scholarly journals Role of Sox2 in Learning, Memory, and Postoperative Cognitive Dysfunction in Mice

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 727
Author(s):  
Lingli Gui ◽  
Zhen Luo ◽  
Weiran Shan ◽  
Zhiyi Zuo
Keyword(s):  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Environmental Enrichment ◽  
Postoperative Cognitive Dysfunction ◽  
Sirtuin 1 ◽  
Immunofluorescent Staining ◽  
Control Group ◽  
Barnes Maze ◽  
Clinical Issue

Postoperative cognitive dysfunction (POCD) is a significant clinical issue. Its neuropathogenesis has not been clearly identified and effective interventions for clinical use to reduce POCD have not been established. This study was designed to determine whether environmental enrichment (EE) or cognitive enrichment (CE) reduces POCD and whether sex-determining region Y-box-2 regulated by sirtuin 1, plays a role in the effect. Eighteen-month-old male mice were subjected to right-common-carotid-artery exposure under sevoflurane anesthesia. Some of them stayed in cages with EE or CE after the surgery. Learning and memory of mice were tested by a Barnes maze and fear conditioning, starting 2 weeks after the surgery. Sex-determining region Y-box-2 (Sox2) in the brain was silenced by small hairpin RNA (shRNA). Immunofluorescent staining was used to quantify Sox2-positive cells. Surgery reduced Sox2-positive cells in the hippocampus (64 ± 9 cells vs. 91 ± 9 cells in control group, n = 6, p < 0.001) and impaired learning and memory (time to identify target box one day after training sessions in the Barnes maze test: 132 ± 53 s vs. 79 ± 53 s in control group, n = 10, p = 0.040). EE or CE applied after surgery attenuated this reduction of Sox2 cells and POCD. Surgery reduced sirtuin 1 activity and CE attenuated this reduction. Resveratrol, a sirtuin 1 activator, attenuated POCD and surgery-induced decrease of Sox2-positive cells. Silencing shRNA reduced the Sox2-positive cells in the hippocampus and impaired learning and memory in mice without surgery. These results suggest a role of Sox2 in learning, memory, and POCD. EE and CE attenuated POCD via maintaining Sox2-positive cells in the hippocampus.

scholarly journals Dysfunction of EAAT3 Enhances LPS-induced Postoperative Cognitive Dysfunction

2021 ◽  
Author(s):  
Xiaoyan Wang ◽  
Yulong Ma ◽  
Aisheng Hou ◽  
Yuxiang Song ◽  
Xin Sui ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Adult Male ◽  
Excitatory Amino Acid ◽  
Postoperative Cognitive Dysfunction ◽  
Male Mice ◽  
Membrane Protein Expression

Abstract Background: Studies have shown that excitatory amino acid transporter 3 (EAAT3) function inhibition is related to several neurodegenerative diseases. Our previous studies also found that the EAAT3 function is intimately linked to learning and memory. In this study, we examined the role of EAAT3 in postoperative cognitive dysfunction (POCD) and explored the potential benefit of riluzole against POCD. Methods: We measured EAAT3 protein expression in hippocampus of male mice at different ages. Next, we established a recombinant adeno-associated viral (rAAV)-mediated shRNA to knockdown EAAT3 expression in the hippocampus of adult male mice. And then the mice received 2μg of lipopolysaccharide (LPS) intracerebroventricular microinjection to construct the POCD model. In addition, we intraperitoneally injected 4mg/kg of riluzole 2 days before LPS microinjection for consecutive 3 days in elderly male mice. Cognitive function was assessed using a Morris water maze 24h after LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activation of EAAT3 function by riluzole. Results: We found that the expression of EAAT3 was significantly decreased in old mice and EAAT3 knockdown in hippocampus aggravated LPS-induced learning and memory deficits in adult male mice. LPS significantly inhibited hippocampal EAAT3 membrane protein expression and GluA1 protein phosphorylation level in adult male mice. Moreover, riluzole pretreatment significantly increased hippocampal EAAT3 membrane protein expression and ameliorated LPS-induced cognitive impairment in old male mice. Conclusions: Our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and riluzole may be a promising strategy for prevention and treating of POCD in the elderly people.

