Experimental Neurology最新文献

{"title":"Mechanistic study on Lnc-Gstm5 regulation of the SUV39H1/H3K9me3 axis in hyperbaric oxygen-mediated suppression of inflammatory response following spinal cord injury","authors":"Shaoting Jia ,&nbsp;Mo Liu ,&nbsp;Ding Nan,&nbsp;Lu Yang,&nbsp;Jing Zhang,&nbsp;Jing Yang,&nbsp;Xuehua Liu","doi":"10.1016/j.expneurol.2025.115599","DOIUrl":"10.1016/j.expneurol.2025.115599","url":null,"abstract":"<div><div>Hyperbaric oxygen (HBO) suppresses the inflammatory response following spinal cord injury (SCI). However, the underlying detailed mechanisms are still to be clarified. Here we explored the mechanism of long non-coding RNA (lncRNA) glutathione s-transferase mu 5 (Gstm5) regulating NF-κB signaling pathway in HBO-mediated suppression of inflammatory response following SCI. In the current study, SCI cell model was developed with lipopolysaccharides (LPS)-induced BV2 cells and processed with HBO treatment, si-NC, and si-Lnc-Gstm5. Lnc-Gstm5, NF-κB p65, IL-1β，IL-6, TNF-a, suppressor of variegation 3–9 homolog 1 (SUV39H1), histone 3 lysine 9 trimethylation (H3K9me3), YTH domain containing 2 (YTHDC2) expression level were measured. The mice SCI model was generated and treated with HBO treatment, shRNA-Lnc-Gstm5. Lnc-Gstm5 was identified and BMS score, histopathological injury score, and inflammatory factors were evaluated. We found that HBO suppresses inflammatory response through up-regulating Lnc-Gstm5 level in a manner of YTHDC2-dependent m6A modification. Lnc-Gstm5 recruits SUV39H1 to up-regulate H3K9me3 expression level and suppresses NF-κB signaling pathway by reducing p65 phosphorylation. HBO suppresses the inflammatory response via YTHDC2/Lnc-Gstm5/SUV39H1/H3K9me3/NF-κB axis following SCI in mice. These results reveal a Lnc-Gstm5-driven epigenetic regulation mechanism, and targeting Lnc-Gstm5 represents a promising therapeutic strategy for SCI patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115599"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793704","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":"Levodopa differentially modulates spectral features in cerebellum and basal ganglia in a rodent model of Parkinson's disease","authors":"Shelby Sabourin ,&nbsp;Kelly Modi ,&nbsp;Jack Williams ,&nbsp;Rajveer Singh ,&nbsp;Kainat Akhtar ,&nbsp;Emily Groom ,&nbsp;Simran Utturkar ,&nbsp;Paul J. Feustel ,&nbsp;Eric S. Molho ,&nbsp;Damian S. Shin","doi":"10.1016/j.expneurol.2025.115579","DOIUrl":"10.1016/j.expneurol.2025.115579","url":null,"abstract":"<div><div>The cerebellum has largely remained overlooked for its role in Parkinson's disease (PD). Interrogation of this motor system may reveal innovative targets for therapeutics for PD. Here, we investigate longitudinal changes in spatiospectral dynamics in basal ganglia (BG) and cerebellar nuclei to characterize altered patterns of neural activity in both motor-related brain areas in a rodent model of PD. To do so, we used the unilateral 6-hydroxydopamine (6-OHDA) rat model and recorded local field potentials (LFP) before and during treatment with levodopa and benserazide from three to six weeks post-lesion. Beta oscillations (13–35 Hz) emerged in the ipsilateral striatum of hemiparkinsonian animals at three weeks, whereas beta, theta (4–8 Hz) and alpha (8–12 Hz) oscillations appeared in the DN at six weeks. Levodopa decreased striatal beta oscillations at six weeks post-lesion (<em>p</em> = 0.003) compared to untreated PD animals but did not affect theta oscillations in the striatum and dentate nucleus at this time. These findings suggest that the cerebellum may play a variable role in PD depending on dopamine status: a mirroring/pathologic role during dopamine depletion and a compensatory role during dopamine replacement. This is the first time spectral dynamics in BG and cerebellum have been investigated longitudinally in a PD model, and our findings provide clearer insight regarding the dynamic engagement of the cerebellum during dopamine depletion and replacement therapy. A better understanding about the role of the cerebellum in PD pathophysiology may unmask future targets for therapeutic development.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115579"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660763","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":"Molecular regulation of exercise training on hippocampal neuroprotection in post-traumatic brain injury: A systematic review","authors":"Farhan Yousaf ,&nbsp;Sean Kao ,&nbsp;Shahid Ishaq ,&nbsp;Shin-Da Lee","doi":"10.1016/j.expneurol.2025.115587","DOIUrl":"10.1016/j.expneurol.2025.115587","url":null,"abstract":"<div><h3>Objective</h3><div>Traumatic brain injury (TBI) induces oxidative stress, neuroinflammation, programmed cell death, mitochondrial dysfunction, impaired neurotrophic signaling, and neurogenesis, contributing to hippocampal dysfunction. Exercise training is a promising non-pharmacological intervention with potential neuroprotective effects. This systematic review aimed to evaluate the effectiveness of exercise training on the neurobiological mechanisms and cognitive function post-TBI.