Brain Research最新文献

{"title":"Targeting eukaryotic elongation factor 2 (eEF2)/eEF2 kinase in neurological and neuropsychiatric Disorders: Mechanisms, therapeutic Implications, and translational challenges.","authors":"Ruzan W Mohammady, Rawan K Samir, Rana M Sayed, Marina H Malak, Marian K Magdy, Rawan G Mohamed, Aya H Tawfiq, Rahma A Kamel, Nada M Kamel","doi":"10.1016/j.brainres.2026.150368","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150368","url":null,"abstract":"<p><p>Eukaryotic elongation factor 2 kinase (eEF2K) phosphorylates eukaryotic elongation factor 2 (eEF2) and slows translation elongation. In the nervous system, this pathway links neuronal activity, calcium signaling, energy status, and stress responses to selective protein synthesis programs that shape synaptic plasticity, circuit excitability, and cell survival. Dysregulated eEF2K/eEF2 signaling has been implicated in epilepsy, Alzheimer's disease, Parkinson's disease, major depressive disorder, Down syndrome, and other brain conditions. However, the literature remains fragmented, largely preclinical, and often interpreted in an overly therapeutic manner. This review synthesizes the field using a mechanistic framework. Across disorders, altered eEF2 phosphorylation converges on five major axes: synaptic plasticity and excitatory/inhibitory balance, oxidative and mitochondrial stress responses, neuroinflammation/neuroimmune regulation, and aging-related neurogenesis and cognitive resilience. In chronic neurodegenerative and neurodevelopmental settings, excessive eEF2K activity is frequently associated with impaired de novo protein synthesis, synaptic dysfunction, and cognitive decline, whereas genetic or pharmacological suppression can improve selected behavioral and electrophysiological outcomes. By contrast, in acute metabolic stress or certain immune-cell contexts, eEF2K activity may serve adaptive and anti-inflammatory functions. These findings indicate that eEF2K has context-dependent, rather than uniformly pathogenic, roles. We also highlight major translational barriers, including dependence on rodent models, limited causal human data, incomplete cell-type resolution, and the off-target liabilities of commonly used inhibitors such as NH125 and A-484954. Overall, the eEF2K/eEF2 axis represents a biologically important but therapeutically complex target that will require selective, cell-aware, and stage-specific modulation. Future progress depends on better biomarkers, human models, and more selective brain-penetrant inhibitors.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1886 ","pages":"150368"},"PeriodicalIF":2.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroacupuncture at \"Siguan\" acupoints alleviates post-stroke depression by inhibiting ER stress-induced apoptosis in the prefrontal cortex.","authors":"Zhu Yan, Liu Puyi, Zhang Peng, Ye Haimin, Shi Xuehui, Liu Weiai, Kang Zhen","doi":"10.1016/j.brainres.2026.150367","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150367","url":null,"abstract":"<p><p>This study investigated the complex mechanisms underlying post-stroke depression (PSD) and the challenges associated with its clinical prevention and treatment. Specifically, it examined the effects of electroacupuncture at the \"Siguan\" acupoints on PSD and the relationship with the PERK-ATF4-CHOP endoplasmic reticulum stress (ERS) pathway. A rat model of PSD was established by combining middle cerebral artery occlusion (MCAO) with solitary rearing and chronic unpredictable mild stress (CUMS). Successfully modeled rats were randomly assigned to four groups: the model group, the electroacupuncture group, the drug group, and the sham operation group. The electroacupuncture group received 21 days of electroacupuncture at the \"Siguan\" acupoints (bilateral Hegu LI4 and Taichong LR3). Behavioral changes were assessed using a blinded method. Histopathological and molecular biological methods were then employed to comprehensively examine neuronal damage, apoptosis, and the expression of key proteins in the ERS pathway in the prefrontal cortex.The results showed that, compared with the model group, both electroacupuncture and medication significantly improved depressive‑like behavior, alleviated neuronal injury in the prefrontal cortex, and reduced apoptosis. At the molecular level, these effects were significantly associated with inhibition of the PERK-ATF4-CHOP ERS pathway, as evidenced by decreased levels of GRP78, p-PERK, CHOP, and downstream pro‑apoptotic proteins (Bax and cleaved caspase‑3). Notably, electroacupuncture demonstrated particular efficacy in promoting weight gain and modulating pathways such as p-PERK. These findings suggest that electroacupuncture at the \"Siguan\" acupoints may alleviate depressive‑like behavior in PSD rats by inhibiting the PERK-ATF4-CHOP pathway in the prefrontal cortex, thereby reducing endoplasmic reticulum stress‑induced neuronal apoptosis. This provides a novel potential molecular mechanism for electroacupuncture treatment of PSD.