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Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke.

Cui L, Murikinati SR, Wang D, Zhang X, Duan WM, Zhao LR - PLoS ONE (2013)

Bottom Line: In this study, we determined the effects of SCF+G-CSF on neuronal network remodeling in the aged brain of chronic stroke.These data suggest that SCF+G-CSF treatment in chronic stroke remodels neural circuits in the aged brain.This study provides evidence to support the development of a new therapeutic strategy for chronic stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York, USA.

ABSTRACT
Stroke has a high incidence in the elderly. Stroke enters the chronic phase 3 months after initial stroke onset. Currently, there is no pharmaceutical treatment available for chronic stroke. We have demonstrated the therapeutic effects of the combination of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke. However, it remains unclear how SCF+G-CSF repairs the brain in chronic stroke. In this study, we determined the effects of SCF+G-CSF on neuronal network remodeling in the aged brain of chronic stroke. Cortical brain ischemia was produced in 16-18 month-old transgenic mice expressing yellow fluorescent protein in layer V pyramidal neurons. SCF+G-CSF was subcutaneously injected for 7 days beginning at 3.5 months post-ischemia. Using both live brain imaging and immunohistochemistry, we observed that SCF+G-CSF increased the mushroom-type spines on the apical dendrites of layer V pyramidal neurons adjacent to the infarct cavities 2 and 6 weeks after treatment. SCF+G-CSF also augmented dendritic branches and post-synaptic density protein 95 puncta in the peri-infarct cortex 6 weeks after treatment. These data suggest that SCF+G-CSF treatment in chronic stroke remodels neural circuits in the aged brain. This study provides evidence to support the development of a new therapeutic strategy for chronic stroke.

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Related in: MedlinePlus

Dynamics of the apical dendritic spines of layer V pyramidal neurons in the peri-infarct cortex of aged brain before SCF+G-CSF treatment (week 0), 2 and 6 weeks after treatment in the phase of chronic stroke by live brain imaging.(A) Upper panels: Representative Z-stack images with 1-µm intervals display the three types of spines–mushroom type, thin type and uncertain type spines. Lower panels: Representative live brain images show the apical dendritic spines in the right cortex of an intact control or in the peri-infarct cortex of stroke mice with vehicle injection or stroke mice with SCF+G-CSF (S+G) treatment at 6 weeks (6 w) post-treatment. Scale bars (red), 1 µm. (B and C) Quantification of apical spine density (B) and the percentage of different types of spines (C) in the peri-infarct cortex before treatment (week 0). (D and E) Quantification of apical spine density (D) and the percentage of different subtypes of spines (E) in the peri-infarct cortex 2 weeks after SCF+G-CSF treatment. (F and G) Quantification of apical spine density (F) and percentage of different subtypes of spines (G) in the peri-infarct cortex 6 weeks after SCF+G-CSF treatment in the aged brain of chronic stroke. *P<0.05. Intact control, n = 3; stroke+vehicle, n = 6; stroke+S+G, n = 6. Mean ± S.E.M. M-type, mushroom type spine; T-type, thin type spine; U-type, uncertain type spine. Apical spine density: number of spines per 10 µm dendrite length.
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pone-0064684-g003: Dynamics of the apical dendritic spines of layer V pyramidal neurons in the peri-infarct cortex of aged brain before SCF+G-CSF treatment (week 0), 2 and 6 weeks after treatment in the phase of chronic stroke by live brain imaging.(A) Upper panels: Representative Z-stack images with 1-µm intervals display the three types of spines–mushroom type, thin type and uncertain type spines. Lower panels: Representative live brain images show the apical dendritic spines in the right cortex of an intact control or in the peri-infarct cortex of stroke mice with vehicle injection or stroke mice with SCF+G-CSF (S+G) treatment at 6 weeks (6 w) post-treatment. Scale bars (red), 1 µm. (B and C) Quantification of apical spine density (B) and the percentage of different types of spines (C) in the peri-infarct cortex before treatment (week 0). (D and E) Quantification of apical spine density (D) and the percentage of different subtypes of spines (E) in the peri-infarct cortex 2 weeks after SCF+G-CSF treatment. (F and G) Quantification of apical spine density (F) and percentage of different subtypes of spines (G) in the peri-infarct cortex 6 weeks after SCF+G-CSF treatment in the aged brain of chronic stroke. *P<0.05. Intact control, n = 3; stroke+vehicle, n = 6; stroke+S+G, n = 6. Mean ± S.E.M. M-type, mushroom type spine; T-type, thin type spine; U-type, uncertain type spine. Apical spine density: number of spines per 10 µm dendrite length.

