Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways

Yi, Shanyong; Chen, Ke; Zhang, Lihua; Shi, Wanying; Zhang, Yaxing; Niu, Shiba; Jia, Miaomiao; Cong, Bin; Li, Yingmin

doi:10.3389/fncel.2019.00190

Cited by 58 publications

(49 citation statements)

References 39 publications

(45 reference statements)

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“…Thionin staining is a traditional method used to observe pathological changes in neurons (Yi et al, 2019). As shown in Figure 2, the neuronal structures were clear, and Nissl bodies were evenly distributed in the cytoplasm in the control group and the stress group at 1 and 3 days.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have indicated that prolonged stress could result in various mental disorders, including anxiety, depression, and other neuropsychiatric diseases (Goldstein, 2011). A rat model of restraint and forced ice-water swimming is an ideal model that well reflects the effect of complex physical and psychological stress on the body (Yi et al, 2017, 2019). In this study, we established rat models with different durations of restraint and forced ice-water swimming and found that the rats showed obvious disorders, such as anxiety, with prolongation of stress exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Protein kinase R-like endoplasmic reticulum kinase (PERK) is an important sensing element for ERS and a trigger of the PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor (ATF4)-CHOP pathway (Hetz, 2012). When ERS is prolonged and/or severe, the ERS PERK-eIF2α-ATF4-CHOP pathway will be activated and induce cell death (Kang et al, 2017; Yi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress-Mediated Basolateral Amygdala GABAergic Neuron Injury Is Associated With Stress-Induced Mental Disorders in Rats

Wang

Shi

Zhang

et al. 2019

Front. Cell. Neurosci.

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The amygdala is an important center of fear learning and memory and plays a critical role in regulating stress disorders. Previous studies have shown that changes in the amygdala caused by stress are an important cause of mental disorders including anxiety, but the specific mechanism remains unclear. Therefore, the purpose of this study was to investigate whether mental disorders induced by stress are related to γ-aminobutyric acid (GABA)ergic neuron damage in the basolateral amygdala (BLA) and whether endoplasmic reticulum stress (ERS) is involved in the injury process. Rat models of different durations of stress were established by restraint and forced ice-water swimming. Behavioral tests and high-performance liquid chromatography (HPLC) were used to detect anxiety in rats and changes in neurotransmitter levels in the BLA. Morphological approaches and microscopy-based multicolor tissue cytometry (MMTC) were used to detect the damage-induced changes in GABAergic neurons in the BLA. Immunofluorescence double labeling was used to detect the expression of ERS-related proteins before and after the inhibition of protein kinase R-like endoplasmic reticulum kinase (PERK) pathway. Stress resulted in damage to GABAergic neurons in the BLA, decreased GABA and increased glutamic acid (GLU) levels, perturbation of the excitation/inhibition (E/I) ratio in the BLA, and obvious anxiety disorders in rats. Moreover, ERS-mediated GABAergic neuron injury was an important cause of neurotransmitter level changes in the BLA. These results suggested that ERS-mediated GABAergic neuron injury in the BLA may be an important cause of stress-induced mental disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress-Mediated Basolateral Amygdala GABAergic Neuron Injury Is Associated With Stress-Induced Mental Disorders in Rats

Wang

Shi

Zhang

et al. 2019

Front. Cell. Neurosci.

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“…Activated ASK1 induces and increases the expression of JNK by increasing the transcription of JNK. It has been found that the expression of JNK is significantly decreased after the application of IRE1 α phosphokinase inhibitor [ 43 ]. Our results of Western blot also show that PF interferes with SC-EXOs to affect the expression of ER stress downstream factors in DRGn, inhibits the expression of apoptotic factors Caspase-12 and Caspase-3, reduce apoptosis, and alleviates ER stress by exosomes.…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin Effect of Schwann Cell-Derived Exosomes Ameliorates Dorsal Root Ganglion Neurons Apoptosis through IRE1α Pathway

