Qingsheng Meng, Songxue Su, Lei Lei, Yubing Zhang, Jiabin Duan, Xiuhua Ren, Yihang Song, Xiaoyu Hu, Shiyue Chen, Weidong Zang, Zhen Zhang, Jing Cao
{"title":"chop介导的海马突触可塑性和神经元活动的破坏有助于慢性疼痛相关的认知缺陷。","authors":"Qingsheng Meng, Songxue Su, Lei Lei, Yubing Zhang, Jiabin Duan, Xiuhua Ren, Yihang Song, Xiaoyu Hu, Shiyue Chen, Weidong Zang, Zhen Zhang, Jing Cao","doi":"10.1111/cns.70160","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objectives</h3>\n \n <p>Endoplasmic reticulum (ER) stress-induced protein homeostasis perturbation is a core pathological element in the pathogenesis of neurodegenerative diseases. This study aims to clarify the unique role played by C/EBP homologous protein (CHOP) as a biomarker of the unfolded protein response (UPR) in the etiology of chronic pain and related cognitive impairments following chronic constrictive nerve injury (CCI).</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>The memory capability following CCI was assessed utilizing the Morris water maze (MWM) and fear conditioning test (FCT). Activation of the UPR was quantified by assessing levels of CHOP and key ER stress sensors. The terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and the levels of cleaved caspase-3 were utilized to assess apoptosis level. Synaptic plasticity was assessed via a modified Golgi-Cox staining method, and long-term potentiation (LTP) measurements were taken. Neuronal activity was determined by immunofluorescence and fiber photometry. Knockdown of CHOP and alleviation of ER stress were selectively induced by LV-Ddit3-shRNAs and the chemical chaperone 4-phenylbutyric acid (4-PBA), respectively.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Mice subjected to CCI displayed enduring pain and cognitive impairments evident on Days 21–28 post-surgery. Following CCI, changes in the dorsal CA1 (dCA1) manifested as ER dilation, upregulation of CHOP and upstream signaling molecules, reduced dendritic spine density, and PSD95 levels, and impaired LTP. Additionally, the co-localization of CaMKIIα/c-Fos and CaMKIIα<sup>dCA1</sup>-mediated calcium signaling was significantly reduced, while the activation of CaMKIIα was found to mitigate cognitive impairments in CCI mice. Selective knockdown of CHOP enhanced synaptic plasticity and CaMKIIα neuron activity, while 4-PBA treatment alleviated ER stress, synergistically improving cognitive deficits associated with chronic pain.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>CCI-induced CHOP upregulation impairs dCA1 synaptic plasticity and neuronal activity, leading to chronic pain-related cognitive deficits.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 1","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736631/pdf/","citationCount":"0","resultStr":"{\"title\":\"CHOP-Mediated Disruption of Hippocampal Synaptic Plasticity and Neuronal Activity Contributes to Chronic Pain-Related Cognitive Deficits\",\"authors\":\"Qingsheng Meng, Songxue Su, Lei Lei, Yubing Zhang, Jiabin Duan, Xiuhua Ren, Yihang Song, Xiaoyu Hu, Shiyue Chen, Weidong Zang, Zhen Zhang, Jing Cao\",\"doi\":\"10.1111/cns.70160\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objectives</h3>\\n \\n <p>Endoplasmic reticulum (ER) stress-induced protein homeostasis perturbation is a core pathological element in the pathogenesis of neurodegenerative diseases. This study aims to clarify the unique role played by C/EBP homologous protein (CHOP) as a biomarker of the unfolded protein response (UPR) in the etiology of chronic pain and related cognitive impairments following chronic constrictive nerve injury (CCI).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>The memory capability following CCI was assessed utilizing the Morris water maze (MWM) and fear conditioning test (FCT). Activation of the UPR was quantified by assessing levels of CHOP and key ER stress sensors. The terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and the levels of cleaved caspase-3 were utilized to assess apoptosis level. Synaptic plasticity was assessed via a modified Golgi-Cox staining method, and long-term potentiation (LTP) measurements were taken. Neuronal activity was determined by immunofluorescence and fiber photometry. 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CHOP-Mediated Disruption of Hippocampal Synaptic Plasticity and Neuronal Activity Contributes to Chronic Pain-Related Cognitive Deficits
Objectives
Endoplasmic reticulum (ER) stress-induced protein homeostasis perturbation is a core pathological element in the pathogenesis of neurodegenerative diseases. This study aims to clarify the unique role played by C/EBP homologous protein (CHOP) as a biomarker of the unfolded protein response (UPR) in the etiology of chronic pain and related cognitive impairments following chronic constrictive nerve injury (CCI).
Methods
The memory capability following CCI was assessed utilizing the Morris water maze (MWM) and fear conditioning test (FCT). Activation of the UPR was quantified by assessing levels of CHOP and key ER stress sensors. The terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and the levels of cleaved caspase-3 were utilized to assess apoptosis level. Synaptic plasticity was assessed via a modified Golgi-Cox staining method, and long-term potentiation (LTP) measurements were taken. Neuronal activity was determined by immunofluorescence and fiber photometry. Knockdown of CHOP and alleviation of ER stress were selectively induced by LV-Ddit3-shRNAs and the chemical chaperone 4-phenylbutyric acid (4-PBA), respectively.
Results
Mice subjected to CCI displayed enduring pain and cognitive impairments evident on Days 21–28 post-surgery. Following CCI, changes in the dorsal CA1 (dCA1) manifested as ER dilation, upregulation of CHOP and upstream signaling molecules, reduced dendritic spine density, and PSD95 levels, and impaired LTP. Additionally, the co-localization of CaMKIIα/c-Fos and CaMKIIαdCA1-mediated calcium signaling was significantly reduced, while the activation of CaMKIIα was found to mitigate cognitive impairments in CCI mice. Selective knockdown of CHOP enhanced synaptic plasticity and CaMKIIα neuron activity, while 4-PBA treatment alleviated ER stress, synergistically improving cognitive deficits associated with chronic pain.
Conclusion
CCI-induced CHOP upregulation impairs dCA1 synaptic plasticity and neuronal activity, leading to chronic pain-related cognitive deficits.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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