scholarly journals Dysfunction of EAAT3 enhances LPS-induced Postoperative Cognitive Dysfunction

2021 ◽  
Author(s):  
Xiaoyan Wang ◽  
Yulong Ma ◽  
Aisheng Hou ◽  
Yuxiang Song ◽  
Xin Sui ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Adult Male ◽  
Excitatory Amino Acid ◽  
Postoperative Cognitive Dysfunction ◽  
Male Mice ◽  
Membrane Protein Expression

Abstract Background Studies have shown that excitatory amino acid transporter 3 (EAAT3) function inhibition is related to several neurodegenerative diseases. Our previous studies also found that the EAAT3 function is intimately linked to learning and memory. In this study, we examined the role of EAAT3 in postoperative cognitive dysfunction (POCD) and explored the potential benefit of riluzole against POCD. Methods We measured EAAT3 protein expression in hippocampus of male mice at different ages. Next, we established a recombinant adeno-associated viral (rAAV)-mediated shRNA to knockdown EAAT3 expression in the hippocampus of adult male mice. And then the mice received 2µg of lipopolysaccharide (LPS) intracerebroventricular microinjection to construct the POCD model. In addition, we intraperitoneally injected 4mg/kg of riluzole 2 days before LPS microinjection for consecutive 3 days in elderly male mice. Cognitive function was assessed using a Morris water maze 24h after LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activation of EAAT3 function by riluzole. Results We found that the expression of EAAT3 was significantly decreased in old mice and EAAT3 knockdown in hippocampus aggravated LPS-induced learning and memory deficits in adult male mice. LPS significantly inhibited hippocampal EAAT3 membrane protein expression and GluA1 protein phosphorylation level in adult male mice. Moreover, riluzole pretreatment significantly increased hippocampal EAAT3 membrane protein expression and ameliorated LPS-induced cognitive impairment in old male mice. Conclusions Our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and riluzole may be a promising strategy for prevention and treating of POCD in the elderly people.

scholarly journals Amantadine Alleviates Postoperative Cognitive Dysfunction Possibly by Increasing Glial Cell Line-derived Neurotrophic Factor in Rats

2014 ◽  
Vol 121 (4) ◽  
pp. 773-785 ◽  
Author(s):  
Junfeng Zhang ◽  
Hongying Tan ◽  
Wei Jiang ◽  
Zhiyi Zuo
Keyword(s):  
Fear Conditioning ◽  
Cell Line ◽  
Glial Cell ◽  
Cognitive Dysfunction ◽  
Neurotrophic Factor ◽  
Postoperative Cognitive Dysfunction ◽  
Control Group ◽  
Intracerebroventricular Injection ◽  
Barnes Maze ◽  
Surgery Group

Abstract Background: Postoperative cognitive dysfunction is a clinical entity that is associated with poor outcome. We determined the effectiveness of amantadine in reducing surgery-induced cognitive impairment and the role of glial cell line-derived neurotrophic factor (GDNF) in this effect. Methods: Four-month old male Fischer 344 rats were subjected to right carotid exposure under intravenous anesthesia. Some rats received intraperitoneal injection of 25 mg/kg/day amantadine for 3 days with the first dose at 15 min before the surgery or intracerebroventricular injection of GDNF or an anti-GDNF antibody at the end of surgery. One week later, rats were started to be tested by Barnes maze and fear conditioning. Hippocampus was harvested at 6 h, 24 h or 10 days after the surgery for biochemical analysis. C8-B4 cells, a microglial cell line, were pretreated with 1 ng/ml GDNF for 30 min before being exposed to 5 ng/ml lipopolysaccharide for 2 h. Results: Surgery increased the time to identify the target box in the Barnes maze when tested 1 day [22 (median) (11–66) (interquartile range) of control group vs. 158 (29–180) of surgery group, n = 15, P = 0.022) or 8 days after the training sessions and reduced context-related freezing behavior in the fear conditioning test. These effects were attenuated by amantadine (25 (14–90), n = 15, P = 0.029 compared with surgery group at 1 day after the training sessions in Barnes maze) and intracerebroventricular GDNF. Amantadine increased GDNF that was co-localized with glial fibrillary acidic protein, an astrocytic marker, in the hippocampus. Intracerebroventricular injection of an anti-GDNF antibody but not the denatured antibody blocked the effects of amantadine on cognition. Surgery induced neuroinflammation that was inhibited by amantadine. Lipopolysaccharide increased interleukin 1β production from C8-B4 cells. This effect was inhibited by GDNF. Conclusions: Our results suggest that amantadine attenuated surgery-induced learning and memory impairment. This effect may be mediated by GDNF via inhibition of neuroinflammation.

