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In Vivo Expression of Reprogramming Factors Increases Hippocampal Neurogenesis and Synaptic Plasticity in Chronic Hypoxic-Ischemic Brain Injury

View Article: PubMed Central - PubMed

ABSTRACT

Neurogenesis and synaptic plasticity can be stimulated in vivo in the brain. In this study, we hypothesized that in vivo expression of reprogramming factors such as Klf4, Sox2, Oct4, and c-Myc would facilitate endogenous neurogenesis and functional recovery. CD-1® mice were induced at 1 week of age by unilaterally carotid artery ligation and exposure to hypoxia. At 6 weeks of age, mice were injected GFP only or both four reprogramming factors and GFP into lateral ventricle. Passive avoidance task and open field test were performed to evaluate neurobehavioral function. Neurogenesis and synaptic activity in the hippocampus were evaluated using immunohistochemistry, qRT-PCR, and/or western blot analyses. Whereas BrdU+GFAP+ cells in the subgranular zone of the hippocampus were not significantly different, the numbers of BrdU+βIII-tubulin+ and BrdU+NeuN+ cells were significantly higher in treatment group than control group. Expressions of synaptophysin and PSD-95 were also higher in treatment group than control group. Importantly, passive avoidance task and open field test showed improvement in long-term memory and decreased anxiety in treatment group. In conclusion, in vivo expression of reprogramming factors improved behavioral functions in chronic hypoxic-ischemic brain injury. The mechanisms underlying these repair processes included endogenous neurogenesis and synaptic plasticity in the hippocampus.

No MeSH data available.


Related in: MedlinePlus

Effects of reprogramming factor expression on neurobehavioral functions after chronic hypoxic-ischemic brain injury. Passive avoidance task and open field test results showed that expression of the four reprogramming factors improved long-term memory and decreased anxiety 8 weeks after the treatment. (a) Expression of the four reprogramming factors significantly improved retention test performance 24 hours after an aversive stimulus 8 weeks after the treatment (140.9 ± 42.5 seconds) relative to that in the initial assessment (57.9 ± 15.3 seconds), whereas the performance was not statistically improved in the control group (t = 2.916, p < 0.05; n = 7 per group). The result suggests that the expression of reprogramming factors improves long-term memory 8 weeks after the treatment. (b) The total distance of movement was assessed for 15 min. The percentage of the inner zone/outer zone increased in the treatment group (27.4 ± 1.3%) compared to the control group (23.5 ± 1.1%) (t = 2.568, p < 0.05; n = 8 and n = 9 per group, resp.). (c) Among the total of 16 zones, 4 central zones are an inner zone, and 12 peripheral zones are an outer zone. ∗p < 0.05.
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fig2: Effects of reprogramming factor expression on neurobehavioral functions after chronic hypoxic-ischemic brain injury. Passive avoidance task and open field test results showed that expression of the four reprogramming factors improved long-term memory and decreased anxiety 8 weeks after the treatment. (a) Expression of the four reprogramming factors significantly improved retention test performance 24 hours after an aversive stimulus 8 weeks after the treatment (140.9 ± 42.5 seconds) relative to that in the initial assessment (57.9 ± 15.3 seconds), whereas the performance was not statistically improved in the control group (t = 2.916, p < 0.05; n = 7 per group). The result suggests that the expression of reprogramming factors improves long-term memory 8 weeks after the treatment. (b) The total distance of movement was assessed for 15 min. The percentage of the inner zone/outer zone increased in the treatment group (27.4 ± 1.3%) compared to the control group (23.5 ± 1.1%) (t = 2.568, p < 0.05; n = 8 and n = 9 per group, resp.). (c) Among the total of 16 zones, 4 central zones are an inner zone, and 12 peripheral zones are an outer zone. ∗p < 0.05.

Mentions: To determine whether the in vivo expression of four reprogramming factors improved cognitive function, passive avoidance task was performed before the surgical treatment and 8 weeks after intervention in the control and treatment groups (n = 7 per group). Expression of the reprogramming factors significantly improved retention test performance 24 hours after an aversive stimulus at 8 weeks after the treatment (140.9 ± 42.5 seconds) relative to that in the initial assessment (57.9 ± 15.3 seconds) (t = 2.916, p < 0.05), whereas the performance was not statistically improved in the control group (Figure 2(a)). The result suggests that in vivo expression of reprogramming factors improves long-term memory 8 weeks after the treatment. Additionally, when the step-through latency was evaluated in the passive avoidance task, there was no significant difference between sham-operated control group (205.7 ± 55.7 seconds) and treatment group (235.7 ± 45.7 seconds) (n = 6 per group; Figure S2A in Supplementary Material available online at http://dx.doi.org/10.1155/2016/2580837).


