Robert Westphal1, Akira Sumiyoshi2, Camilla Simmons3, Michel Mesquita3, Tobias C Wood3, Steve C R Williams3, Anthony C Vernon4, Diana Cash3. 1. Department of Neuroimaging, King's College London, Institute of Psychiatry, Psychology & Neuroscience, UK. Electronic address: robert.westphal@psych.ox.ac.uk. 2. Institute of Development, Ageing and Cancer, Tohoku University, Japan. 3. Department of Neuroimaging, King's College London, Institute of Psychiatry, Psychology & Neuroscience, UK. 4. Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology & Neuroscience, UK.
Abstract
BACKGROUND: The unilaterally-lesioned 6-hydroxydopamine (6-OHDA) rat is one of the most commonly used experimental models of Parkinson's disease (PD). Here we investigated whether magnetic resonance imaging (MRI) that is widely used in human PD research, has the potential to non-invasively detect macroscopic structural brain changes in the 6-OHDA rat in ways translatable to humans. METHODS: We measured the gray matter (GM) composition in the unilateral 6-OHDA rat in comparison to sham animals using whole-brain voxel-based morphometry (VBM) - an unbiased MR image analysis technique. The number of nigral dopamine (DA) neurons and the density of their cortical projections were examined post-mortem using immunohistochemistry. RESULTS: VBM revealed widespread bilateral changes in gray matter volume (GMV) on a topographic scale in the brains of 6-OHDA rats, compared to sham-operated rats. The greatest changes were in the lesioned hemisphere, which displayed reductions of GMV in motor, cingulate and somatosensory cortex. Histopathological results revealed dopaminergic cell loss in the substantia nigra (SN) and a denervation in the striatum, as well as in the frontal, somatosensory and cingulate cortices. CONCLUSION: Unilateral nigrostriatal 6-OHDA lesioning leads to widespread GMV changes, which extend beyond the nigrostriatal system and resemble advanced Parkinsonism. This study highlights the potential of structural MRI, and VBM in particular, for the system-level phenotyping of rodent models of Parkinsonism and provides a methodological framework for future studies in novel rodent models as they become available to the research community.
BACKGROUND: The unilaterally-lesioned 6-hydroxydopamine (6-OHDA) rat is one of the most commonly used experimental models of Parkinson's disease (PD). Here we investigated whether magnetic resonance imaging (MRI) that is widely used in humanPD research, has the potential to non-invasively detect macroscopic structural brain changes in the 6-OHDArat in ways translatable to humans. METHODS: We measured the gray matter (GM) composition in the unilateral 6-OHDArat in comparison to sham animals using whole-brain voxel-based morphometry (VBM) - an unbiased MR image analysis technique. The number of nigral dopamine (DA) neurons and the density of their cortical projections were examined post-mortem using immunohistochemistry. RESULTS: VBM revealed widespread bilateral changes in gray matter volume (GMV) on a topographic scale in the brains of 6-OHDArats, compared to sham-operated rats. The greatest changes were in the lesioned hemisphere, which displayed reductions of GMV in motor, cingulate and somatosensory cortex. Histopathological results revealed dopaminergic cell loss in the substantia nigra (SN) and a denervation in the striatum, as well as in the frontal, somatosensory and cingulate cortices. CONCLUSION: Unilateral nigrostriatal 6-OHDA lesioning leads to widespread GMV changes, which extend beyond the nigrostriatal system and resemble advanced Parkinsonism. This study highlights the potential of structural MRI, and VBM in particular, for the system-level phenotyping of rodent models of Parkinsonism and provides a methodological framework for future studies in novel rodent models as they become available to the research community.
Authors: Michel Modo; William R Crum; Madeline Gerwig; Anthony C Vernon; Priya Patel; Michael J Jackson; Sarah Rose; Peter Jenner; Mahmoud M Iravani Journal: PLoS One Date: 2017-07-24 Impact factor: 3.240
Authors: Robert Westphal; Camilla Simmons; Michel B Mesquita; Tobias C Wood; Steve C R Williams; Anthony C Vernon; Diana Cash Journal: PLoS One Date: 2017-03-01 Impact factor: 3.240
Authors: Edward J R Fletcher; Clare J Finlay; Ana Amor Lopez; William R Crum; Anthony C Vernon; Susan Duty Journal: Front Neurosci Date: 2020-09-15 Impact factor: 4.677