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150367"},"PeriodicalIF":2.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exacerbation of sensory dysfunction by hematoma-induced circuitry damage in a mouse model of thalamic hemorrhage.","authors":"Yingqing Wu, Jia Deng, Shilei Hao, Ning Hu, Bochu Wang","doi":"10.1016/j.brainres.2026.150356","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150356","url":null,"abstract":"<p><p>Sensory impairment following stroke is a prevalent and challenging complication that imposes significant burdens and risks on patients. Despite the frequency of hemorrhage-induced sensory impairments in the thalamus, a comprehensive understanding of the underlying mechanisms and therapeutic targets remains incomplete. Here, we examine circuit connectivity and electrophysiological properties to study pathogenesis, as well as molecular target efficacy. Using a mouse model of thalamic hemorrhage and conducting behavioral assessments, thalamic hemorrhage can induce specific sensory dysfunction. Within the context of thalamic-related circuitry connections, damage thresholds in upstream circuits are higher compared to downstream regions. Electrophysiological characterization revealed that post-hemorrhagic thalamic neurons exhibited narrower action potential (AP) widths and reduced decay times, indicating heightened neuronal excitability. Additionally, transcriptomic analysis identified the PI3K-AKT signaling pathway and pharmacological inhibition targeting this pathway significantly mitigated the severity of sensory impairments. These findings provide novel insights into the pathogenesis of sensory impairments and present potential therapeutic targets for post-hemorrhagic sensory impairments.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150356"},"PeriodicalIF":2.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral GABAergic markers in late-life depression: Links to clinical outcomes.","authors":"Sara Rezaei, Etienne Sibille, Daphne Voineskos, Tarek K Rajji, Yuliya S Nikolova, Breno S Diniz, Erica L Vieira","doi":"10.1016/j.brainres.2026.150365","DOIUrl":"10.1016/j.brainres.2026.150365","url":null,"abstract":"<p><p>Late-life depression (LLD) is a debilitating condition, characterized by mood disturbance and cognitive decline. Gamma-aminobutyric acidergic (GABAergic) deficits are a hallmark of both aging and depression; however, few studies have examined the GABAergic system in LLD. We hypothesized that there would be significant decrease in peripheral GABA levels and γ-aminobutyric acid type A (GABA-A) receptor subunit expression in individuals with LLD compared to healthy controls (HC). In this study, we measured plasma GABA levels and the mRNA expression of four GABA-A receptor subunits (GABRA1, GABRA4, GABRA5, and GABRR2) in peripheral blood mononuclear cells (PBMCs) from 87 older adults (LLD, n = 46; HC, n = 41). Plasma GABA levels were quantified using enzyme-linked immunosorbent assay (ELISA), and receptor subunit expression was assessed by quantitative-real time (RT-qPCR). There were no significant differences between LLD and HC in plasma GABA levels or GABA-A receptor subunit expression. In LLD, within-group analyses showed GABRA5, GABRR2, GABRA4, GABRA1 expression were negatively correlated with cognitive performance on the Montreal Cognitive Assessment MoCA scores (ρ = -0.464, p = 0.045, ρ = -0.515, p = 0.041; ρ = -0.414, p = 0.078, and ρ = -0.477, p = 0.062 respectively). This is the first study that investigated GABA-A receptor subunit expression in the periphery of individuals with LLD. Our findings suggest that altered peripheral GABA-A receptor subunit expression, even in the absence of between-group differences, is associated with reduced cognitive function in LLD.