In Vivo Expression of Reprogramming Factors Increases Hippocampal Neurogenesis and Synaptic Plasticity in Chronic Hypoxic-Ischemic Brain Injury
Effects of reprogramming factor expression on neurobehavioral functions after chronic hypoxic-ischemic brain injury. Passive avoidance task and open field test results showed that expression of the four reprogramming factors improved long-term memory and decreased anxiety 8 weeks after the treatment. (a) Expression of the four reprogramming factors significantly improved retention test performance 24 hours after an aversive stimulus 8 weeks after the treatment (140.9 ± 42.5 seconds) relative to that in the initial assessment (57.9 ± 15.3 seconds), whereas the performance was not statistically improved in the control group (t = 2.916, p < 0.05; n = 7 per group). The result suggests that the expression of reprogramming factors improves long-term memory 8 weeks after the treatment. (b) The total distance of movement was assessed for 15 min. The percentage of the inner zone/outer zone increased in the treatment group (27.4 ± 1.3%) compared to the control group (23.5 ± 1.1%) (t = 2.568, p < 0.05; n = 8 and n = 9 per group, resp.). (c) Among the total of 16 zones, 4 central zones are an inner zone, and 12 peripheral zones are an outer zone. ∗p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120183&req=5

fig2: Effects of reprogramming factor expression on neurobehavioral functions after chronic hypoxic-ischemic brain injury. Passive avoidance task and open field test results showed that expression of the four reprogramming factors improved long-term memory and decreased anxiety 8 weeks after the treatment. (a) Expression of the four reprogramming factors significantly improved retention test performance 24 hours after an aversive stimulus 8 weeks after the treatment (140.9 ± 42.5 seconds) relative to that in the initial assessment (57.9 ± 15.3 seconds), whereas the performance was not statistically improved in the control group (t = 2.916, p < 0.05; n = 7 per group). The result suggests that the expression of reprogramming factors improves long-term memory 8 weeks after the treatment. (b) The total distance of movement was assessed for 15 min. The percentage of the inner zone/outer zone increased in the treatment group (27.4 ± 1.3%) compared to the control group (23.5 ± 1.1%) (t = 2.568, p < 0.05; n = 8 and n = 9 per group, resp.). (c) Among the total of 16 zones, 4 central zones are an inner zone, and 12 peripheral zones are an outer zone. ∗p < 0.05.
Mentions: To determine whether the in vivo expression of four reprogramming factors improved cognitive function, passive avoidance task was performed before the surgical treatment and 8 weeks after intervention in the control and treatment groups (n = 7 per group). Expression of the reprogramming factors significantly improved retention test performance 24 hours after an aversive stimulus at 8 weeks after the treatment (140.9 ± 42.5 seconds) relative to that in the initial assessment (57.9 ± 15.3 seconds) (t = 2.916, p < 0.05), whereas the performance was not statistically improved in the control group (Figure 2(a)). The result suggests that in vivo expression of reprogramming factors improves long-term memory 8 weeks after the treatment. Additionally, when the step-through latency was evaluated in the passive avoidance task, there was no significant difference between sham-operated control group (205.7 ± 55.7 seconds) and treatment group (235.7 ± 45.7 seconds) (n = 6 per group; Figure S2A in Supplementary Material available online at http://dx.doi.org/10.1155/2016/2580837).

View Article: PubMed Central - PubMed

ABSTRACT

Neurogenesis and synaptic plasticity can be stimulated in vivo in the brain. In this study, we hypothesized that in vivo expression of reprogramming factors such as Klf4, Sox2, Oct4, and c-Myc would facilitate endogenous neurogenesis and functional recovery. CD-1&reg; mice were induced at 1 week of age by unilaterally carotid artery ligation and exposure to hypoxia. At 6 weeks of age, mice were injected GFP only or both four reprogramming factors and GFP into lateral ventricle. Passive avoidance task and open field test were performed to evaluate neurobehavioral function. Neurogenesis and synaptic activity in the hippocampus were evaluated using immunohistochemistry, qRT-PCR, and/or western blot analyses. Whereas BrdU+GFAP+ cells in the subgranular zone of the hippocampus were not significantly different, the numbers of BrdU+&beta;III-tubulin+ and BrdU+NeuN+ cells were significantly higher in treatment group than control group. Expressions of synaptophysin and PSD-95 were also higher in treatment group than control group. Importantly, passive avoidance task and open field test showed improvement in long-term memory and decreased anxiety in treatment group. In conclusion, in vivo expression of reprogramming factors improved behavioral functions in chronic hypoxic-ischemic brain injury. The mechanisms underlying these repair processes included endogenous neurogenesis and synaptic plasticity in the hippocampus.

No MeSH data available.


Related in: MedlinePlus