Experimental Neurology最新文献

{"title":"Targeting the NLRP3 inflammasome in Parkinson's disease: From molecular mechanism to therapeutic strategy","authors":"Jin-Yu Liang ,&nbsp;Xiao-Lei Yuan ,&nbsp;Jia-Mei Jiang ,&nbsp;Ping Zhang ,&nbsp;Kuang Tan","doi":"10.1016/j.expneurol.2025.115167","DOIUrl":"10.1016/j.expneurol.2025.115167","url":null,"abstract":"<div><div>Parkinson's disease is the second most common neurodegenerative disease, characterized by substantial loss of dopaminergic (DA) neurons, the formation of Lewy bodies (LBs) in the substantia nigra, and pronounced neuroinflammation. The nucleotide-binding domain like leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome is one of the pattern recognition receptors (PRRs) that function as intracellular sensors in response to both pathogenic microbes and sterile triggers associated with Parkinson's disease. These triggers include reactive oxygen species (ROS), misfolding protein aggregation, and potassium ion (K⁺) efflux. Upon activation, it recruits and activates caspase-1, then processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, which mediate neuroinflammation in Parkinson's disease. In this review, we provide a comprehensive overview of NLRP3 inflammasome, detailing its structure, activation pathways, and the factors that trigger its activation. We also explore the pathological mechanisms by which NLRP3 contributes to Parkinson's disease and discuss potential strategies for targeting NLRP3 as a therapeutic approach.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115167"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcome measures in rodent models for spinal cord injury and their human correlates","authors":"L.A.T. Jones ,&nbsp;E.C. Field-Fote ,&nbsp;D. Magnuson ,&nbsp;V. Tom ,&nbsp;D.M. Basso ,&nbsp;K. Fouad ,&nbsp;M.J. Mulcahey","doi":"10.1016/j.expneurol.2025.115169","DOIUrl":"10.1016/j.expneurol.2025.115169","url":null,"abstract":"<div><div>Pre-clinical research is intended to inform clinical research, however, communication between these researchers is lacking. A better understanding of what can be learned from animal and human models and what cannot, is essential. This includes a better understanding of where underlying constructs in outcome measures in rodents and humans align and where they diverge to improve dialogue between human and animal researchers. The goal of this review is to promote an understanding of similarities and differences in outcome measures and encourage consideration of these differences when planning, interpreting, and communicating findings from animal or human experiments. Seven individuals with a range of expertise in human and animal research and outcome measures reviewed rat and human measures focused on sensorimotor and functional outcomes. They then discussed where measures corresponded and where they did not, based on the underlying construct the assessment is intended to measure. Key findings are that measures of impairment (such as strength) often used in clinical trials are not commonly used in rodents. Measures such as speed and distance of locomotion are commonly assessed in humans and, while not commonly assessed in rodents, can be collected through existing outcome measures. Additional findings are that animal and human outcome measures are often developed and evaluated differently, with more standardized processes applied to human outcome measures. A deeper understanding and communication of similarities and differences in outcome measures, and where differences are necessary due to interspecies differences, may improve translation from animals to humans and humans to animals.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115169"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral, biochemical, and molecular characterization of MPTP/p-intoxicated mice","authors":"Xiaolu Tang ,&nbsp;Jinhua Xue ,&nbsp;Rui Chen ,&nbsp;Jiawei Xing ,&nbsp;Xiaying Lu ,&nbsp;Lili Cui","doi":"10.1016/j.expneurol.2025.115168","DOIUrl":"10.1016/j.expneurol.2025.115168","url":null,"abstract":"<div><div>The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most extensively utilized animal model for Parkinson's disease (PD). Treatment regimens are classified into three categories: acute, subacute, and chronic. Among these, the MPTP with probenecid (MPTP/p)-induced chronic mouse model is favored for its capacity to sustain long-term striatal dopamine depletion, though the resultant behavioral, biochemical, and molecular alterations require further validation<em>.