运动调控FMRP-TXNIP/NLRP3/GSDMD通路改善PTSD模型小鼠行为障碍的机制研究

Mechanistic study on exercise ameliorating behavioral impairments in PTSD model mice via regulation of the FMRP-TXNIP/NLRP3/GSDMD pathway

摘要

目的 探讨运动干预对创伤后应激障碍(PTSD)模型小鼠的改善作用,并分析其对FMRP及TXNIP/NLRP3/GSDMD炎症信号通路的调控作用。方法 将42只C57BL/6J雄性小鼠随机分为对照组和PTSD组,随后将2组进一步细分:对照组、运动组、PTSD组和PTSD+运动组。使用SPS&S法构建小鼠PTSD模型;利用高架十字迷宫实验评估小鼠的焦虑样行为,利用Y迷宫实验评估小鼠的学习记忆能力,利用强迫游泳实验评估小鼠的绝望样行为;运用Western blot实验和免疫荧光检测小鼠脑组织中FMRP、TXNIP、NLRP3及GSDMD的表达变化。采用两因素析因设计方差分析评估PTSD造模与运动干预的主效应及交互作用。结果 与对照组相比,PTSD组小鼠表现出焦虑、抑郁样行为及学习记忆障碍(P<0.05)。海马组织内GSDMD、TXNIP及NLRP3蛋白表达量升高(P<0.05),而FMRP表达水平下调(P<0.05)。经4周小鼠专用跑步机运动干预后,PTSD样小鼠行为学症状得到改善,GSDMD、TXNIP及NLRP3蛋白表达水平下降,FMRP表达水平升高。两因素析因分析显示,运动干预对行为学指标OE%及蛋白表达具有主效应(P<0.05),且主要在分子层面发现与PTSD造模存在交互作用(P<0.05)。结论 运动可改善SPS&S诱导的PTSD样行为,其作用可能通过上调FMRP表达并抑制TXNIP/NLRP3/GSDMD相关炎症信号通路有关。

Abstract

Objective To investigate whether exercise ameliorates behavioral deficits in a mouse model of post-traumatic stress disorder (PTSD) and to examine its regulatory effects on the FMRP-associated TXNIP/NLRP3/GSDMD inflammatory signaling pathway. Methods 42 male C57BL/6J mice were randomly divided into a control group (Ctrl) and a PTSD group. Each group was further subdivided into a non-exercise group (Ctrl, PTSD) and an exercise group (Ctrl+Exercise, PTSD+Exercise). A PTSD mouse model was established using the SPS&S method. Anxiety-like behaviors were assessed using the elevated plus maze test, learning and memory ability were assessed using the Y-maze test, and depression-like behaviors were evaluated using the forced swimming test. Expression levels of FMRP, TXNIP, NLRP3 and GSDMD in brain tissue were examined by Western blot and immunofluorescence. A-two-way factorial design analysis of variance was used to evaluate the main effects and inderaction effects of PTSD modeling and exercise intervention. Results Compared with the Ctrl group, PTSD mice displayed pronounced anxiety- and depression-like behaviors together with impaired learning and memory (P<0.05). In the hippocampus, the protein expression levels of GSDMD, TXNIP and NLRP3 were significantly increased (P<0.05), whereas FMRP expression level was reduced (P<0.05). Four weeks of treadmill exercise markedly alleviated behavioral abnormalities in PTSD mice, accompanied by decreased expression levels of GSDMD, TXNIP and NLRP3 and increased FMRP expression level. Two-way factorial ANOVA revealed a significant main effect of exercise intervention on both the behavioural measure (percentage of open-arm entries) and protein expression levels(P<0.05), with interaction effects between exercise intervention and PTSD modelling being predominantly observed at the molecular level(P<0.05). Conclusion Exercise ameliorates SPS&S-induced PTSD-like behaviors in mice and this protective effect may involve upregulation of FMRP and suppression of the TXNIP/NLRP3/GSDMD-associated inflammatory signaling pathway.

关键词

创伤后应激障碍 / SPS&S模型 / 运动干预 / 神经炎症

Key words

post-traumatic stress disorder / SPS&S model / exercise intervention / neuroinflammation

