Experimental Neurology最新文献

{"title":"Impact of surgical interventions on postoperative cognitive dysfunction: A focus on gene expression in the hippocampus and cerebral cortex and peripheral blood cells","authors":"Li Hu ,&nbsp;Shan-peng Liu ,&nbsp;Jintao Sun ,&nbsp;Zhuonan Sun ,&nbsp;Liuyi Song ,&nbsp;Cuiying Liu ,&nbsp;Jian Lu ,&nbsp;Zhipeng Zhu ,&nbsp;Heng Zhao ,&nbsp;Hongmei Zhou","doi":"10.1016/j.expneurol.2025.115459","DOIUrl":"10.1016/j.expneurol.2025.115459","url":null,"abstract":"<div><h3>Background</h3><div>Postoperative cognitive dysfunction (POCD) is a common surgical complication with unclear mechanisms. This study aimed to characterize hippocampal, cortical, and PBMC gene expression changes after surgery to identify biomarkers and therapeutic targets.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice underwent tibial fracture with intramedullary fixation. Behavioral tests (MWM, OFT, NOR) before and after surgery classified animals into control, surgery without POCD (G1), and surgery with POCD (G2) using <em>Z</em>-scores. Bulk RNA-seq was performed on hippocampus, cortex, and PBMCs, followed by network and pathway analyses. qRT-PCR validated hub genes, including RPL30 and RPS3A1. Functional assays involved hippocampal RPL30 knockdown in POCD mice with behavioral assessment. Hippocampal proteomics was performed and integrated with transcriptomic data to link gene expression with protein function and metabolic alterations.</div></div><div><h3>Results</h3><div>The study identified DEGs involved in cortical protein export, nicotine metabolism, and mitophagy; hippocampal endocannabinoid and IL-17 signaling; and PBMC lysosomal and MAPK pathways. Twelve hub genes, including RPL30 and RPS3A1, were identified; qRT-PCR confirmed their upregulation in POCD. RPL30 knockdown improved cognition. Proteomics revealed 80 differentially expressed proteins, with pathways related to TORC1 signaling, histone modification, lysosomal regulation, and energy metabolism.</div></div><div><h3>Conclusions</h3><div>This study identified key genes, proteins, and molecular pathways associated with postoperative cognitive dysfunction, including RPL30, RPS3A1, and pathways related to TORC1 signaling, histone modification, lysosomal regulation, and energy metabolism. These findings provide novel biomarkers and potential therapeutic targets for the early detection and intervention of POCD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115459"},"PeriodicalIF":4.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045073","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":"5xFAD mutations induce hearing impairment in the Ahl-corrected 5xFAD mice","authors":"Hongguo Su ,&nbsp;Fan Wu ,&nbsp;Khujista Haque ,&nbsp;Shengyu Zou ,&nbsp;Shanshan Zhang ,&nbsp;Kumar Sambamurti ,&nbsp;Su-Hua Sha","doi":"10.1016/j.expneurol.2025.115463","DOIUrl":"10.1016/j.expneurol.2025.115463","url":null,"abstract":"<div><div>Age-related hearing impairment (ARHI) has been strongly associated with cognitive impairment in case-controlled and longitudinal population-based studies. However, a mechanistic link between ARHL and Alzheimer's disease (AD)-related dementia remains unclear. In this study, we developed <em>Ahl</em>-corrected C57BL/6-background 5xFAD mice (referred to as FAD2), an AD mouse model suitable for precise assessment of auditory function, along with their wildtype littermates (WT2). WT2 mice of both sexes exhibited stable auditory brainstem response (ABR) thresholds from 3–4 months to 9–10 months of age at frequencies of 8, 16, and 32 kHz. In contrast, FAD2 mice showed significant threshold elevations at 9–10 months, with greater impairment at higher frequencies and in females. Interestingly, both sexes of FAD2 mice at 3–4 months of age exhibited significantly elevated ABR suprathreshold wave I amplitudes at 32 kHz compared to WT2 mice at that age, suggesting early auditory nerve hyperexcitability. These amplitudes gradually declined by 9–10 months, with female FAD2 mice showing significantly lower values than WT2 mice. Notably, hearing impairments at 9–10 months were not associated with sensory hair cell loss or brain amyloid deposition but correlated with early wave I amplitude elevations. Degeneration of myelin in spiral ganglion neurons (SGNs) was observed in severely hearing-impaired FAD2 mice. Additionally, acoustic startle response (ASR) was significantly reduced at 6–7 months in FAD2 mice of both sexes.</div><div>These findings suggest that 5xFAD mutations induce early auditory nerve hyperexcitability, leading to SGN degeneration and ARHL. Furthermore, the early ASR decline implies alteration in central nervous system circuits alterations, potentially marking early neurodegenerative changes.