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150365"},"PeriodicalIF":2.6,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"uPAR exhibits age- and region-dependent expression in the brains of mice with Alzheimer's disease-like pathology.","authors":"Lauren E Sarko, Ella Klaus, Viktoriya Bondarenko, Callista Secker, Mackenzie S Mnuk, Kaitlyn M Marino, Daniel C Shippy, Tyler K Ulland, Krishanu Saha, Marina E Emborg, Jeanette M Metzger","doi":"10.1016/j.brainres.2026.150364","DOIUrl":"https://doi.org/10.1016/j.brainres.2026.150364","url":null,"abstract":"<p><p>The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell surface protein that regulates leukocyte adhesion, migration, and activation, thereby contributing to inflammation and tissue remodeling. However, its role in Alzheimer's disease (AD), particularly in relation to glial dysfunction, remains poorly defined. Here, we investigated the temporal and spatial regulation of uPAR expression across AD mouse models with intact or deficient adaptive immunity. Using immunohistochemistry, we assessed uPAR expression in Rag2/Il2rg^-^/- (Rag), Rag2/Il2rg^-^/--5xFAD (Rag-5xFAD), C57BL/6 (WT), and 5xFAD mice across multiple brain regions. uPAR expression increased with age and was significantly elevated in 5xFAD mice, with robust upregulation evident by 6 months irrespective of immune status. Immunofluorescence revealed that uPAR localized predominantly to Iba1⁺ microglia clustered around Aβ plaques, with limited neuronal expression. Bulk RNA sequencing of Rag-5xFAD brain tissue demonstrated enrichment of disease-associated microglia (DAM) and senescence-related transcriptional programs. These findings indicate that uPAR marks a subset of plaque-associated glial cells undergoing functional and transcriptional remodeling in AD, independent of peripheral adaptive immune signaling. Collectively, our results identify uPAR as a marker of dysfunctional, DAM-like microglia and implicate it in senescence-associated neuroinflammatory pathways. This work provides a framework for future studies targeting uPAR-expressing glial populations as a potential therapeutic strategy in AD.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1886 ","pages":"150364"},"PeriodicalIF":2.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurochemical impact of psychostimulants: Longitudinal MRI analysis of brain iron content in children with ADHD.","authors":"Hugo A E Morandini, Sjoerd B Vos, Paola Chivers, Tim J Silk, Pradeep Rao","doi":"10.1016/j.brainres.2026.150354","DOIUrl":"10.1016/j.brainres.2026.150354","url":null,"abstract":"<p><strong>Background: </strong>Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder in school-aged children and has been associated with impaired brain iron homeostasis. Evidence has shown that psychostimulant treatment may affect brain iron content in children with ADHD, however, longitudinal evidence remains limited. The present longitudinal study investigated the effect of psychostimulant treatment duration and age at treatment onset on brain iron content in children with ADHD.</p><p><strong>Methods: </strong>Neuroimaging and phenotypical data were collected from the publicly available Oregon ADHD-1000 dataset. After screening, data from 29 psychostimulant-medicated children with ADHD and 38 neurotypical children were included. Individual General Estimating Equation (GEE) models were used to investigate the effect of groups, treatment duration and age at treatment onset on brain iron content across time. Bonferroni correction was applied for multiple comparisons.</p><p><strong>Results: </strong>GEE analyses revealed no significant group effect on nigral, thalamic and striatal iron content. However, a significant group effect was found in the globus pallidus, with lower iron content in psychostimulant-medicated children with ADHD compared to their NT peers. Within the ADHD group, Bonferroni corrected post hoc comparison showed that earlier treatment onset (≤ 8 years) was associated with significantly higher iron content in the basal ganglia and thalamus compared to later treatment onset (≥ 9 years).</p><p><strong>Conclusion: </strong>Evidence has shown that medication-naïve children with ADHD may exhibit lower brain iron content compared to NT children and the current findings suggest that age at psychostimulant treatment onset, rather than treatment duration, may influence brain iron content in children with ADHD.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150354"},"PeriodicalIF":2.