</em> To systematically evaluate these abnormalities in the chronic MPTP/p mouse model, we conducted observations over a 12-month period. The results showed that these mice displayed reduced locomotor activity, minor gait abnormalities, and anxiety-like behavior within one week following the final MPTP/p injection. No significant motor disorders were observed from 1 to 12 months post-final injection, with exception of increased exploratory activity in the elevated plus maze from 2 to 8 months. One month after the final MPTP/p injection, there was a significant decrease in dopaminergic neurons in the ventral midbrain, which partially recovered after 12 months. A single MPTP/p injection temporarily increased striatal DA and its metabolites. Proteomics of ventral midbrain tissue indicated that the recovery of dopaminergic neurons might be linked to the upregulation of proteins like Bone morphogenetic protein type II receptor (<em>Bmpr2) and</em> Glutathione S-transferase mu 2 (Gstm2) once MPTP toxicity was removed. Our study indicated that the optimal time to evaluate behavioral abnormalities in chronic MPTP/p mouse model is within one week after modeling. Moreover, the upregulated expression of related proteins, such as Bmpr2 and Gstm2, in the ventral midbrain of the model mice after modeling may represent important targets for the future treatment of Parkinson's disease.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115168"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship among depression, fatigue, and sleep after traumatic brain injury: The role of physical exercise as a non-pharmacological therapy","authors":"Fernando da Silva Fiorin ,&nbsp;Douglas Buchmann Godinho ,&nbsp;Eduarda Bitencourt dos Santos ,&nbsp;Aderbal S. Aguiar Jr ,&nbsp;Felipe Barreto Schuch ,&nbsp;Marco Túlio de Mello ,&nbsp;Zsolt Radak ,&nbsp;Michele Rechia Fighera ,&nbsp;Luiz Fernando Freire Royes","doi":"10.1016/j.expneurol.2025.115156","DOIUrl":"10.1016/j.expneurol.2025.115156","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a burdensome condition frequently associated with an increased risk of psychiatric disorders. Although the exact molecular signaling pathways have not yet been fully defined, the compromised integrity of functional brain networks in regions such as the prefrontal cortex and anterior cingulate cortex has been linked to persistent symptoms, including depression, fatigue, and sleep disorders. Understanding how TBI affects neural physiology enables the development of effective interventions. One such strategy may be physical exercise, which promotes neural repair and behavioral rehabilitation after TBI. However, there are caveats to consider when interpreting the effects of physical exercise on TBI-induced mental health issues. This review will highlight the main findings from the literature investigating how different physical exercise protocols affect the progression of TBI-induced depression, fatigue, and sleep disturbances. Furthermore, we aim to explore potential neurobiological pathways that explain how physical exercise influences depression, fatigue, and sleep following TBI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115156"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An optogenetic mouse model of hindlimb spasticity after spinal cord injury","authors":"Sara Goltash,&nbsp;Riham Khodr,&nbsp;Tuan V. Bui ,&nbsp;Alex M. Laliberte","doi":"10.1016/j.expneurol.2025.115157","DOIUrl":"10.1016/j.expneurol.2025.115157","url":null,"abstract":"<div><div>Spasticity is a common comorbidity of spinal cord injury (SCI), disrupting motor function and resulting in significant discomfort. While elements of post-SCI spasticity can be assessed using pre-clinical SCI models, the robust measurement of spasticity severity can be difficult due to its periodic and spontaneous appearance. Electrical stimulation of sensory afferents can elicit spasticity-associated motor responses, such as spasms; however, placing surface electrodes on the hindlimbs of awake animals can induce stress or encumbrance that could influence the expression of behaviour. Therefore, we have generated a mouse model of SCI-related spasticity that utilizes optogenetics to activate a subset of cutaneous VGLUT2+ sensory afferents to produce reliable incidences of spasticity-associated responses in the hindlimb. To examine the efficacy of this optogenetic SCI spasticity model, a T9-T10 complete transection injury was performed in Islet1-Cre+/−;VGLUT2-Flp+/−;CreON-FlpON-CatCh+/− mice, followed