Abstract
ObjectiveAs a high-level nerve center that regulates visceral and endocrine activity, the hypothalamus plays an important role in regulating the body’s stress response. Previous studies have shown that stress can cause damage to hypothalamic neurons. The present study aimed to further clarify the mechanism of endoplasmic reticulum stress (ERS) involvement in hypothalamic neuronal injury.MethodsA 7-day stressed rat model was established with daily restraining for 8 h and forced ice-water swimming for 5 min. The rats were randomly divided into control, stress, stress + GSK2606414 (PERK phosphorylation inhibitor), stress + KIRA6 (IRE1 phosphokinase activity inhibitor), GSK2606414, and KIRA6 groups. The pathological changes of hypothalamic neurons were observed by thionine staining. Expression of ERS proteins GRP78, ATF4, ASK1, JNK, and CHOP in the hypothalamic neurons were observed by immunohistochemical staining. The expression of JNK and CHOP mRNA in the hypothalamic neurons were observed by RNA in situ hybridization (RNA Scope) and the expression of related proteins and mRNA was semiquantitatively analyzed by microscopy-based multicolor tissue cytometry (MMTC).ResultsThionine staining revealed that stress exposure resulted in edema, a lack of Nissl bodies, and pyknosis in hypothalamic neurons. Immunohistochemistry and RNA Scope showed that stress exposure significantly increased the expression of GRP78, ATF4, ASK1, CHOP, JNK, JNK mRNA, and CHOP mRNA. Treatment with PERK and IRE1 inhibitors attenuated pathological damage and downregulated the expression of ATF4, ASK1, JNK, CHOP, JNK mRNA, and CHOP mRNA.ConclusionStress caused pathological changes in rat hypothalamic neurons. ERS PERK-ATF4-CHOP and IRE1-ASK1-JNK pathways were involved in the injury process.
Highlights
Stress is a systemic, non-specific reaction in response to external, or internal threatening stimuli (Reser, 2016)
Immunohistochemistry and RNA Scope showed that stress exposure significantly increased the expression of GRP78, activating transcription factor 4 (ATF4), ASK1, CHOP, JNK, JNK mRNA, and CHOP mRNA
endoplasmic reticulum stress (ERS) PERK-ATF4-CHOP and IRE1-ASK1-JNK pathways were involved in the injury process
Summary
Non-specific reaction in response to external, or internal threatening stimuli (Reser, 2016). The hypothalamus-pituitary-adrenal (HPA) axis plays a critical role in the body’s stress response. The hypothalamus is activated when the body is stimulated by internal or external risk factors, which promotes adrenal cortex synthesis, and the release of glucocorticoids through the HPA axis; Glucocorticoids can enhance the body’s resistance to risk factors by mobilizing energy and regulating metabolism, while long-term stress exposure or excessive stress can lead to varying degrees of damage, and dysfunction (McLaughlin et al, 2007; Vegas et al, 2018). There is no detailed report on the damage related to this mechanism
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