model of Parkinson’s Disease

Bridge, Charlotte 2023. Investigating the role of dopamine in cognitive impairments in a rat model of Parkinson’s Disease. PhD Thesis, Cardiff University.
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Thesis Summary Non-motor symptoms are a major component of Parkinson’s Disease and have a significant impact on quality of life. Outcome measures of pre-clinical studies primarily focus on alleviating motor dysfunction with dopamine-replacement strategies. Therefore, the overall aim of this thesis was to understand more about the role of dopamine in cognitive impairments through dopamine depletion and restoration manipulations in the unilateral 6-OHDA rat model using the Lateralised Choice Reaction Time task (LCRT). Experiment 1 investigated cell replacement therapy on cognitive impairments in the LCRT task using human fetal (hfVM) and two different human embryonic stem cell- (hESC) derived dopaminergic progenitor intrastriatal transplants. Whilst hfVM and hESC-derived grafts could effectively alleviate motor impairments, hESC-derived grafts were unable to restore visuospatial function compared to controls, and on certain LCRT parameters, were significantly impaired compared to hfVM grafted rats. Experiment 2 used a TH and GCH1 AAV viral vector at two titres, alongside the dopamine precursor, L-DOPA, to evaluate the impact of dose on cognitive function. The highest AAV titre improved simple motor behaviour whilst significantly impairing visuospatial function. L-DOPA at increasing doses improved visuospatial function in high titre AAV rats, whilst in a dose response manner, impairing LCRT performance in lesioned sham rats. Histological analysis revealed off-target cortical expression and limited biodistribution throughout the striatum. Experiment 3 found greater striatal biodistribution of the viral vector to improve visuospatial function. Experiment 4 used unilateral 6-OHDA infusions in the medial and lateral striatum to understand the contribution of the two major dopaminergic midbrain-striatal circuits on LCRT performance. Medial striatal lesions impaired both visuospatial function and incentive motivation, whereas lateral striatal lesions did not, but did induce forelimb akinesia. Experiment 5 subsequently aimed to restore dopamine restricted to those same striatal subregions and found only lateral AAV infusions improved visuospatial function. This thesis outlines the complex role of dopamine in cognitive impairments, highlighting that a fine-tuned balance and optimisation of its delivery for therapeutic intervention for PD is required.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 5 December 2023
Last Modified: 08 Dec 2023 02:05

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