中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (11): 2082-2088.doi: 10.4103/1673-5374.282268

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

孕中期轻度宫内低灌注对仔鼠学习和记忆能力的影响

  

  • 出版日期:2020-11-15 发布日期:2020-08-23
  • 基金资助:
    中国国家重点研究计划（2018YFC1002902）。

Effects of mild intrauterine hypoperfusion in the second trimester on memory and learning function in rat offspring

Shao-Wei Yin1, 2 , Yuan Wang3 , Yi-Lin Meng1, 2 , Cai-Xia Liu1, 2   

  1. 1 Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
    2 Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Shenyang, Liaoning Province, China
    3 Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2020-11-15 Published:2020-08-23
  • Contact: Cai-Xia Liu, MD, PhD,liucaixia_sj@163.com.
  • Supported by:
    This work was supported by the National Key Research & Department Program of China, No. 2018YFC1002902 (to CXL).

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摘要：

轻度宫内低灌注(MIUH)是影响胎儿和子代生长发育的严重病理事件，可导致生长受限、低出生体质量和神经发育障碍等不良临床结局。目前，胎盘灌注不足如何影响后代神经系统发育的机制仍存在争议。为了研究MIUH对子代学习记忆功能的影响，实验在妊娠中期(第17天)SD孕鼠子宫动脉和卵巢子宫动脉上放置2.5 mm长、0.24 mm内径的线圈建立MIUH孕鼠模型，然后腹腔注射120 mg/kg氯化锂或生理盐水，设为MIUH+Li组和MIUH组，同时设单独腹腔注射120 mg/kg氯化锂或生理盐水的开腹不放置线圈组孕鼠为Li组和假手术组。(1)为检测出生后4周子代鼠学习记忆能力的改变情况，使用水迷宫实验进行检测发现，与假手术组相比，MIUH组仔鼠的逃生潜伏期和上台前行程增加、寻找目标象限时间和目标象限持续时间下降；(2)对出生后4周子代鼠海马组织进行免疫荧光染色和Western blot显示，与假手术组相比，MIUH组海马组织中Nestin和Ki67蛋白(细胞增殖相关蛋白)表达及免疫反应明显下调；(3)进一步出生后4周子代鼠脑组织进行的Western blot实验检测相关信号通路相关蛋白的变化发现，与假手术组相比，MIUH组GSK-3β表达上调，β-Catenin表达下调。与MIUH组相比，MIUH+Li组p-GSK-3β和β-Catenin的表达上调。上述数据说明，MIUH可能通过调节GSK-3β信号通路降低仔鼠的学习记忆功能。

orcid: 0000-0001-7019-0266 (Cai-Xia Liu)

关键词: β-连环素, 发育神经生物学, 糖原合成酶激酶3, 学习, 锂, 记忆, 宫内, 后代, 胎盘疾病, 信号通路

Abstract: Mild intrauterine hypoperfusion (MIUH) is a serious pathological event that affects the growth and development of fetuses and offspring. MIUH can lead to growth restriction, low birth weight, neurodevelopmental disorders, and other adverse clinical outcomes. To study the effects of MIUH on learning and memory function in offspring, a model of MIUH was established by placing a coil (length 2.5 mm, diam- eter 0.24 mm) on the uterine artery and ovarian uterine artery of Sprague-Dawley rats in the second trimester of pregnancy (day 17). Next, 120 mg/kg lithium chloride (the MIUH + Li group) or normal saline (the MIUH group) was injected intraperitoneally into these rats. In addition, 120 mg/kg lithium chloride (the Li group) or normal saline (the SHAM group) was injected intraperitoneally into pregnant rats without coil placement. The Morris water maze was used to detect changes in learning and memory ability in the offspring at 4 weeks after birth. In the MIUH group, the escape latency and journey length before reaching the platform were both increased, and the number of times that the platform was crossed and the activity time in the target quadrant within 90 seconds were both decreased compared with the SHAM group. Immunofluorescence double staining and western blot assays demonstrated that hippocampal nestin and Ki67 (both cell-proliferation-related proteins) expression was significantly downregulated in the MIUH group compared with the SHAM group. Fur- thermore, western blot assays were conducted to investigate changes in related signaling pathway proteins in the brains of offspring rats, and revealed that glycogen synthase kinase 3β (GSK3β) expression was upregulated and β-catenin expression was downregulated in the MIUH group compared with the SHAM group. In addition, compared with the MIUH group, the expression levels of p-GSK3β and β-cat- enin were upregulated in the MIUH + Li group. These results suggest that MIUH may affect learning and memory function in rat offspring by regulating the GSK3β signaling pathway. The experimental procedures were approved by Animal Ethics Committee of Shengjing Hospi- tal of China Medical University (approval No. 2018PS07K) in June 2018.

Key words: developmental neurobiology, glycogen synthase kinase 3, intrauterine, learning, lithium, memory, offspring, placenta diseases, signal pathways, β-catenin