scholarly journals Dysfunction of EAAT3 Enhances LPS-induced Postoperative Cognitive Dysfunction

2021 ◽  
Author(s):  
Xiaoyan Wang ◽  
Yulong Ma ◽  
Aisheng Hou ◽  
Yuxiang Song ◽  
Xin Sui ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Adult Male ◽  
Excitatory Amino Acid ◽  
Postoperative Cognitive Dysfunction ◽  
Male Mice ◽  
Membrane Protein Expression

Abstract Background: Studies have shown that excitatory amino acid transporter 3 (EAAT3) function inhibition is related to several neurodegenerative diseases. Our previous studies also found that the EAAT3 function is intimately linked to learning and memory. In this study, we examined the role of EAAT3 in postoperative cognitive dysfunction (POCD) and explored the potential benefit of riluzole against POCD. Methods: We measured EAAT3 protein expression in hippocampus of male mice at different ages. Next, we established a recombinant adeno-associated viral (rAAV)-mediated shRNA to knockdown EAAT3 expression in the hippocampus of adult male mice. And then the mice received 2μg of lipopolysaccharide (LPS) intracerebroventricular microinjection to construct the POCD model. In addition, we intraperitoneally injected 4mg/kg of riluzole 2 days before LPS microinjection for consecutive 3 days in elderly male mice. Cognitive function was assessed using a Morris water maze 24h after LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activation of EAAT3 function by riluzole. Results: We found that the expression of EAAT3 was significantly decreased in old mice and EAAT3 knockdown in hippocampus aggravated LPS-induced learning and memory deficits in adult male mice. LPS significantly inhibited hippocampal EAAT3 membrane protein expression and GluA1 protein phosphorylation level in adult male mice. Moreover, riluzole pretreatment significantly increased hippocampal EAAT3 membrane protein expression and ameliorated LPS-induced cognitive impairment in old male mice. Conclusions: Our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and riluzole may be a promising strategy for prevention and treating of POCD in the elderly people.

scholarly journals Dysfunction of EAAT3 Enhances LPS-Induced Postoperative Cognitive Dysfunction

2021 ◽  
Author(s):  
Xiaoyan Wang ◽  
Yulong Ma ◽  
Aisheng Hou ◽  
Yuxiang Song ◽  
Xin Sui ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Adult Male ◽  
Excitatory Amino Acid ◽  
Postoperative Cognitive Dysfunction ◽  
Male Mice ◽  
Membrane Protein Expression