Zhu

Han

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. Diabetic peripheral neuropathy (DPN) is a common complication of diabetes but its pathogenesis is not fully clarified. Endoplasmic reticulum (ER) stress has been confirmed to be involved in the development of DPN. Dorsal root ganglion neuron (DRGn) is the target cell of DPN injure in the peripheral neurons system. Schwann cell (SCs)-derived exosomes (SC-EXOs) can carry IRE1α signal transduction factors in ER stress to DRGn. The aim of this study is to investigate the effect of SC-EXOs treated with paeoniflorin (PF) on DRGn stimulated by high glucose. Methods. SCs were divided into Control group (Control), 150 mM glucose group (HG), high osmotic pressure group (HOP), and low, middle, and high dose PF group (PF1, PF10, and PF100). Exosomes were obtained from SCs by ultracentrifugation and identified according to marker proteins, including CD63, Alix, Hsp70, and TSG101. ER stress initiating factor GRP78, the IRE1α pathway information transmission factor IRE1α, and the phosphorylation level of IRE1α were detected by Western blot, DRGn is divided into Control group (Control), 50 mM glucose group + Control exosomes group (HG + EXOs Control), 50 mM glucose group (HG), and 50 mM glucose group + administration exosomes group (HG + EXOs PF1, HG + EXOs PF10, and HG + EXOs PF100); ER morphology of primary DRGn was observed by using the transmission electron microscope, the level of DRGn apoptosis was analyzed by TUNEL, and the downstream proteins of ER stress including CHOP, XBP1S, JNK, and p-JNK in DRG and the expression of apoptosis-related proteins Bcl-2, Bax, Caspase-3, and Caspase-12 were measured by Western blot. Results. Compared with the exosomes in the HG group, the exosomes after the intervention of PF can significantly reduce the expression of GRP78, IRE1α, and the phosphorylation level of IRE1α P < 0.05 ; compared with the DRGn in the HG group, the SC-EXOs treated with PF could regulate the expression of proteins downstream of IRE1α pathway in ER stress ( P < 0.05 or P < 0.01 ), improve the morphological integrity of ER, and reduce apoptosis in DRGn ( P < 0.05 or P < 0.01 ). Conclusion. PF regulates the information of ER stress carried by SC-EXOs and further affects downstream of IRE1α pathway in DRGn, thus reducing ER stress-induced apoptosis. PF can interfere with DPN through affecting information communication carried by EXOs between SCs and DRGn.

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“…The serial section technique was used to select one from every five sections from each rat for a total of three sections. Microscopy-based multicolor tissue cytometry (MMTC) is employed to quantify DAB-positive cells [ 18 , 21 ]. Sections (the entire VTA) were scanned using the TissueFAXS quantitative imaging system coupled to a Zeiss® AxioImagerZ2 Microscope (Jena, Germany), and the number of immunohistochemically positive cells was counted by HistoQuest® (TissueGnostics, Vienna, Austria).…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is Associated with the Mesencephalic Dopaminergic Neuron Injury in Stressed Rats

Niu

Shi

et al. 2021

Analytical Cellular Pathology

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An increasing number of people are in a state of stress due to social and psychological pressures, which may result in mental disorders. Previous studies indicated that mesencephalic dopaminergic neurons are associated with not only reward-related behaviors but also with stress-induced mental disorders. To explore the effect of stress on dopaminergic neuron and potential mechanism, we established stressed rat models of different time durations and observed pathological changes in dopaminergic neurons of the ventral tegmental area (VTA) through HE and thionine staining. Immunohistochemistry coupled with microscopy-based multicolor tissue cytometry (MMTC) was employed to investigate the number changes of dopaminergic neurons. Double immunofluorescence labelling was used to investigate expression changes of endoplasmic reticulum stress (ERS) protein GRP78 and CHOP in dopaminergic neurons. Our results showed that prolonged stress led to pathological alteration in dopaminergic neurons of VTA, such as missing of Nissl bodies and pyknosis in dopaminergic neurons. Immunohistochemistry with MMTC indicated that chronic stress exposure resulted in a significant decrease in dopaminergic neurons. Double immunofluorescence labelling showed that the endoplasmic reticulum stress protein took part in the injury of dopaminergic neurons. Taken together, these results indicated the involvement of ERS in mesencephalic dopaminergic neuron injury induced by stress exposure.

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Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways

Cited by 58 publications

References 39 publications

Endoplasmic Reticulum Stress-Mediated Basolateral Amygdala GABAergic Neuron Injury Is Associated With Stress-Induced Mental Disorders in Rats

Endoplasmic Reticulum Stress-Mediated Basolateral Amygdala GABAergic Neuron Injury Is Associated With Stress-Induced Mental Disorders in Rats

Paeoniflorin Effect of Schwann Cell-Derived Exosomes Ameliorates Dorsal Root Ganglion Neurons Apoptosis through IRE1α Pathway

Endoplasmic Reticulum Stress Is Associated with the Mesencephalic Dopaminergic Neuron Injury in Stressed Rats

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