by the implantation of EMG electrodes into the left and right gastrocnemius and tibialis anterior muscles. EMG recordings were performed during episodic optogenetic stimulation (1–2 sessions per week until 5 weeks post-injury (wpi); <em>n</em> = 10 females, 5 males). A subset of these mice (<em>n</em> = 3 females, 2 males) was also tested at 10 wpi. During each recording session, an optic fiber coupled to a 470 nm wavelength LED was used to deliver 9 × 100 ms light pulses to the palmar surface of each hind paw. The results of these recordings demonstrated significant increases in the amplitude of EMG responses to the light stimulus from 2 wpi to 10 wpi, suggesting increased excitability of cutaneous sensorimotor pathways. Interestingly, this effect was significantly greater in the female cohort than in the males. Incidences of prolonged involuntary muscle contraction in response to the stimulus (fictive spasms) were also detected through EMG and visual observation during the testing period, supporting the presence of spasticity. As such, the optogenetic mouse model developed for this study appears to elicit spasticity-associated behaviours in SCI mice reliably and may be valuable for studying SCI-related limb spasticity mechanisms and therapeutic.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115157"},"PeriodicalIF":4.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: COVID-19 and the central nervous system: Emerging insights from experimental neurology","authors":"Takayoshi Shimohata","doi":"10.1016/j.expneurol.2025.115165","DOIUrl":"10.1016/j.expneurol.2025.115165","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115165"},"PeriodicalIF":4.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Microglia-mediated pericytes migration and fibroblast transition via S1P/S1P3/YAP signaling pathway after spinal cord injury” [Vol. 379 of Experimental Neurology (September 2024)]","authors":"Ziyuan Yu,&nbsp;Huabin Zhang,&nbsp;Linxi Li,&nbsp;Zhi Li,&nbsp;Danmin Chen,&nbsp;Xiao Pang,&nbsp;Yunxiang Ji,&nbsp;Yezhong Wang","doi":"10.1016/j.expneurol.2025.115148","DOIUrl":"10.1016/j.expneurol.2025.115148","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115148"},"PeriodicalIF":4.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of mGluR1 and mGluR5 in the lateral habenula produces the opposite effects in the regulation of depressive-like behaviors in the hemiparkinsonian rats","authors":"Kuncheng Liu ,&nbsp;Yanping Hui ,&nbsp;Yaxin Yang ,&nbsp;Yuan Guo ,&nbsp;Li Zhang","doi":"10.1016/j.expneurol.2025.115154","DOIUrl":"10.1016/j.expneurol.2025.115154","url":null,"abstract":"<div><div>Depression is one of the most common non-motor symptoms in Parkinson's disease (PD) and the hyperactivity of the lateral habenula (LHb) may contribute to depression. The present study was performed to investigate the effects and mechanisms of group I metabotropic glutamate receptors (mGluRs) in the LHb on PD-related depressive-like behaviors. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) were used to establish the PD rat model. The group I mGluRs agonist and antagonists for mGluR1 and mGluR5 were microinjected into the LHb to observe their effects on PD-related depressive-like behaviors, electrical activities of the LHb, release of monoamines in the medial prefrontal cortex (mPFC) in sham and the lesioned rats. Lesions of the SNc induced depressive-like behaviors and hyperactivity of LHb neurons. Activation of group I mGluRs by 3,5-DHPG induced or enhanced depressive-like behaviors, increased the firing rate of the LHb neurons, and decreased dopamine (DA) and serotonin (5-HT) levels in the mPFC in the two groups of rats. Blockade of mGluR1 by YM298198 also produced similar effects with 3,5-DHPG, however, blockade of mGluR5 by MTEP produced opposite effects. Western blotting data showed that lesions of the SNc in rats down-regulated the expression of mGluR1 and mGluR5 in the LHb. These results suggest that mGluR1 and mGluR5 in the LHb induce opposite effects on depressive-like behaviors, which may attribute to the changed firing rate of LHb neurons by the presynaptic and postsynaptic mechanisms, and the changes in the monoamine levels.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115154"},"PeriodicalIF":4.