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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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Parkinsonian-like motor phenotype in Lactacystin-lesioned animals.(A) Saline-injected controls show no deficits in the GSM test for either limb at any time-point. (B) Lesioned animals develop a progressive impairment in the grip strength of the contralateral forelimb in the GSM test. Data shown in (A, B) are mean grip force (G) ± SEM. **p<0.01 contralateral limb vs. ipsilateral limb. (C) Lesioned animals, but not saline controls show motor co-ordination deficits as evidenced by shortened latency to fall in the accelerating rotarod test at all time-points post-surgery. Data shown are mean latency to fall (sec) ± SEM. *p<0.05; **p<0.01; saline vs. lactacystin-injected. (D) Lactacystin-lesioning induces significant contralateral circling in response to apomorphine challenge (0.1 mg/kg s.c.) at all time-points post-surgery. Data shown are mean net contraversive rotations ± SEM. ***p<0.001; saline (N = 5) vs. lactacystin-injected (N = 7).
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pone-0017269-g002: Parkinsonian-like motor phenotype in Lactacystin-lesioned animals.(A) Saline-injected controls show no deficits in the GSM test for either limb at any time-point. (B) Lesioned animals develop a progressive impairment in the grip strength of the contralateral forelimb in the GSM test. Data shown in (A, B) are mean grip force (G) ± SEM. **p<0.01 contralateral limb vs. ipsilateral limb. (C) Lesioned animals, but not saline controls show motor co-ordination deficits as evidenced by shortened latency to fall in the accelerating rotarod test at all time-points post-surgery. Data shown are mean latency to fall (sec) ± SEM. *p<0.05; **p<0.01; saline vs. lactacystin-injected. (D) Lactacystin-lesioning induces significant contralateral circling in response to apomorphine challenge (0.1 mg/kg s.c.) at all time-points post-surgery. Data shown are mean net contraversive rotations ± SEM. ***p<0.001; saline (N = 5) vs. lactacystin-injected (N = 7).

Mentions: Forepaw grip strength improved with time in saline controls [F(3,30) = 13.49, p<0.0001, Figure 2A]. By contrast, in lesioned animals [F(1,36) = 19.95, p<0.001, Figure 2B], there was a significant impairment in grip strength of the contralateral forepaw by wk 1 (p<0.05), which was maintained at wk 3 (p<0.01) and wk 5 (p<0.01). As there was no significant difference in forepaw grip strength prior to the administration of lactacystin (i.e. baseline), grip strength in both forepaws evolved differently over time (F(3,36) = 11.79, p<0.001). Forepaw grip strength was therefore significantly affected by administration of lactacystin into the L-MFB by week 1, but did not exhibit a progressive worsening of this deficit.


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)

Parkinsonian-like motor phenotype in Lactacystin-lesioned animals.(A) Saline-injected controls show no deficits in the GSM test for either limb at any time-point. (B) Lesioned animals develop a progressive impairment in the grip strength of the contralateral forelimb in the GSM test. Data shown in (A, B) are mean grip force (G) ± SEM. **p<0.01 contralateral limb vs. ipsilateral limb. (C) Lesioned animals, but not saline controls show motor co-ordination deficits as evidenced by shortened latency to fall in the accelerating rotarod test at all time-points post-surgery. Data shown are mean latency to fall (sec) ± SEM. *p<0.05; **p<0.01; saline vs. lactacystin-injected. (D) Lactacystin-lesioning induces significant contralateral circling in response to apomorphine challenge (0.1 mg/kg s.c.) at all time-points post-surgery. Data shown are mean net contraversive rotations ± SEM. ***p<0.001; saline (N = 5) vs. lactacystin-injected (N = 7).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045435&req=5

pone-0017269-g002: Parkinsonian-like motor phenotype in Lactacystin-lesioned animals.(A) Saline-injected controls show no deficits in the GSM test for either limb at any time-point. (B) Lesioned animals develop a progressive impairment in the grip strength of the contralateral forelimb in the GSM test. Data shown in (A, B) are mean grip force (G) ± SEM. **p<0.01 contralateral limb vs. ipsilateral limb. (C) Lesioned animals, but not saline controls show motor co-ordination deficits as evidenced by shortened latency to fall in the accelerating rotarod test at all time-points post-surgery. Data shown are mean latency to fall (sec) ± SEM. *p<0.05; **p<0.01; saline vs. lactacystin-injected. (D) Lactacystin-lesioning induces significant contralateral circling in response to apomorphine challenge (0.1 mg/kg s.c.) at all time-points post-surgery. Data shown are mean net contraversive rotations ± SEM. ***p<0.001; saline (N = 5) vs. lactacystin-injected (N = 7).
Mentions: Forepaw grip strength improved with time in saline controls [F(3,30) = 13.49, p<0.0001, Figure 2A]. By contrast, in lesioned animals [F(1,36) = 19.95, p<0.001, Figure 2B], there was a significant impairment in grip strength of the contralateral forepaw by wk 1 (p<0.05), which was maintained at wk 3 (p<0.01) and wk 5 (p<0.01). As there was no significant difference in forepaw grip strength prior to the administration of lactacystin (i.e. baseline), grip strength in both forepaws evolved differently over time (F(3,36) = 11.79, p<0.001). Forepaw grip strength was therefore significantly affected by administration of lactacystin into the L-MFB by week 1, but did not exhibit a progressive worsening of this deficit.

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