A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice.
A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice.
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DNA高甲基化介导的NR2B表达减少诱导老年小鼠围术期神经认知障碍
DOI：
10.1111/cns.14097
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发表时间：
2023-05
影响因子：
5.5
通讯作者：
Xiong L
中科院分区：
文献类型：
--
作者：
Xu F;Cong P;Zhang B;Dong H;Zuo W;Wu T;Tian L;Xiong L
本研究旨在探讨NR2B基因在PND发病机制中的作用及DNA甲基化对NR2B基因表达的影响。18月龄C57BL/6J小鼠在1.4%异氟醚麻醉下进行实验性剖腹手术。使用Barnes迷宫和情景恐惧条件反射测试来评估海马区依赖的学习和记忆。Western blotting和qRT-PCR分别检测NR2B蛋白和mRNA的表达水平，亚硫酸氢盐定向测序法检测NR2B基因甲基化情况。电生理学方法测定大鼠长时程突触可塑性(LTP)。接受剖腹手术的小鼠表现出海马体依赖的认知缺陷，并伴有NR2B表达减少和LTP缺陷。NR2B在背侧海马区的过度表达可改善剖腹小鼠的学习记忆能力。尤其是开腹手术导致NR2B基因高甲基化所致的NR2B表达下降。术前应用S-腺苷蛋氨酸可使NR2B基因去甲基化，上调NR2B表达，改善LTP，对PND有剂量依赖性治疗作用。此外，抑制NR2B消除了SAM预处理的好处。剖腹手术通过NR2B基因的高甲基化导致海马区依赖的认知能力下降，使我们能够从表观遗传学的角度理解PND的发病机制。DNA高甲基化导致NR2B表达下降是老年小鼠PND发病机制之一，SAM可作为NR2B基因去甲基化的“去甲基化”试剂，而不是过去预测的纯粹的“高甲基化”试剂，对PND发挥剂量依赖的治疗作用。
This study was designed to investigate the role of NR2B and the contribution of DNA methylation to NR2B expression in the pathogenesis of PND. Eighteen‐month‐old C57BL/6J mice were subjected to experimental laparotomy under 1.4% isoflurane anesthesia. Hippocampus‐dependent learning and memory were evaluated by using the Barnes maze and contextual fear conditioning tests. The protein and mRNA expression levels of NR2B were evaluated by western blotting and qRT–PCR respectively, and the methylation of the NR2B gene was examined by using targeted bisulfite sequencing. Long‐term synaptic plasticity (LTP) was measured by electrophysiology. Mice that underwent laparotomy exhibited hippocampus‐dependent cognitive deficits accompanied by decreased NR2B expressions and LTP deficiency. The overexpression of NR2B in the dorsal hippocampus could improve learning and memory in mice subjected to laparotomy. In particular, the decreased NR2B expressions induced by laparotomy was attributed to the NR2B gene hypermethylation. Preoperative administration of S‐adenosylmethionine (SAM) could hypomethylate the NR2B gene, upregulate NR2B expression and improve LTP, exerting a dose‐dependent therapeutic effect against PND. Moreover, inhibiting NR2B abrogated the benefits of SAM pretreatment. Laparotomy cause hippocampus‐dependent cognitive decline by hypermethylating the NR2B gene, allowing us to understand the pathogenesis of PND in an epigenetic landscape. A decrease in NR2B expression mediated by DNA hypermethylation contributes to the pathogenesis of PND in aged mice, and SAM can function as a “hypomethylating” agent to hypomethylate the NR2B gene, rather than a pure “hypermethylating” agent as it used to be predicted, exerting a dose‐dependent therapeutic effect against PND.
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适当的运动水平可减轻肠道菌群失调和戊酸增加，从而改善小鼠手术后的神经可塑性和认知功能
影响因子：
11
作者：
Lai Z;Shan W;Li J;Min J;Zeng X;Zuo Z
通讯作者：
Zuo Z
影响因子：
11
作者：
Heaney CF;Namjoshi SV;Uneri A;Bach EC;Weiner JL;Raab-Graham KF
通讯作者：
Raab-Graham KF
影响因子：
2.9
作者：
Mawhinney LJ;de Rivero Vaccari JP;Alonso OF;Jimenez CA;Furones C;Moreno WJ;Lewis MC;Dietrich WD;Bramlett HM
通讯作者：
Bramlett HM
DOI：
10.1177/0271678x21999553
发表时间：
2021-09
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Chandra PK;Cikic S;Baddoo MC;Rutkai I;Guidry JJ;Flemington EK;Katakam PV;Busija DW
通讯作者：
Busija DW
记忆基因的 DNA 甲基化操作与七氟烷诱导的老年大鼠认知障碍有关
影响因子：
4.8
作者：
Ni, Cheng;Qian, Min;Zheng, Hui
通讯作者：
Zheng, Hui