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"395 ","pages":"Article 115463"},"PeriodicalIF":4.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052582","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 “RAD001 (everolimus) attenuates experimental autoimmune neuritis by inhibiting the mTOR pathway, elevating Akt activity and polarizing M2 macrophages” [Exp. Neurol. 280 (2016) 106–114]","authors":"Ranran Han ,&nbsp;Juan Gao ,&nbsp;Hui Zhai,&nbsp;Jinting Xiao,&nbsp;Ya'’nan Ding,&nbsp;Junwei Hao","doi":"10.1016/j.expneurol.2025.115452","DOIUrl":"10.1016/j.expneurol.2025.115452","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115452"},"PeriodicalIF":4.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032827","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":"Spautin-1 alleviates depression-like behaviors in mice after traumatic brain injury by inhibiting MMP3 expression in microglia in the Hippocampal CA1 region","authors":"Jian-Kai Sun ,&nbsp;Xiao-Yi Ma ,&nbsp;Lan-Tao Liu ,&nbsp;Jing-Yu Hui ,&nbsp;Yue Fu ,&nbsp;Jian-lei Ge ,&nbsp;Ya-Mei Zhang ,&nbsp;Hong Xi ,&nbsp;Dong-Xue Zhang ,&nbsp;Li-Min Zhang ,&nbsp;Hui-Tao Miao","doi":"10.1016/j.expneurol.2025.115462","DOIUrl":"10.1016/j.expneurol.2025.115462","url":null,"abstract":"<div><h3>Background</h3><div>Although the treatment of depressive symptoms after traumatic brain injury (TBI) remains challenging, the underlying neurological mechanisms remain poorly understood. This study investigated the potential role of Spautin-1 in mitigating depression-like behaviors in mice following TBI by inhibiting matrix metalloproteinase-3 (MMP3) expression in microglial within the CA1 region of the hippocampus. The findings demonstrated that Spautin-1 treatment significantly reduced MMP3 expression and microglial activation, which led to an improvement in depression-like behaviors. This suggests that targeting MMP3 in microglia may offer a novel therapeutic approach for managing post-TBI depressive symptoms.</div></div><div><h3>Methods</h3><div>Mild TBI was induced in mice using the Feeney weight-drop paradigm after the immediate administration of Spautin-1 into the left lateral ventricle. Behavioral and pathological changes were assessed at various time points post-injury using neurological severity scores (NSS), the forced swim test (FST), the tail suspension test (TST), and the social interaction test (SI) task. Molecular and structural alterations were analyzed through transcriptomic analysis, real-time quantitative PCR, electron microscopy, local field potential (LFP) recordings, and immunofluorescence staining.</div></div><div><h3>Results</h3><div>Mild TBI reduced in the SI index, increased immobility time in behavioral tests, and exacerbated microinjury, as indicated by the upregulation of Iba1, GFAP, and MMP3-positive, USP13-positive, and Beclin-1-positive microglia. Quantitative polymerase chain reaction (qPCR) analysis showed that MMP3 expression was significantly increased after TBI. Notably, Spautin-1 administration effectively reversed these pathological and functional deficits: it reduced the intensity of MMP3 by 63.4 %, decreased the intensity of Iba1 by 33.5 %, improved the ratio of social interaction by 36.7 %, and lessened the immobility time in TST by 26.2 % as well as the immobility time in SI by 33.9 %. Additionally, TBI resulted in the accumulation of autophagic vacuoles and abnormal organelles. Functional impairments in the CA1 region were observed, including weakened δ-γ and θ-γ phase coupling, reduced expression of c-Fos-positive GAD2 and VGLUT1, decreased MAP2 levels, and diminished δ and θ oscillatory power.</div></div><div><h3>Conclusions</h3><div>Spautin-1 alleviates depression-like behaviors in mice following mild TBI by inhibiting the MMP3 signaling pathway in microglia within the CA1 region of the hippocampus, indicating a potential therapeutic strategy for addressing post-TBI depression.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115462"},"PeriodicalIF":4.