[1] Merians A N, Spiller T, Harpaz-Rotem I, et al. Post-traumatic stress disorder[J]. Medical Clinics of North America, 2023,107(1):85-99.
[2] Kachadourian L K, Harpaz-Rotem I, Tsai J, et al. Posttraumatic stress disorder symptoms, functioning, and suicidal ideation in US military veterans: A symptomics approach[J]. Primary Care Companion for CNS Disorders, 2019,21(2):1802402.
[3] Alorfi N M. Pharmacological management of post-traumatic stress disorder: A qualitative analysis of clinicaltrials.gov[J]. Drug Design, Development and Therapy, 2025(19):9697-9708.
[4] Hori H, Kim Y. Inflammation and post-traumatic stress disorder[J]. Psychiatry and Clinical Neurosciences, 2019,73(4):143-153.
[5] 王昊若,葛茜,吕海侠.创伤后应激障碍的记忆损害相关结构研究进展[J].国际精神病学杂志,2020,47(1):18-20.
Wang Haoruo, Ge Qian, Lyu Haixia. Research progress on memory impairment-related structures in post-traumatic stress disorder[J]. Journal of International Psychiatry, 2020,47(1):18-20.
[6] Michopoulos V, Powers A, Gillespie C F, et al. Inflammation in fear-and anxiety-based disorders: PTSD, GAD, and beyond[J]. Neuropsychopharmacology, 2017,42(1):254-270.
[7] Yang L D, Xing W L, Shi Y, et al. Stress-induced NLRP3 inflammasome activation and myelin alterations in the hippocampus of PTSD rats[J]. Neuroscience, 2024,555:156-166.
[8] Wen Y, Liu Y R, Tang T T, et al. mROS-TXNIP axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI[J]. International Journal of Biochemistry & Cell Biology, 2018(98):43-53.
[9] Vasudevan S O, Behl B, Rathinam V A. Pyroptosis-induced inflammation and tissue damage[J]. Seminars in Immunology, 2023,69:101781.
[10] Yu Y, Wu D M, Li J, et al. Bixin attenuates experimental autoimmune encephalomyelitis by suppressing TXNIP/NLRP3 inflammasome activity and activating NRF2 signaling[J]. Frontiers in Immunology, 2020,(11):593368.
[11] Monday H R, Kharod S C, Yoon Y J, et al. Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals[J]. Neuron, 2022,110(16):2588-2606.
[12] Nie P Y, Tong L, Li M D, et al. miR-142 downregulation alleviates rat PTSD-like behaviors, reduces the level of inflammatory cytokine expression and apoptosis in hippocampus, and upregulates the expression of fragile X mental retardation protein[J]. Journal of Neuroinflammation, 2021,18(1):17.
[13] Radder D L M, Ligia S D L A, Domingos J, et al. Physiotherapy in Parkinson's disease: A meta-analysis of present treatment modalities[J]. Neurorehabilitation and Neural Repair, 2020,34(10):871-880.
[14] Yuan Z C, Peng C G, Yang L L, et al. Effects of physical activity on patients with posttraumatic stress disorder: A systematic review and meta-analysis of randomized controlled trials[J]. Medicine, 2025,104(3):e41139.
[15] 苏畅,许子萱,金硕,等.运动促进海马神经再生与树突发育缓解创伤后应激障碍小鼠的恐惧与焦虑[J].解剖学报,2025,56(4):389-397.
Su Chang, Xu Zixuan, Jin Shuo, et al. Exercise alleviating fear and anxiety in mice with post-traumatic stress disorder by promoting hippocampal neuroregeneration and dendritic development[J]. Acta Anatomica Sinica, 2025,56(4):389-397.
[16] Wang Z F, Jiang B, Wang X T, et al. Relationship between physical activity and individual mental health after traumatic events: A systematic review[J]. European Journal of Psychotraumatology, 2023,14(2):2205667.
[17] Li J M, Tong L, Schock B C, et al. Post-traumatic stress disorder: focus on neuroinflammation[J]. Molecular Neurobiology, 2023,60(7):3963-3978.
[18] Wang M L, Pan W, Xu Y, et al. Microglia-mediated neuroinflammation: A potential target for the treatment of cardiovascular diseases[J]. Journal of Inflammation Research, 2022(15):3083-3094.
[19] Han X J, Xu T S, Fang Q J, et al. Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy[J]. Redox Biology, 2021(44):102010.
[20] Choi J W, Jo S W, Kim D E, et al. Aerobic exercise attenuates LPS-induced cognitive dysfunction by reducing oxidative stress, glial activation, and neuroinflammation[J]. Redox Biology, 2024,71:103101.
[21] Yang C W, He Y X, Ren S, et al. Hydrogen attenuates cognitive impairment in rat models of vascular dementia by inhibiting oxidative stress and NLRP3 inflammasome activation[J]. Advanced Healthcare Materials, 2024,13(20):2400400.
[22] Wang Y, Yuan H L, Shen D, et al. Artemisinin attenuated ischemic stroke induced pyroptosis by inhibiting ROS/TXNIP/NLRP3/caspase-1 signaling pathway[J]. Biomedicine & Pharmacotherapy, 2024(177):116894.
[23] Parrott J M, Oster T, Lee H Y. Altered inflammatory response in FMRP-deficient microglia[J]. Science, 2021,24(11):103293.
[24] Deng Q, Bai Q Q, Yang Y, et al. A new mechanism regulating microglial NLRP3 inflammasome: FMR1 mediates NLRP3 mRNA stability[J]. PLoS One, 2026,21(2):e0341867.
[25] Choi E H, Park S J. TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target[J]. Experimental & Molecular Medicine, 2023,55(7):1348-1356.
[26] Liu L, Tang J, Liang X, et al. Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress[J]. Molecular Psychiatry, 2024,29(7):2031-2042.
[27] Fang Y F, Zhang Q L, Lin Z Y. Assessment of the effectiveness of exercise interventions in the treatment of PTSD: Based on a systematic evaluation and meta-analysis[J]. Frontiers in Psychology, 2026(16):1702199.

基金资助

国家自然科学基金项目(32260208)