Mentions: To determine whether there are any morphological changes in the apical dendritic spines of the layer V pyramidal neurons surrounding infarct cavities in the aged brain of chronic stroke, we quantified mushroom type (M-type), thin type (T-type) and uncertain type (U-type) spines (Figure 1A) before treatment (week 0). As shown in Figure 3B and C, the most abundant spine types in the brain of the intact control group were mushroom and thin spines, while uncertain spines only constituted a small portion of the total spines. However, mushroom type, thin type, and mushroom+thin (M+T)-type spines were significantly decreased in the peri-infarct cortex of the aged chronic stroke brain at week 0 as compared with those of the intact control mice (Figure 3B and C, P<0.05) (one- way ANOVA: M-type, F(2,6) = 8.59, P = 0.02; T-type, F(2,6) = 6.10, P = 0.04; M+T-type, F(2,6) = 12.96, P = 0.007). In addition, a significant increase in uncertain spines was also seen in all chronic stroke mice that would receive vehicle or SCF+G-CSF treatment later (Figure 3B and C, P<0.05) (one- way ANOVA: F(2,6) = 14.23, P = 0.005; stroke groups vs. intact control group). No significant differences in each type of spines in the peri-infarct cortex were observed between the vehicle controls and SCF+G-CSF group at week 0 (Figure 3B and C, P>0.05). Mushroom and thin spines contribute to building up synaptic connections with other neurons, and uncertain spines are often seen in the brain of neurodegenerative diseases [21]. These data therefore suggest that the morphological changes in the apical dendritic spines of the layer V pyramidal neurons surrounding the cortical infarct cavities in the chronic phase are cortical infarct-related. This may imply that the apical dendritic spines of the layer V pyramidal neurons in the cortex adjacent to the infarct cavities undergo degeneration because they lose synaptic connections with the neurons that have been lost due to the ischemic damage in the early stage of stroke.


Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke.

Cui L, Murikinati SR, Wang D, Zhang X, Duan WM, Zhao LR - PLoS ONE (2013)

Dynamics of the apical dendritic spines of layer V pyramidal neurons in the peri-infarct cortex of aged brain before SCF+G-CSF treatment (week 0), 2 and 6 weeks after treatment in the phase of chronic stroke by live brain imaging.(A) Upper panels: Representative Z-stack images with 1-µm intervals display the three types of spines–mushroom type, thin type and uncertain type spines. Lower panels: Representative live brain images show the apical dendritic spines in the right cortex of an intact control or in the peri-infarct cortex of stroke mice with vehicle injection or stroke mice with SCF+G-CSF (S+G) treatment at 6 weeks (6 w) post-treatment. Scale bars (red), 1 µm. (B and C) Quantification of apical spine density (B) and the percentage of different types of spines (C) in the peri-infarct cortex before treatment (week 0). (D and E) Quantification of apical spine density (D) and the percentage of different subtypes of spines (E) in the peri-infarct cortex 2 weeks after SCF+G-CSF treatment. (F and G) Quantification of apical spine density (F) and percentage of different subtypes of spines (G) in the peri-infarct cortex 6 weeks after SCF+G-CSF treatment in the aged brain of chronic stroke. *P<0.05. Intact control, n = 3; stroke+vehicle, n = 6; stroke+S+G, n = 6. Mean ± S.E.M. M-type, mushroom type spine; T-type, thin type spine; U-type, uncertain type spine. Apical spine density: number of spines per 10 µm dendrite length.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672166&req=5

