Wu Jie, Liu Cui, Zhang Ling, He Bing, Shi Wei-Ping, Shi Hai-Lei, Qin Chuan
Pathology Department, Comparative Medical Center, Peking Union Medical College (PUMC) and Institute of Laboratory Animal Science, Chinese Academy of Medical Science (CAMS), Panjiayuan Nanli No. 5, Beijing, 100021, People's Republic of China.
Department of Pathology, Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, Shandong province, 266003, People's Republic of China.
Transl Neurosci. 2021 Apr 29;12(1):154-163. doi: 10.1515/tnsci-2020-0168. eCollection 2021 Jan 1.
To investigate the effects of chronic restraint stress on cognition and the probable molecular mechanism in mice.
In the current work, a restraining tube was used as a way to induce chronic stress in mice. The protein levels were determined with ELISA and western blot. A series of behavior tests, including the Morris water maze, elevated plus maze, open field test, and novel object recognition test, were also performed to examine the anxiety and the ability of learning and memory. Moreover, murine neuroblastoma N2a cells were used to confirm the findings from mice under chronic stress.
Decreased synaptic functions were impaired in chronic stress with the downregulation of PSD95, GluR-1, the neurotrophic factor BDNF, and immediate-onset genes Arc and Egr. Chronic restraint decreased the histone acetylation level in hippocampal neurons while HDAC2 was increased and was co-localized with glucocorticoid receptors. Moreover, chronic stress inhibited the PI3K/AKT signaling pathway and induced energy metabolism dysfunctions.
This work examining the elevated levels of HDAC2 in the hippocampus may provide new insights and targets for drug development for treating many neurodegenerative diseases.
研究慢性束缚应激对小鼠认知的影响及其可能的分子机制。
在本研究中，使用束缚管对小鼠施加慢性应激。采用酶联免疫吸附测定（ELISA）和蛋白质免疫印迹法检测蛋白质水平。还进行了一系列行为测试，包括莫里斯水迷宫实验、高架十字迷宫实验、旷场实验和新物体识别实验，以检测焦虑以及学习和记忆能力。此外，利用小鼠神经母细胞瘤N2a细胞来验证慢性应激小鼠的实验结果。
慢性应激时突触功能降低，突触后致密蛋白95（PSD95）、谷氨酸受体1（GluR-1）、神经营养因子脑源性神经营因子（BDNF）以及即早基因Arc和Egr下调。慢性束缚降低了海马神经元中的组蛋白乙酰化水平，而组蛋白去乙酰化酶2（HDAC2）水平升高且与糖皮质激素受体共定位。此外，慢性应激抑制了磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）信号通路并导致能量代谢功能障碍。
本研究对海马中HDAC2水平升高的研究可能为治疗多种神经退行性疾病的药物开发提供新的见解和靶点。