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular expression of low-density lipoprotein receptor-related protein 1 and amyloid beta deposition in human and rat epileptogenic brain","authors":"Annemieke Rozeboom ,&nbsp;Diede W.M. Broekaart ,&nbsp;Jasper J. Anink ,&nbsp;Lynn Boonkamp ,&nbsp;Sander Idema ,&nbsp;Charlotte E. Teunissen ,&nbsp;Eleonora Aronica ,&nbsp;Jan A. Gorter ,&nbsp;Erwin A. van Vliet","doi":"10.1016/j.expneurol.2025.115149","DOIUrl":"10.1016/j.expneurol.2025.115149","url":null,"abstract":"<div><div>Decreased capillary expression of low-density lipoprotein receptor-related protein 1 (LRP1) has been linked to increased brain amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Aβ accumulation has also been observed in (a subset of) temporal lobe epilepsy (TLE) patients, suggesting a potential link between epilepsy and AD. This study examines cellular LRP1 expression in human and rat epileptogenic brain tissue to explore LRP1's role in epilepsy.</div><div>LRP1 expression and localization were analyzed in hippocampal sections from patients with status epilepticus (SE, <em>n</em> = 12), TLE (n = 12), autopsy controls (<em>n</em> = 20), and AD (<em>n</em> = 10) using immunohistochemistry. Soluble Aβ levels and deposits were compared across TLE, AD, and control tissues. LRP1 expression was also studied in an electrical post-SE rat model of TLE.</div><div>Decreased capillary LRP1 expression was found in both human and rat brain tissue (SE and TLE). Higher LRP1 expression was detected in CA1 neurons (only in human TLE) and glial cells (SE and TLE). Aβ deposits were observed in only one out of 12 TLE patients, and soluble Aβ levels were not significantly elevated. In contrast, AD patients showed decreased capillary LRP1 expression accompanied by Aβ plaques and increased soluble Aβ40/42 levels.</div><div>The significant reduction in LRP1 expression in brain capillaries in both adult human and rat TLE was not clearly associated with notable Aβ accumulation implying that alternative amyloid clearance mechanisms beyond LRP1 in blood vessels might be at play. It also supports previous findings indicating that Aβ pathology may be less prominent in adult TLE than some studies suggest.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115149"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A post-injury immune challenge with lipopolysaccharide following adult traumatic brain injury alters neuroinflammation and the gut microbiome acutely, but has little effect on chronic outcomes","authors":"Sarah S.J. Rewell ,&nbsp;Ali Shad ,&nbsp;Lingjun Chen ,&nbsp;Matthew Macowan ,&nbsp;Erskine Chu ,&nbsp;Natasha Gandasasmita ,&nbsp;Pablo M. Casillas-Espinosa ,&nbsp;Jian Li ,&nbsp;Terence J. O'Brien ,&nbsp;Bridgette D. Semple","doi":"10.1016/j.expneurol.2025.115150","DOIUrl":"10.1016/j.expneurol.2025.115150","url":null,"abstract":"<div><div>Patients with a traumatic brain injury (TBI) are susceptible to hospital-acquired infections, presenting a significant challenge to an already-compromised immune system. The consequences and mechanisms by which this dual insult worsens outcomes are poorly understood. This study aimed to explore how a systemic immune stimulus (lipopolysaccharide, LPS) influences outcomes following experimental TBI in young adult mice. Male and female C57Bl/6J mice underwent controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS or saline-vehicle at 4 days post-TBI, before behavioral assessment and tissue collection at 6 h, 24 h, 7 days or 6 months. LPS induced acute sickness behaviors including weight loss, transient hypoactivity, and increased anxiety-like behavior. Early systemic immune activation by LPS was confirmed by increased spleen weight and serum cytokines. In brain tissue, gene expression analysis revealed a time course of inflammatory immune activation in TBI or LPS-treated mice (e.g., IL-1β, IL-6, CCL2, TNFα), which was exacerbated in TBI + LPS mice. This group also presented with fecal microbiome dysbiosis at 24 h post-LPS, with reduced bacterial diversity and changes in the relative abundance of key bacterial genera associated with sub-acute neurobehavioral and immune changes. Chronically, TBI induced hyperactivity and cognitive deficits, brain atrophy, and increased seizure susceptibility, similarly in vehicle and LPS-treated groups. Together, findings suggest that an immune challenge with LPS early after TBI, akin to a hospital-acquired infection, alters the acute neuroinflammatory response to injury, but has no lasting effects. Future studies could consider more clinically-relevant models of infection to build upon these findings.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115150"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}