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated metabolomics and network pharmacology leveraging UPLC-Q-TOF-MS reveal material basis and metabolic mechanisms underlying Tongqiao Huoxue Decoction's efficacy in cerebral infarction.","authors":"Tiantian Wang, Lincheng Bai, Siyu Liu, Ruijiao Wang, Qingna Li, Jiaqi Xu, Meng Yang, Peiliang Dong, Hua Han","doi":"10.1016/j.brainres.2026.150338","DOIUrl":"10.1016/j.brainres.2026.150338","url":null,"abstract":"<p><p>Cerebral infarction (CI) is a common manifestation of stroke, which is a form of cerebral ischaemia. Tongqiao Huoxue Decoction (THD) is a proven therapeutic formulation for stroke treatment. As a therapeutic formulation renowned for promoting blood circulation and removing blood stasis, it is widely applied in clinical practice. However, the molecular mechanisms underlying its therapeutic effects are not yet clear. The purpose of this study is to evaluate the therapeutic effects of THD in CI rats and to delve into its potential mechanisms of action through pharmacodynamic experiments and metabolomic analysis. Results demonstrated that THD treatment was associated with reduced symptoms and metabolic disturbances in CI rats. Metabolomics analysis revealed the therapeutic effects of THD, modulating levels of 31 differential metabolites in urine and 41 in blood. These effects were associated with biosynthesis of unsaturated fatty acid, Glycerophospholipid metabolism, Arachidonic acid metabolism, Sphingolipid metabolism, Taurine and Hypotaurine metabolism, Glutathione metabolism, Linoleic acid metabolism. Network pharmacology revealed 49 bioactive compounds targeting 407 targets involved in Lipid and atherosclerosis, PI3K-Akt signaling, and Calcium signaling pathways. Finally, molecular docking analysis was performed to evaluate the binding interactions between the compounds from THD and the potential targets. Based on the results, kaempferol was thus suggested as a candidate bioactive constituent. These findings contribute to a better understanding of CI pathogenesis and provide a basis for further investigations into THD.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150338"},"PeriodicalIF":2.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The activity of D2 dopamine receptors of the ventral tegmental area changed the induced- cognitive responses of the lateral hypothalamic cholinergic stimulation following neuropathic pain.","authors":"Maryam Kohandani, Mohammad Taghi Mohammadi, Zahra Bahari, Narges Marefati, Alireza Mohammadi, Mehdi Raei","doi":"10.1016/j.brainres.2026.150357","DOIUrl":"10.1016/j.brainres.2026.150357","url":null,"abstract":"<p><strong>Background: </strong>Dopaminergic neurons within the ventral tegmental area (VTA) is involved in the development of cognitive dysfunction during chronic pain. It is controlling cognitive behaviors via its various projection pathways to different areas in the brain including lateral hypothalamus (LH). The activation of LH induced analgesia during chronic pain. In the current study, we assessed whether D2 dopamine receptors activity within the VTA can change the induced-cognitive responses of LH following its cholinergic stimulation during neuropathic pain in rats. Aditionally, we assessed whether cholinergic stimulation of LH can change firing rate of VTA neurons.</p><p><strong>Methods: </strong>Male Wistar rats were implanted with two separate cannulae into the LH and VTA on the same side. After 4 days' recovery of cannulation surgery, animals underwent second surgery for induction of neuropathic pain (chronic constriction injury of sciatic nerve, CCI). Citicoline (1 µg/1µl normal saline), as an acetylcholine precursor, that activates the LH projecting neurons, were microinjected into the LH. In the other groups, D2-like dopamine receptor antagonist, sulpiride (1 µg/1µl normal saline) or agonist, bromocriptine (1 µg/1µl normal saline) were microinjected into VTA, 5 min prior intra-LH injection of citicoline. Cognitive and electrophysiology studies were assessed 15-30 minutes after drug injection.</p><p><strong>Results: </strong>Stimulation of LH via citicoline significantly induced analgesic and learning/memory enhancer effects. Additionally, intra-VTA injection of bromocriptine significantly increased analgesic and learning/memory enhancer effects of LH. Interestingly, sulpiride significantly decreased analgesic and learning/memory enhancer effects of LH. Stimulation of LH via citicoline effectively increased firing rate of VTA neurons. Intra-VTA injection of bromocriptine and sulpiride significantly increased and decreased firing rate of VTA neurons, respectively.</p><p><strong>Conclusion: </strong>The present study suggest that the analgesic and memory enhancer effects which produced by LH cholinergic stimulation is mediated by D2-like dopamine receptors of VTA in neuropathic pain. Additionally, the cholinergic stimulation of LH via citicoline can increase firing rate of VTA neurons during neuropathic pain and intra-VTA injection of sulpiride effectively reversed the effects of citicoline on firing rate of VTA neurons.