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045072","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":"Circadian timing and entrainment properties of the SCN pacemaker in the PS19 mouse model of tau pathology","authors":"Nicklaus R. Halloy ,&nbsp;Megan Formanowicz ,&nbsp;Nguyen Nhi Lien Pham ,&nbsp;Kari R. Hoyt ,&nbsp;Karl Obrietan","doi":"10.1016/j.expneurol.2025.115458","DOIUrl":"10.1016/j.expneurol.2025.115458","url":null,"abstract":"<div><div>Tauopathies are a group of neurodegenerative disorders caused by the misfolded microtubule-associated protein tau (MAPT), leading to its abnormal accumulation and hyperphosphorylation, and resulting in neuronal dysfunction and death. Tauopathy patients also experience disruptions to circadian rhythms of behavior and sleep. The connection between tau pathology and circadian dysfunction is not well understood, especially regarding the role of the suprachiasmatic nucleus (SCN), the brain's central circadian pacemaker. Here, we conducted histological and functional analyses of the SCN in the PS19 (Prnp-huMAPT*P301S) mouse model of tauopathy. The SCN of PS19 mice had accumulation of phosphorylated tau as early as 2 months of age, and tau pathology was detected in both major neuronal subpopulations of the SCN: VIPergic (core) and AVPergic (shell) neurons. To assess SCN timing and entrainment properties, daily locomotor activity was monitored in PS19 and wild-type (WT) mice from 3 to 11 months-of-age. Activity profiles, rates of re-entrainment to changes in the light/dark cycle, and intrinsic circadian timing properties were largely unaffected in PS19 mice compared to age-matched WT mice. Finally, profiling circadian gene expression in tau fibril-seeded SCN explants from PS19 and WT mice did not reveal differences in network-level oscillator properties. Together, these findings suggest that tau pathology within the SCN is not sufficient to trigger marked disruptions of core circadian timing mechanisms in this tauopathy model. Further, these results raise the possibility that circadian disruptions in tauopathies arise from dysfunction in SCN-gated output pathways or downstream clock-gated circuits rather than the SCN oscillator itself.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"395 ","pages":"Article 115458"},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039567","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":"Longitudinal analysis of age-dependent phenotypes in hemizygous male and heterozygous female Cdkl5 mutant mice","authors":"Aiswaria Lekshmi Kannan ,&nbsp;Abhisarika Patnaik ,&nbsp;Alexandra Theurer ,&nbsp;Luisa Demuth ,&nbsp;Martin Korte ,&nbsp;Nicoletta Landsberger ,&nbsp;Marta Zagrebelsky","doi":"10.1016/j.expneurol.2025.115457","DOIUrl":"10.1016/j.expneurol.2025.115457","url":null,"abstract":"<div><div>Mutations in cyclin-dependent kinase-like 5 (<em>CDKL5</em>) gene trigger a severe neurodevelopmental disorder marked by motor impairment, intellectual disability, autistic-like behaviors, and early-onset epilepsy. Although several <em>Cdkl5</em>-deficient animal models mimic key aspects of the human condition, including hyperactivity and behavioral abnormalities, compromised neuronal architecture and connectivity, and altered activity-dependent synaptic plasticity they fall short of providing a unified understanding of the disorder's cellular and molecular underpinnings. These inconsistencies likely stem from variations in the analyzed brain regions, differences in the ages, sexes and genetic backgrounds of experimental subjects. In this study, we focus on characterizing distinct phenotypes, i.e. activity-dependent synaptic plasticity, hippocampal dendritic spine density, and behavior and provide a longitudinal study of their temporal evolution and sex/genotype-specific patterns. Our findings reveal that in both male and female <em>Cdkl5</em> deficient mice, disruptions in synaptic plasticity and changes in dendritic spine density develop dynamically in an age-, region- and hemisphere-dependent manner. Collectively, our results expand on previous observations by demonstrating how pathological phenotypes evolve in <em>Cdkl5</em> mutant mice with age and differ between sexes. Given the absence of a cure and the limited treatment options, our work underscores the urgent need for a deeper understanding of <em>Cdkl5</em> mutant phenotypes particularly including female subjects. This insight is crucial for the development of effective therapeutic strategies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115457"},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039584","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":"Suvorexant attenuates cognitive impairment associated with circadian rhythm sleep-wake disorders by modulating microglia activation via the BMAL1/NLRP3 pathway","authors":"Yujie Hu ,&nbsp;Tian Yun ,&nbsp;Dan Hou,&nbsp;Guoshuai Yang","doi":"10.1016/j.expneurol.2025.115464","DOIUrl":"10.1016/j.expneurol.2025.115464","url":null,"abstract":"<div><h3>Background</h3><div>Circadian rhythm sleep-wake disorders (CRSD) and cognitive impairment are common features of many neurological disorders. Suvorexant is a novel drug for the treatment of insomnia. The study aimed to investigate the effects and potential mechanisms of suvorexant in alleviating CRSD.