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间歇性低氧预处理对创伤后应激障碍模型小鼠恐惧和焦虑行为的改善作用

丁伏生^1,2, 成祥², 赵彤², 赵永歧², 张广波², 吴海涛², 朱玲玲^2,*, 吴奎武²

¹安徽医科大学研究生院，合肥 230023；²军事医学研究院军事认知与脑科学研究所，北京 100850

摘要

间歇性低氧(intermittent hypoxia, IH)对高血压、心肌梗死、脑缺血以及抑郁症有一定预防和治疗作用，但IH对创伤后应激障碍(post-traumatic stress disorder, PTSD)的作用尚不清楚。本研究采用不可逃避足底电击联合场景再现制备PTSD小鼠模型，通过旷场测试、高架十字迷宫测试及条件性恐惧测试反映其恐惧和焦虑水平；通过Y迷宫测试反映其空间记忆能力；通过免疫组化染色检测海马、杏仁核和内侧前额叶皮层Fos阳性神经元的数量；采用Western blot方法检测海马、杏仁核和内侧前额叶皮层低氧诱导因子1α (hypoxia inducible factor-1α, HIF-1α)、血管内皮生长因子(vascular endothelial growth factor, VEGF)和脑源性神经营养因子(brain derived neurotrophic factor, BDNF)蛋白表达水平。结果显示，IH与模型(电击)对高架十字迷宫测试中进入开放臂次数所占百分比、条件性恐惧测试中僵住时间和排便数量存在交互作用，IH能增加PTSD模型小鼠在高架十字迷宫中开放臂运动次数，减少条件性恐惧测试中僵住时间和排便数量。同时，IH预处理能减少PTSD模型小鼠海马、杏仁核和内侧前额叶皮层Fos阳性神经元的数量，增加这些脑组织中HIF-1α、VEGF和BDNF蛋白的表达水平。以上结果表明，IH预处理对PTSD模型小鼠恐惧和焦虑行为有改善作用，提示IH有可能成为预防PTSD的有效手段。

关键词： 创伤后应激障碍; 间歇性低氧预处理; Fos阳性神经元; 低氧诱导因子1α; 脑源性神经营养因子

分类号：R749.99

Intermittent hypoxic preconditioning relieves fear and anxiety behavior in post-traumatic stress model mice

DING Fu-Sheng^1,2, CHENG Xiang², ZHAO Tong², ZHAO Yong-Qi², ZHANG Guang-Bo², WU Hai-Tao², ZHU Ling-Ling^2,*, WU Kui-Wu²

¹Graduate School of Anhui Medical University, Hefei 230023, China；²Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China

Abstract

Intermittent hypoxia (IH) has preventive and therapeutic effects on hypertension, myocardial infarction, cerebral ischemia and depression, but its effect on post-traumatic stress disorder (PTSD) has not been known. In this study, we used inescapable electric foot shock combined with context recapture to build PTSD mouse model. The levels of fear and anxiety were valued by the open field, the elevated plus maze (EPM) and the fear conditioning tests; the level of spatial memory was valued by Y maze test; the number of Fos positive neurons in hippocampus, amygdala and medial prefrontal cortex was valued by immunohistochemical staining; and the protein expressions of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) in these brain area were valued by Western blot. The results showed that IH and model (foot shock) had an interaction on percentage of entering open arms (OE%) in EPM and freezing time and the number of fecal pellets in fear conditioning test. IH increased OE% in EPM and reduced the freezing time and the number of fecal pellets in fear conditioning test in PTSD model mice. At the same time, IH reduced the number of Fos positive neurons in the hippocampus, amygdala and medial prefrontal cortex of PTSD model mice, and increased the protein expression levels of HIF-1α, VEGF and BDNF in these brain tissues. In conclusion, IH pretreatment can relieve fear and anxiety behavior in post-traumatic stress model mice, suggesting that IH may be an effective means of preventing PTSD.

Key words: post-traumatic stress disorder; intermittent hypoxic preconditioning; Fos positive neurons; HIF-1α; BDNF

收稿日期：2019-01-11　　录用日期：2019-03-14

通讯作者：朱玲玲　　E-mail: linglingzhuamms@126.com

DOI: 10.13294/j.aps.2019.0033

引用本文：

丁伏生, 成祥, 赵彤, 赵永歧, 张广波, 吴海涛, 朱玲玲, 吴奎武. 间歇性低氧预处理对创伤后应激障碍模型小鼠恐惧和焦虑行为的改善作用[J]. 生理学报 2019; 71 (4): 537-546.

DING Fu-Sheng, CHENG Xiang, ZHAO Tong, ZHAO Yong-Qi, ZHANG Guang-Bo, WU Hai-Tao, ZHU Ling-Ling, WU Kui-Wu. Intermittent hypoxic preconditioning relieves fear and anxiety behavior in post-traumatic stress model mice. Acta Physiol Sin 2019; 71 (4): 537-546 (in Chinese with English abstract).