pone-0064684-g003: Dynamics of the apical dendritic spines of layer V pyramidal neurons in the peri-infarct cortex of aged brain before SCF+G-CSF treatment (week 0), 2 and 6 weeks after treatment in the phase of chronic stroke by live brain imaging.(A) Upper panels: Representative Z-stack images with 1-µm intervals display the three types of spines–mushroom type, thin type and uncertain type spines. Lower panels: Representative live brain images show the apical dendritic spines in the right cortex of an intact control or in the peri-infarct cortex of stroke mice with vehicle injection or stroke mice with SCF+G-CSF (S+G) treatment at 6 weeks (6 w) post-treatment. Scale bars (red), 1 µm. (B and C) Quantification of apical spine density (B) and the percentage of different types of spines (C) in the peri-infarct cortex before treatment (week 0). (D and E) Quantification of apical spine density (D) and the percentage of different subtypes of spines (E) in the peri-infarct cortex 2 weeks after SCF+G-CSF treatment. (F and G) Quantification of apical spine density (F) and percentage of different subtypes of spines (G) in the peri-infarct cortex 6 weeks after SCF+G-CSF treatment in the aged brain of chronic stroke. *P<0.05. Intact control, n = 3; stroke+vehicle, n = 6; stroke+S+G, n = 6. Mean ± S.E.M. M-type, mushroom type spine; T-type, thin type spine; U-type, uncertain type spine. Apical spine density: number of spines per 10 µm dendrite length.
Mentions: To determine whether there are any morphological changes in the apical dendritic spines of the layer V pyramidal neurons surrounding infarct cavities in the aged brain of chronic stroke, we quantified mushroom type (M-type), thin type (T-type) and uncertain type (U-type) spines (Figure 1A) before treatment (week 0). As shown in Figure 3B and C, the most abundant spine types in the brain of the intact control group were mushroom and thin spines, while uncertain spines only constituted a small portion of the total spines. However, mushroom type, thin type, and mushroom+thin (M+T)-type spines were significantly decreased in the peri-infarct cortex of the aged chronic stroke brain at week 0 as compared with those of the intact control mice (Figure 3B and C, P<0.05) (one- way ANOVA: M-type, F(2,6) = 8.59, P = 0.02; T-type, F(2,6) = 6.10, P = 0.04; M+T-type, F(2,6) = 12.96, P = 0.007). In addition, a significant increase in uncertain spines was also seen in all chronic stroke mice that would receive vehicle or SCF+G-CSF treatment later (Figure 3B and C, P<0.05) (one- way ANOVA: F(2,6) = 14.23, P = 0.005; stroke groups vs. intact control group). No significant differences in each type of spines in the peri-infarct cortex were observed between the vehicle controls and SCF+G-CSF group at week 0 (Figure 3B and C, P>0.05). Mushroom and thin spines contribute to building up synaptic connections with other neurons, and uncertain spines are often seen in the brain of neurodegenerative diseases [21]. These data therefore suggest that the morphological changes in the apical dendritic spines of the layer V pyramidal neurons surrounding the cortical infarct cavities in the chronic phase are cortical infarct-related. This may imply that the apical dendritic spines of the layer V pyramidal neurons in the cortex adjacent to the infarct cavities undergo degeneration because they lose synaptic connections with the neurons that have been lost due to the ischemic damage in the early stage of stroke.

Bottom Line: In this study, we determined the effects of SCF+G-CSF on neuronal network remodeling in the aged brain of chronic stroke.These data suggest that SCF+G-CSF treatment in chronic stroke remodels neural circuits in the aged brain.This study provides evidence to support the development of a new therapeutic strategy for chronic stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York, USA.

ABSTRACT
Stroke has a high incidence in the elderly. Stroke enters the chronic phase 3 months after initial stroke onset. Currently, there is no pharmaceutical treatment available for chronic stroke. We have demonstrated the therapeutic effects of the combination of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke. However, it remains unclear how SCF+G-CSF repairs the brain in chronic stroke. In this study, we determined the effects of SCF+G-CSF on neuronal network remodeling in the aged brain of chronic stroke. Cortical brain ischemia was produced in 16-18 month-old transgenic mice expressing yellow fluorescent protein in layer V pyramidal neurons. SCF+G-CSF was subcutaneously injected for 7 days beginning at 3.5 months post-ischemia. Using both live brain imaging and immunohistochemistry, we observed that SCF+G-CSF increased the mushroom-type spines on the apical dendrites of layer V pyramidal neurons adjacent to the infarct cavities 2 and 6 weeks after treatment. SCF+G-CSF also augmented dendritic branches and post-synaptic density protein 95 puncta in the peri-infarct cortex 6 weeks after treatment. These data suggest that SCF+G-CSF treatment in chronic stroke remodels neural circuits in the aged brain. This study provides evidence to support the development of a new therapeutic strategy for chronic stroke.

Show MeSH
Related in: MedlinePlus