Abstract Background: Studies have shown that excitatory amino acid transporter 3 (EAAT3) function inhibition is related to several neurodegenerative diseases. Our previous studies also found that the EAAT3 function is intimately linked to learning and memory. In this study, we examined the role of EAAT3 in postoperative cognitive dysfunction (POCD) and explored the potential benefit of riluzole against POCD. Methods: We performed mutation analysis of SLC1A1 (encoding EAAT3) gene exons in patients of different age groups and measured EAAT3 protein expression in hippocampus of mice at different ages. Next, we established a recombinant adeno-associated viral (rAAV)-mediated shRNA to knockdown EAAT3 expression in the hippocampus of adult male mice. And then the mice received 2μg of lipopolysaccharide (LPS) intracerebroventricular microinjection to construct the POCD model. In addition, we intraperitoneally injected 4mg/kg of riluzole 2 days before LPS microinjection for consecutive 3 days in elderly male mice. Cognitive function was assessed using a Morris water maze 24h after LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activation of EAAT3 function by riluzole. Results: We found that point mutation of SLC1A1 gene exon in elderly patients was significantly different from children and adult people, and expression of EAAT3 was significantly decreased in old mice. And EAAT3 knockdown in hippocampus aggravated LPS-induced learning and memory deficits in adult male mice, and LPS significantly inhibited hippocampal EAAT3 membrane protein expression and GluA1 protein phosphorylation level in adult male mice. Moreover, riluzole pretreatment significantly increased hippocampal EAAT3 membrane protein expression and ameliorated LPS-induced cognitive impairment in old male mice. Conclusions: Our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and riluzole may be a promising strategy for prevention and treating of POCD in the elderly people.

scholarly journals Effects of L-655,708 on expression changes of GABA, glutamate, and beta-endorphin induced by propofol anesthesia in rats

2018 ◽  
Vol 16 ◽  
pp. 205873921879670
Author(s):  
Jin Wang ◽  
Xinyi Li ◽  
Huisheng Wu ◽  
Jianjuan Ke ◽  
Zongze Zhang ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Cognitive Dysfunction ◽  
Sham Group ◽  
Postoperative Cognitive Dysfunction ◽  
Expression Level ◽  
Control Group ◽  
Beta Endorphin ◽  
Anesthetized Rats ◽  
Significant Difference ◽  
Dentate Gyrus Region

Anesthetics are considered to be one of the important inducing factors of postoperative cognitive dysfunction (POCD). The hippocampal region of the rat is one of the action sites of general anesthesia drugs. L 655,708, a reverse agonist of gamma aminobutyric acid (GABA) receptor, can significantly improve short-term memory dysfunction in mice after anesthetized with isoflurane. So the purpose of this study is to investigate the effects of L-655,708 on expression of GABA, glutamate (GLU), and beta-endorphin (β-EP) in the dentate gyrus region of the hippocampus and cognition of rats anesthetized with propofol. In all, 30 male Sprague–Dawley (SD) rats were randomly allocated into the control group, sham group, and L-655,708 group, with 10 in each group. The cognitive function of rats was measured by Morris water maze before and 1 h after administration. Then the rats were sacrificed for brain tissues. Immunohistochemistry was used to study the expression of GABA, GLU, and β-EP in the hippocampus of anesthetized rats in each group. Compared with the control group, the latency of the sham group and L-655,708 group were significantly prolonged after administration ( P < 0.05). However, L-655,708 could shorten the prolonged latency ( P < 0.05). There was no significant difference in times of accessing original platform area between the three groups before and after medication ( P > 0.05). The expression level of GABA in the dentate gyrus region of hippocampus of rats in the sham group was significantly higher than that in the control group ( P < 0.05), while the expression level in the L-655,708 group was significantly lower than that in the sham group ( P < 0.05). No significant difference was found in the expression of GLU in the dentate gyrus region of hippocampus of rats in each group ( P > 0.05). Compared with the control group, the expression of β-EP was significantly lower in the dentate gyrus region of the hippocampus of sham group rats ( P < 0.05). However, the expression of β-EP in the L-655,708 group was significantly higher than that in the sham group ( P < 0.05). Cognitive dysfunction in rats anesthetized with propofol may be related to high expression of GABA and low expression of β-EP in the hippocampus. The mechanism of L-655,708 in reducing the cognitive impairment in propofol anesthetized rats may be bound up with down-regulating the expression of GABA and increasing the expression of β-EP in the hippocampus.

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