Effect of unilateral neurodegeneration on brain morphology, connectivity and pharmacology in Parkinson's disease rat models : a multimodal MRI study with corroborative techniques

• Main Author: Westphal, Robert
• Other Authors: Vernon, Anthony Christopher ; Cash, Diana
• Published: King's College London (University of London) 2016
• Subjects: 616.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695776

The unilaterally-lesioned 6-OHDA rat is one of the most commonly used experimental models of Parkinson’s disease (PD), a progressive neurodegenerative movement disorder characterized by nigral dopaminergic cell loss and striatal dopamine deficiency, which underlie many of the typical motor symptoms seen in patients. Here I investigated whether magnetic resonance imaging (MRI), which is a neuroimaging technology widely-used in human PD, has the potential to non-invasively detect and characterize parkinsonism and monitor the effect of pharmacotherapy in the 6-OHDA rat. To this end, I used resting-state functional MRI (rsfMRI), structural MRI and pharmacological MRI, alongside a battery of corroborative methods to morphologically, functionally, behaviourally and histologically phenotype the 6-OHDA rat. Using high resolution three-dimensional MRI and automated voxel-based morphometry (VBM) I found the grey matter volume loss in various brain areas, including the substantia nigra and the sensorimotor cortex, three weeks after 6-OHDA lesioning. The VBM analysis results were consistent with the findings reported in patients. These structural changes were associated with marked dopaminergic cell loss and cortical denervation confirmed by post-mortem histological examination. An attempt to reverse the dopaminergic neurodegeneration using the anti-diabetic drug exendin-4 was not successful. Together with structural brain changes in the 6-OHDA rat, I also found a functional reorganization in the resting-state network, whereby the lesioned hemisphere was found to have a decreased overall connectivity whereas the contralateral hemisphere showed compensatory changes as evidenced by increased functional connectivity. After the administration of the unselective dopamine agonist apomorphine in 6-OHDA rats, I found electrophysiological, behavioural and metabolic evidence of an imbalance in the basal ganglia (BG) activation, which is consistent with striatal dopamine receptor supersensitivity in the denervated hemisphere and in agreement with the classic model of BG circuitry changes in PD. Focussing on the thalamus, I further demonstrated that the beneficial effect of apomorphine lies in attenuating the increased glucose utilization and increasing of neuronal synchronization. Finally, I attempted to establish another, more progressive PD rat model in our laboratory, which, unlike the 6-OHDA rat, features adeno viral vector induced overexpression of alpha-synuclein, a protein that accumulates in PD. I evaluated its utility for longitudinal MRI experiments to test the aforementioned biomarkers identified in 6-OHDA rats, but the alpha-synuclein model failed to show the expected time course of behavioural and atrophic brain changes. My findings support the utility of preclinical MRI to detect subtle anatomical and functional brain changes. In particular, rodent-specific whole-brain VBM and rsfMRI will be a valuable technique for in vivo measurements of developing pathology in more relevant (i.e. progressive) models of PD, and may be particularly useful for correlating early, histologically undetectable, but MRI sensitive changes with behavioural deficits. This way, we might be able to provide valuable insights into the complex mechanisms underlying PD therefore providing a direct link between human and rat imaging studies.