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":" ","pages":"150357"},"PeriodicalIF":2.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased hemispheric functional connectivity compensates speech perception in older adults with hearing loss","authors":"Yi Liu ,&nbsp;Junhua Ding ,&nbsp;Songjian Wang ,&nbsp;Nuonan Kou ,&nbsp;Shuo Wang","doi":"10.1016/j.brainres.2026.150201","DOIUrl":"10.1016/j.brainres.2026.150201","url":null,"abstract":"<div><div>Age-related hearing loss (ARHL) is associated with widespread cortical reorganization, yet the adaptive mechanisms of functional connectivity across disease stages and brain states remain unclear. Using functional near-infrared spectroscopy (fNIRS), we examined both resting-state and speech perception-evoked functional connectivity (FC) in older adults with normal hearing, mild hearing loss, or moderate-to-severe hearing loss. FC alterations were found to be both state-dependent (i.e., varying with the cognitive state) and stage-dependent (i.e., depending on the severity of hearing loss). At rest, only the most impaired group showed localized increases in right-hemispheric FC. During speech perception, the mildly impaired group exhibited widespread FC enhancements across cross-hemispheric networks. These task-evoked enhancements were absent in the severely impaired group, suggesting a breakdown in adaptive recruitment. Subnetwork-level analyses further revealed spatially specific alterations in right-lateralized frontoparietal and frontotemporal circuits, as well as interhemispheric pathways linking left-hemisphere language hubs with right-hemisphere regions supporting attention, executive function, and top-down linguistic prediction. Collectively, our findings delineate a nonlinear trajectory of neural adaptation in ARHL, highlight a temporally bounded window of plasticity in early stages, and underscore the essential role of cross-hemispheric reorganization in sustaining speech processing under cognitive load.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1876 ","pages":"Article 150201"},"PeriodicalIF":2.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of repopulated microglia-associated genes in microglia depleted/repopulated mice after spinal cord injury","authors":"Shiyuan Xue ,&nbsp;Die Hu ,&nbsp;Liping Li ,&nbsp;Yuerong Sun ,&nbsp;Xinyi Wei ,&nbsp;Yan Xiao ,&nbsp;Qiling Jiang ,&nbsp;Chao Qi ,&nbsp;Haitao Fu","doi":"10.1016/j.brainres.2026.150189","DOIUrl":"10.1016/j.brainres.2026.150189","url":null,"abstract":"<div><div>This study aimed to investigate the effects of repopulated microglia on neural repair and functional recovery and identify repopulated microglia-associated repair-promoting genes after spinal cord injury (SCI) in mice following depletion of microglia via the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397. Mice were divided into control, sustained microglial depletion, and microglial depletion/repopulation groups according to being treated standard or PLX3397 diet. Mice in all groups were subjected to a complete spinal cord crush injury. Comprehensive assessments were performed using behavioral scoring, immunofluorescence staining 21 days post-injury, and RNA sequencing 21 days post-injury. Results demonstrated that PLX3397 effectively eliminated approximately 95 % of microglia in the mouse spinal cord. Upon drug withdrawal, microglia rapidly repopulated and exhibited a pro-regenerative phenotype. Repopulated microglia significantly promoted post-injury motor functional recovery, increased neuronal survival, and reduced glial scar formation. Transcriptomic analysis identified genes associated with repopulated microglia, which were enriched in immune response, complement activation, phagocytosis, and cytokine signaling pathways. Protein-protein interaction (PPI) network analysis of these associated genes further pinpointed key genes, including<!--> <em>Il1b</em>,<!--> <em>Ccr2</em>, and <em>Il15</em>. This study reveals that repopulated microglia may exert neuroprotective effects by modulating the immune microenvironment. The 336 repopulated microglia-associated genes identified in this study, and the identified key genes that are preferentially upregulated in repopulated microglia may represent novel therapeutic targets for SCI.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1876 ","pages":"Article 150189"},"PeriodicalIF":2.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}