Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway Is Associated with Hypothalamic Neuronal Injury in Different Durations of Stress in Rats.
Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway Is Associated with Hypothalamic Neuronal Injury in Different Durations of Stress in Rats.
复制标题
内质网应激 PERK-ATF4-CHOP 通路与大鼠不同应激持续时间的下丘脑神经元损伤相关。
DOI：
10.3389/fnins.2017.00152
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发表时间：
2017
影响因子：
4.3
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Yi S;Shi W;Wang H;Ma C;Zhang X;Wang S;Cong B;Li Y
下丘脑是下丘脑-垂体-肾上腺（HPA）轴的起始部分，在调节中枢神经系统的应激中起关键作用。本研究的目的是确定是否内质网应激下丘脑神经元的差异刺激不同的持续时间的应激暴露，最终导致神经元的病理变化，通过影响HPA轴功能。有必要为更好的形态学证据的机制参与应激诱导的神经元损伤。采用每天束缚8h和强迫冰水游泳5 min的方法建立大鼠应激模型。胁迫诱导过程持续1、3、7、14和21天。采用酶联免疫吸附试验（ELISA）测定血清糖皮质激素水平。硫代巴比妥酸染色观察下丘脑神经元形态学变化。采用免疫组织化学和显微镜下组织细胞术（MMTC）检测内质网应激蛋白GRP 78、ATF 4和CHOP表达的变化。血清糖皮质激素水平显着增加后，3天的应激暴露和水平达到高峰，在7天。然而，到21天，水平显著下降。硫代巴比妥酸染色显示，长时间的应激暴露导致下丘脑神经元水肿，尼氏体缺乏，神经元固缩。免疫组化和MMTC显示，增加应激时间显著降低GRP 78表达，尽管ATF 4和CHOP蛋白表达显著增加。应激导致大鼠下丘脑神经元发生内质网应激的病理变化和明显的动态变化。这些结果提示内质网应激PERK-ATF 4-CHOP通路可能与下丘脑神经元损伤有关。
The hypothalamus, which is the initial part of the hypothalamic-pituitary-adrenal (HPA) axis, plays a critical role in regulating stress in the central nervous system. The present study aimed to determine whether endoplasmic reticulum stress in hypothalamic neurons is differentially stimulated by varying durations of stress exposure, which ultimately leads to pathological changes in neurons by affecting HPA axis function. There is a need for better morphological evidence of the mechanisms involved in stress-induced neuron injury. A stress model was established in rats by restraining for 8 h and forced ice-water swimming for 5 min each day. The stress-inducing process lasted for 1, 3, 7, 14, and 21 days. Enzyme-linked immunosorbent assay (ELISA) was used to assay serum glucocorticoid levels. Thionine staining was used to observe morphological changes in hypothalamic neurons. Immunohistochemistry and microscopy-based multicolor tissue cytometry (MMTC) was used to detect changes in expression of endoplasmic reticulum stress protein GRP78, ATF4, and CHOP. Serum glucocorticoid levels significantly increased after 3 days of stress exposure and the levels peaked by 7 days. By 21 days, however, the levels were significantly decreased. Thionine staining revealed that prolonged stress exposure resulted in hypothalamic neurons with edema, a lack of Nissl bodies, and pyknotic neurons. Immunohistochemistry and MMTC showed that increasing stress periods significantly decreased GRP78 expression, although ATF4 and CHOP protein expression significantly increased. Stress resulted in pathological changes and significant dynamic changes because of endoplasmic reticulum stress in rat hypothalamic neurons. These results suggested that the endoplasmic reticulum stress PERK-ATF4-CHOP pathway may be associated with hypothalamic neuronal injury.