</div></div><div><h3>Methods</h3><div>The photothermal displacement-induced CRSD model rats were treated with suvorexant to investigate its impact on cognitive function, the BMAL1/NLRP3 axis-related genes, the microglial marker IBA1, Aβ levels, and the expression of inflammatory factors. Subsequently, hippocampal delivery of sh-BMAL1 was used to investigate the specific mechanism by which suvorexant alleviates the CRSD model.</div></div><div><h3>Results</h3><div>Suvorexant treatment significantly decreased sleep latency and escape latency, while increasing sleep time, swimming speed, the number of crossings, and the time spent in each quadrant in the CRSD group. Moreover, Suvorexant was found to upregulate the levels of BMAL1, IL-10, CD206, and TGF-β in CRSD rats, and downregulate the levels of NLRP3, IL-1β, Aβ1–40, Aβ1–42, IL-6, TNF-α, and iNOS. The sh-BMAL1 intervention reversed suvorexant's effects, suggesting that BMAL1 may play a role in how suvorexant influences cognitive impairment in CRSD rats.</div></div><div><h3>Conclusion</h3><div>Suvorexant may improve CRSD-related cognitive impairment by modulating microglial activation and the BMAL1/NLRP3 pathway, providing potential insights into related conditions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115464"},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039555","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":"Changes in neurotransmitter metabolic profiles in copper-loaded rats as assessed by mass spectrometry imaging and the effect of Gandouling intervention","authors":"Yingying Hu ,&nbsp;Wenbin Wei ,&nbsp;Shuoying Liu ,&nbsp;Wei Fang ,&nbsp;Yaowu Liu ,&nbsp;Xiang Fang ,&nbsp;Xiaoqun Wang ,&nbsp;Dianlei Wang","doi":"10.1016/j.expneurol.2025.115460","DOIUrl":"10.1016/j.expneurol.2025.115460","url":null,"abstract":"<div><div>Copper accumulation-induced cognitive impairment represents a significant clinical manifestation in patients with Hepatolenticular Degeneration (HLD). Neurotransmitters play a crucial role in cognitive function, but the effects of their metabolic changes in different brain regions on cognitive dysfunction remain unclear. Thus, we employed desorption electrospray ionization mass spectrometry imaging (DESI-MS) to observe molecular metabolic disturbances and spatial distribution in the brains of copper-loaded rats. The results showed that there were certain changes in metabolic substance levels in nine brain regions of copper-loaded rats, and the cortical region showed the most significant changes, including increased levels of glutamine, adenosine, taurine, and other substances; and decrease levels of γ-aminobutyric acid, hypoxanthine, and other substances. Collectively, these changes suggest disruptions in the glutamine (Gln)-glutamate (Glu)/γ-aminobutyric acid (GABA) cycle. Notably, Gandouling tablets (GDL) intervention restored cognitive abilities in the water maze and reduced copper levels. This study highlights that copper accumulation may induce cognitive deficits by disrupting neurotransmitter balance; conversely, GDL may protect cognitive function by restoring this balance.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"395 ","pages":"Article 115460"},"PeriodicalIF":4.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039581","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":"ADGRB1 contributes to astrocyte-mediated phagocytosis of excitatory synapses","authors":"Fu Hung Shiu ,&nbsp;Emily J. Hill ,&nbsp;Yangping Li ,&nbsp;Shizhen Tang ,&nbsp;Nihar Ettigi ,&nbsp;Alexia T. King ,&nbsp;Bing Yao ,&nbsp;Jingjing Yang ,&nbsp;Steven A. Sloan ,&nbsp;Andrew Escayg","doi":"10.1016/j.expneurol.2025.115451","DOIUrl":"10.1016/j.expneurol.2025.115451","url":null,"abstract":"<div><div>Synapse refinement through the elimination of excess synapses is crucial for proper neuronal circuitry during development and adulthood, and the phagocytic activity of astrocytes plays an important role in this process. Failure to remove excess synapses can lead to neurological and neurodevelopmental disorders like epilepsy and autism spectrum disorder (ASD). The adhesion G protein-coupled receptor BAI1/ADGRB1 contributes to phagocytosis in various tissues, including the clearance of apoptotic myoblasts in skeletal muscle and epithelial cells in the intestine. However, the phagocytic function of ADGRB1 in the