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Restraint Stress Delays the Recovery of Neurological Impairments and Exacerbates Brain Damages through Activating Endoplasmic Reticulum Stress-mediated Neurodegeneration/Autophagy/Apopotosis post Moderate Traumatic Brain Injury

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Abstract

Based on accumulating evidence, patients recovering from mild and moderate traumatic brain injury (TBI) often experience increased sensitivity to stressful events. However, few studies have assessed on the effects and pathophysiological mechanisms of stress on TBI. In the current study, using a mouse model of moderate TBI, we investigated whether restraint stress (RS) regulates secondary neurodegeneration and neuronal cell death, which are commonly associated with neurological dysfunctions. Our data showed that RS significantly reduced body weight recovery, delayed the recovery of neurological functions (motor function, cognitive function and anxiety-like behavior) and exacerbated the brain lesion volume after moderate TBI. Immunofluorescence results indicated that moderate TBI-induced cell insults and blood–brain barrier leakage were aggravated by RS. Further Western blotting experiments showed that RS activated endoplasmic reticulum (ER) stress excessively after moderate TBI and decreased the number of NeuN-positive cells, but increased the number of CHOP/NeuN-co-positive cells by performing immunostaining in the injured cortex after moderate TBI. Moreover, RS increased the ratios of CHOP/Aβ and CHOP/p-Tau co-positive cells in the injured cortex after moderate TBI. However, blocking ER stress with the classic ER stress inhibitor salubrinal remarkably decreased apoptosis and the levels of autophagy-related proteins in the mouse model of moderate TBI plus RS. Collectively, RS delays the recovery of neurological function and deteriorates morphological damage by excessively activating ER stress-mediated neurodegeneration, apoptosis and autophagy after moderate TBI. Thus, monitoring stress levels in patients recovering from non-severe TBI may merit consideration in the future.

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Acknowledgements

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Funding

This study was supported by grants 82072110, 81971800, 81971163 and 81601643 from the National Natural Science Foundation of China and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. These authors have contributed equally to this work.

Authors and Affiliations

  1. Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Affiliated Guangji Hospital, Soochow University, Suzhou, 215123, China

    Cheng Gao, Xueshi Chen, Heng Xu, Hanmu Guo, Lexin Zheng, Ya’nan Yan, Zhiyang Ren, Chengliang Luo, Yuan Gao, Zufeng Wang, Luyang Tao & Tao Wang

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  1. Cheng Gao
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Correspondence to Luyang Tao or Tao Wang.

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The data used or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

WT, GC, CX, XH, YY, GH, GY and TL performed the experiments and analyzed data. WT, ZL, RZ, GC, LC, WZ and TL were responsible for the conception and design of the study and manuscript writing and polishing.

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All the animal procedures were in compliance with the Institutional Animal Use and Care Committee of Soochow University and approved by the Guidelines for Animal Care and Use from the National Institutes of Health (NIH) and the ARRIVE (Animal Research: Reporting In Vivo Experiments).

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Gao, C., Chen, X., Xu, H. et al. Restraint Stress Delays the Recovery of Neurological Impairments and Exacerbates Brain Damages through Activating Endoplasmic Reticulum Stress-mediated Neurodegeneration/Autophagy/Apopotosis post Moderate Traumatic Brain Injury. Mol Neurobiol 59, 1560–1576 (2022). https://doi.org/10.1007/s12035-022-02735-4

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