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Evolution of extra-nigral damage predicts behavioural deficits in a rat proteasome inhibitor model of Parkinson's disease.

Vernon AC, Crum WR, Johansson SM, Modo M - PLoS ONE (2011)

Bottom Line: Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5.Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor.These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, Kings College London, London, United Kingdom.

ABSTRACT
Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

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Time-course of regional brain volumetric changes in saline and lactacystin-injected animals.Significant tissue volume change was observed in (A) the ipsilateral ventral midbrain and (B) ipsilateral corpus striatum at 3 and 5 wks post-surgery compared to the non-injected contralateral hemisphere and both brain hemispheres in saline controls. (C) Lateral ventricle hypertrophy and (D) cortical atrophy were present from 1-wk post-surgery and maintained at 3 and 5 wks in lesioned animals, but not saline controls. (E) No significant change in the volume of the hippocampus was observed in either hemisphere in either group at any time-point. Significant thinning of the primary motor (F) and primary somatosensory cortex were also present from wk 1 post-lesion in lactacystin-injected animals, but not saline controls. Data shown are mean volume (mm3 A–E) or thickness (mm, F, G) ± SEM. ***p<0.001 ipsilateral hemisphere vs. non-injected contralateral hemisphere in lactacystin-injected animals; ★★★p<0.001 ipsilateral hemisphere of lactacystin-lesioned animals vs. ipsilateral hemisphere of saline controls. Saline, N = 5, lactacystin, N = 7.
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pone-0017269-g004: Time-course of regional brain volumetric changes in saline and lactacystin-injected animals.Significant tissue volume change was observed in (A) the ipsilateral ventral midbrain and (B) ipsilateral corpus striatum at 3 and 5 wks post-surgery compared to the non-injected contralateral hemisphere and both brain hemispheres in saline controls. (C) Lateral ventricle hypertrophy and (D) cortical atrophy were present from 1-wk post-surgery and maintained at 3 and 5 wks in lesioned animals, but not saline controls. (E) No significant change in the volume of the hippocampus was observed in either hemisphere in either group at any time-point. Significant thinning of the primary motor (F) and primary somatosensory cortex were also present from wk 1 post-lesion in lactacystin-injected animals, but not saline controls. Data shown are mean volume (mm3 A–E) or thickness (mm, F, G) ± SEM. ***p<0.001 ipsilateral hemisphere vs. non-injected contralateral hemisphere in lactacystin-injected animals; ★★★p<0.001 ipsilateral hemisphere of lactacystin-lesioned animals vs. ipsilateral hemisphere of saline controls. Saline, N = 5, lactacystin, N = 7.

Mentions: Lactacystin microinjection into the L-MFB induced significant gross morphological changes that affected whole brain volume (WBV) compared to saline controls at wk 3 (p<0.05) and wk 5 (p<0.05), but not wk 1 (Figure S2A). These changes were contained within the cerebrum as no significant change in the volume of the cerebellum over time was observed (Figure S2B). For sub-cortical brain regions, a significant volume decrease in the ipsilateral ventral midbrain (VM) appeared from wk 3 onwards, increasing by wk 5, suggesting a progressive degeneration of this structure in lesioned animals. A significant volume decrease was observed in the ipsilateral STR from Wk 3 onwards in lesioned animals compared to saline controls (Figure 4A, B). A trend towards a decreased ipsilateral STR volume was observed at wk 1, but this failed to reach statistical significance (Figure 4B).


Evolution of extra-nigral damage predicts behavioural deficits in a rat proteasome inhibitor model of Parkinson's disease.

Vernon AC, Crum WR, Johansson SM, Modo M - PLoS ONE (2011)

Time-course of regional brain volumetric changes in saline and lactacystin-injected animals.Significant tissue volume change was observed in (A) the ipsilateral ventral midbrain and (B) ipsilateral corpus striatum at 3 and 5 wks post-surgery compared to the non-injected contralateral hemisphere and both brain hemispheres in saline controls. (C) Lateral ventricle hypertrophy and (D) cortical atrophy were present from 1-wk post-surgery and maintained at 3 and 5 wks in lesioned animals, but not saline controls. (E) No significant change in the volume of the hippocampus was observed in either hemisphere in either group at any time-point. Significant thinning of the primary motor (F) and primary somatosensory cortex were also present from wk 1 post-lesion in lactacystin-injected animals, but not saline controls. Data shown are mean volume (mm3 A–E) or thickness (mm, F, G) ± SEM. ***p<0.001 ipsilateral hemisphere vs. non-injected contralateral hemisphere in lactacystin-injected animals; ★★★p<0.001 ipsilateral hemisphere of lactacystin-lesioned animals vs. ipsilateral hemisphere of saline controls. Saline, N = 5, lactacystin, N = 7.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045435&req=5

pone-0017269-g004: Time-course of regional brain volumetric changes in saline and lactacystin-injected animals.Significant tissue volume change was observed in (A) the ipsilateral ventral midbrain and (B) ipsilateral corpus striatum at 3 and 5 wks post-surgery compared to the non-injected contralateral hemisphere and both brain hemispheres in saline controls. (C) Lateral ventricle hypertrophy and (D) cortical atrophy were present from 1-wk post-surgery and maintained at 3 and 5 wks in lesioned animals, but not saline controls. (E) No significant change in the volume of the hippocampus was observed in either hemisphere in either group at any time-point. Significant thinning of the primary motor (F) and primary somatosensory cortex were also present from wk 1 post-lesion in lactacystin-injected animals, but not saline controls. Data shown are mean volume (mm3 A–E) or thickness (mm, F, G) ± SEM. ***p<0.001 ipsilateral hemisphere vs. non-injected contralateral hemisphere in lactacystin-injected animals; ★★★p<0.001 ipsilateral hemisphere of lactacystin-lesioned animals vs. ipsilateral hemisphere of saline controls. Saline, N = 5, lactacystin, N = 7.
Mentions: Lactacystin microinjection into the L-MFB induced significant gross morphological changes that affected whole brain volume (WBV) compared to saline controls at wk 3 (p<0.05) and wk 5 (p<0.05), but not wk 1 (Figure S2A). These changes were contained within the cerebrum as no significant change in the volume of the cerebellum over time was observed (Figure S2B). For sub-cortical brain regions, a significant volume decrease in the ipsilateral ventral midbrain (VM) appeared from wk 3 onwards, increasing by wk 5, suggesting a progressive degeneration of this structure in lesioned animals. A significant volume decrease was observed in the ipsilateral STR from Wk 3 onwards in lesioned animals compared to saline controls (Figure 4A, B). A trend towards a decreased ipsilateral STR volume was observed at wk 1, but this failed to reach statistical significance (Figure 4B).

Bottom Line: Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5.Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor.These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, Kings College London, London, United Kingdom.

ABSTRACT
Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

Show MeSH
Related in: MedlinePlus