brain has not been thoroughly investigated. Given that <em>Adgrb1</em> is highly expressed in astrocytes but not in microglia, we examined changes in astrocyte gene expression resulting from the loss of ADGRB1. Our RNA-seq analysis revealed that astrocytes lacking ADGRB1 exhibit altered expression of genes associated with cytoskeleton organization and chemotaxis, processes that are required for phagocytosis. Using cultured astrocytes from mice lacking full-length ADGRB1 (<em>Adgrb1</em>^exon2−/−) and wildtype (WT) littermates, we found that <em>Adgrb1</em>^exon2−/− astrocytes exhibit significantly reduced phagocytic capacity when compared to similarly prepared astrocytes from WT littermates. Immunostaining of astrocytes and pre-synaptic sites showed less engulfed pre-synaptic elements in astrocytes from <em>Adgrb1</em>^exon2−/− mutants. Finally, immunostaining of pre- and post-synaptic sites revealed a significantly higher density of excitatory synapses in <em>Adgrb1</em>^exon2−/− mutants. Previous studies have shown that ADGRB1 variants are associated with ASD, and mice lacking ADGRB1 exhibit impaired social behavior and increased seizure susceptibility. The findings of this study suggest that the lack of ADGRB1 in astrocytes may result in deficits in astrocyte-mediated phagocytosis, which could potentially contribute to the behavioral abnormalities reported in prior studies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"395 ","pages":"Article 115451"},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032902","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":"Progressive lifespan modifications in the corpus callosum following a single concussion in juvenile male mice monitored by diffusion MRI","authors":"Andre Obenaus ,&nbsp;Brenda P. Noarbe ,&nbsp;Jeong Bin Lee ,&nbsp;Polina E. Panchenko ,&nbsp;Fang Tong ,&nbsp;Sean D. Noarbe ,&nbsp;Claire Bottini ,&nbsp;Yu Chiao Lee ,&nbsp;Jerome Badaut","doi":"10.1016/j.expneurol.2025.115455","DOIUrl":"10.1016/j.expneurol.2025.115455","url":null,"abstract":"<div><h3>Introduction</h3><div>The vulnerability of white matter (WM) in acute and chronic moderate-severe traumatic brain injury (TBI) has been established. In concussion syndromes, including preclinical rodent models, lacking are comprehensive longitudinal studies spanning the mouse lifespan. We previously reported early WM modifications using clinically relevant neuroimaging and histological measures in a model of juvenile concussion at one month post injury (mpi) who then exhibited cognitive deficits at 12mpi. For the first time, we assess corpus callosum (CC) integrity across the lifespan after a single juvenile concussion utilizing diffusion MRI (dMRI).</div></div><div><h3>Methods</h3><div>C57Bl/6 mice were exposed to sham or two severities of closed-head concussion (Grade 1, G1, speed 2 m/s, depth 1 mm; Grade 2, G2, 3 m/s, 3 mm) using an electromagnetic impactor at postnatal day 17. In vivo diffusion tensor imaging was conducted at 1, 3, 6, 12 and 18mpi and processed for dMRI parametric maps: fractional anisotropy (FA), axial (AxD), radial (RD) and mean diffusivity (MD). Hemispheric CC and regional CC data were extracted. To identify the biological basis of altered dMRI metrics, astrocyte and microglia in the CC were characterized at 1, 12 and 18 mpi by immunohistochemistry.</div></div><div><h3>Results</h3><div>Hemispheric CC analysis revealed altered FA and RD trajectories following juvenile concussion. Shams exhibited a temporally linear increase in FA with age while G1/G2 mice had plateaued FA values. G2 concussed mice exhibited high variance of dMRI metrics at 18mpi, which was attributed to the heterogeneity of TBI on the anterior CC. Regional analysis of dMRI metrics at the impact site unveiled significant differences between G2 and sham mice. The dMRI findings appear to be driven, in part, by loss of astrocyte morphology.</div></div><div><h3>Conclusion</h3><div>For the first time, we demonstrate progressive perturbations to WM of male mice after a single juvenile concussion across their lifespan. The CC alterations were dependent on concussion severity with elevated sensitivity in the anterior CC that was related to astrocyte and microglial morphology changes. Our findings suggest that long-term monitoring of children with juvenile concussive episodes using dMRI is warranted, focusing on vulnerable WM tracts.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"394 ","pages":"Article 115455"},"PeriodicalIF":4.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029109","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}