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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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Experimental design and live brain imaging.(A) Schematic diagram of experimental design of this study. At 3.5 months after induction of focal brain ischemia (stroke), mice were randomized to receive subcutaneous injection of vehicle or SCF+G-CSF for 7 days. Intact control mice received subcutaneous injection of vehicle for 7 days. The peri-infarct cortex was scanned through a thinned-skull window with a multiphoton microscope (Mp) before treatment (week 0), 2 and 6 weeks after treatment. At the end of the imaging, mice were transcardially perfused, and brains were removed and processed for immunohistochemistry. (B) A representative brain section from a thy-1-YFPH mouse with chronic stroke displays the peri-infarct cortex where the multiphoton imaging is performed. (C) A representative apical dendrite of the layer V pyramidal neuron expressing YFP illustrates different spine shapes including a mushroom type spine, a thin type spine and uncertain type spines. A mushroom type spine (M-type) with a large spine head and a thick neck. A thin type spine (T-type) with a small head and a narrow neck. Uncertain type spines (U-type) with undetectable heads and an equal diameter in the spine tip and stem or varicosity protuberance from the dendritic shaft.
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pone-0064684-g001: Experimental design and live brain imaging.(A) Schematic diagram of experimental design of this study. At 3.5 months after induction of focal brain ischemia (stroke), mice were randomized to receive subcutaneous injection of vehicle or SCF+G-CSF for 7 days. Intact control mice received subcutaneous injection of vehicle for 7 days. The peri-infarct cortex was scanned through a thinned-skull window with a multiphoton microscope (Mp) before treatment (week 0), 2 and 6 weeks after treatment. At the end of the imaging, mice were transcardially perfused, and brains were removed and processed for immunohistochemistry. (B) A representative brain section from a thy-1-YFPH mouse with chronic stroke displays the peri-infarct cortex where the multiphoton imaging is performed. (C) A representative apical dendrite of the layer V pyramidal neuron expressing YFP illustrates different spine shapes including a mushroom type spine, a thin type spine and uncertain type spines. A mushroom type spine (M-type) with a large spine head and a thick neck. A thin type spine (T-type) with a small head and a narrow neck. Uncertain type spines (U-type) with undetectable heads and an equal diameter in the spine tip and stem or varicosity protuberance from the dendritic shaft.

Mentions: At 3.5 months after brain ischemia, mice were randomly assigned into two groups: 1) stroke+vehicle, in which animals with stroke received equal volumes of saline and 5% dextrose (n = 6); and 2) stroke+SCF+G-CSF, in which animals with stroke received recombinant mouse SCF (200 µg/kg/day; PeproTech) and recombinant human G-CSF (50 µg/kg/day; Amgen) (n = 6). SCF, G-CSF, and vehicle solution were subcutaneously injected for 7 days beginning at 3.5 months after stroke. A third group of age-matched mice without stroke served as an intact control, in which animals received subcutaneous injection of equal volumes of saline and 5% dextrose for 7 days (n = 3). The day before the vehicle and SCF+G-CSF treatment was defined as week 0. The brains of the mice in the three groups were scanned with a multi-photon microscope through a thinned-skull window before treatment (week 0), 2 and 6 weeks after treatment (Figure 1A).


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)

Experimental design and live brain imaging.(A) Schematic diagram of experimental design of this study. At 3.5 months after induction of focal brain ischemia (stroke), mice were randomized to receive subcutaneous injection of vehicle or SCF+G-CSF for 7 days. Intact control mice received subcutaneous injection of vehicle for 7 days. The peri-infarct cortex was scanned through a thinned-skull window with a multiphoton microscope (Mp) before treatment (week 0), 2 and 6 weeks after treatment. At the end of the imaging, mice were transcardially perfused, and brains were removed and processed for immunohistochemistry. (B) A representative brain section from a thy-1-YFPH mouse with chronic stroke displays the peri-infarct cortex where the multiphoton imaging is performed. (C) A representative apical dendrite of the layer V pyramidal neuron expressing YFP illustrates different spine shapes including a mushroom type spine, a thin type spine and uncertain type spines. A mushroom type spine (M-type) with a large spine head and a thick neck. A thin type spine (T-type) with a small head and a narrow neck. Uncertain type spines (U-type) with undetectable heads and an equal diameter in the spine tip and stem or varicosity protuberance from the dendritic shaft.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672166&req=5

pone-0064684-g001: Experimental design and live brain imaging.(A) Schematic diagram of experimental design of this study. At 3.5 months after induction of focal brain ischemia (stroke), mice were randomized to receive subcutaneous injection of vehicle or SCF+G-CSF for 7 days. Intact control mice received subcutaneous injection of vehicle for 7 days. The peri-infarct cortex was scanned through a thinned-skull window with a multiphoton microscope (Mp) before treatment (week 0), 2 and 6 weeks after treatment. At the end of the imaging, mice were transcardially perfused, and brains were removed and processed for immunohistochemistry. (B) A representative brain section from a thy-1-YFPH mouse with chronic stroke displays the peri-infarct cortex where the multiphoton imaging is performed. (C) A representative apical dendrite of the layer V pyramidal neuron expressing YFP illustrates different spine shapes including a mushroom type spine, a thin type spine and uncertain type spines. A mushroom type spine (M-type) with a large spine head and a thick neck. A thin type spine (T-type) with a small head and a narrow neck. Uncertain type spines (U-type) with undetectable heads and an equal diameter in the spine tip and stem or varicosity protuberance from the dendritic shaft.
Mentions: At 3.5 months after brain ischemia, mice were randomly assigned into two groups: 1) stroke+vehicle, in which animals with stroke received equal volumes of saline and 5% dextrose (n = 6); and 2) stroke+SCF+G-CSF, in which animals with stroke received recombinant mouse SCF (200 µg/kg/day; PeproTech) and recombinant human G-CSF (50 µg/kg/day; Amgen) (n = 6). SCF, G-CSF, and vehicle solution were subcutaneously injected for 7 days beginning at 3.5 months after stroke. A third group of age-matched mice without stroke served as an intact control, in which animals received subcutaneous injection of equal volumes of saline and 5% dextrose for 7 days (n = 3). The day before the vehicle and SCF+G-CSF treatment was defined as week 0. The brains of the mice in the three groups were scanned with a multi-photon microscope through a thinned-skull window before treatment (week 0), 2 and 6 weeks after treatment (Figure 1A).

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