</div></div><div><h3>Methods</h3><div>PubMed, Embase, and Web of Science were searched up to July 2025, following the PRISMA 2020 guidelines. Of 1855 records, 44 studies involving post-TBI animals and exercise training as intervention were included. Exercise protocols varied, including voluntary wheel running, treadmill running, and swimming, with durations ranging from 7 to 94 days, and 4–7 sessions per week. The quality of included studies was appraised on the CAMARADES checklist.</div></div><div><h3>Results</h3><div>Exercise training reduced hippocampal reactive oxygen species (ROS), microglial reactivity, pro-inflammatory cytokines, and caspase-3 activity, while increasing total antioxidant capacity (TAC) and anti-apoptotic markers in post-TBI rodents. It elevated PGC-1α, electron transport system activity, BDNF, TrkB, and Synapsin-1 expression, and promoted neurogenesis post-TBI. Functionally, exercise improved cognitive function, spatial learning, and memory, and reduced anxiety and depression-like behaviors in post-TBI rodents.</div></div><div><h3>Conclusion</h3><div>Exercise training reduced oxidative stress, neuroinflammation, apoptosis, and enhanced mitochondrial function, neurotrophic signaling, neurogenesis, and cognitive function in post-TBI rodents. (PROSPERO: CRD420251072276).</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115587"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707905","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":"Exploring the roles of AKR1C1, AKR1C2, and AKR1C3 in the nervous system: Mechanisms and perspectives","authors":"Xinyi Chen ,&nbsp;Lu Gan ,&nbsp;Yunfei Huang ,&nbsp;Shu hua Wei ,&nbsp;Wenhao Wang ,&nbsp;Ying Huang","doi":"10.1016/j.expneurol.2025.115580","DOIUrl":"10.1016/j.expneurol.2025.115580","url":null,"abstract":"<div><div>Aldo-keto reductase 1C (AKR1C) enzymes, including AKR1C1, AKR1C2, and AKR1C3, play crucial roles in the metabolism of steroid hormones and prostaglandins through their catalytic activities. Although their functions have been extensively studied in endocrine tissues and hormone-dependent malignancies, their significance in the nervous system remains underexplored. Emerging evidence suggests that AKR1C enzymes regulate neurosteroid homeostasis, modulate GABAergic neurotransmission, support synaptic plasticity, and participate in cellular defense against oxidative stress. These multifaceted activities implicate AKR1C1–C3 in diverse neural processes, including neuroprotection, emotional regulation, and neurodevelopment. Furthermore, the potential involvement of AKR1C1, AKR1C2, and AKR1C3 in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease suggests their possible therapeutic relevance. This review consolidates current findings on the molecular characteristics, brain region-specific expression, and neurophysiological functions of AKR1C enzymes, and discusses their emerging roles in central nervous system disorders. By presenting these insights, this review offers a valuable framework for researchers to explore new directions in the development of neuroprotective and neuroregenerative strategies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115580"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695968","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":"Azeliragon attenuates cerebral infarction aggravation in diabetic rats: Receptor for advanced glycation end-product as a novel therapeutic target","authors":"Jin Soo Lee ,&nbsp;Bok Seon Yoon ,&nbsp;Seong-Joon Lee ,&nbsp;So Young Park ,&nbsp;Eun Hye Joe ,&nbsp;Young J. Oh ,&nbsp;Eui-Ju Choi","doi":"10.1016/j.expneurol.2025.115588","DOIUrl":"10.1016/j.expneurol.2025.115588","url":null,"abstract":"<div><div>Diabetes mellitus contributes to neurological deterioration in acute ischemic stroke; nonetheless, rapid glucose control strategies have proven ineffective in clinical trials. We investigated whether targeting the receptor for advanced glycation end products (RAGE) could prevent infarction worsening in diabetic cerebral ischemia. To generate a diabetic model, streptozotocin (50 mg/kg) was intraperitoneally injected into male Sprague–Dawley rats (7–8 weeks old). A transient 30-min middle cerebral artery occlusion was performed at 34 days after diabetes induction. Azeliragon (10 mg/kg), a RAGE antagonist, was administered as a single intraperitoneal injection immediately after reperfusion. Total infarct volume, neurological severity, and mechanistic analyses were compared between vehicle and azeliragon groups. The 9.4 T animal magnetic resonance imaging analysis demonstrated that total infarct volume was significantly lower in the azeliragon group compared with the vehicle group (125.3 ± 26.2 mm³ vs. 240.5 ± 21.6 mm³; <em>p</em> = 0.003). Additionally, the modified neurological severity scores were significantly lower in the azeliragon group compared with the vehicle group (6.4 ± 1.7 vs. 11.1 ± 0.7; <em>p</em> = 0.012). The neuroprotective effect was consistently observed in a 4-day hyperglycemic model. Mechanistic analyses, including immunohistochemistry and Western blotting, revealed that azeliragon treatment significantly reduced the levels of reactive oxygen species, apoptotic markers, and key inflammatory mediators. Specifically, the phosphorylated to total NF-κB p65 ratio was significantly lower (<em>p</em> = 0.030), along with the levels of tumor necrosis factor-α and interleukin-1β, in the azeliragon group compared with the vehicle group (<em>p</em> &lt; 0.001 for each). Therefore, RAGE antagonism significantly reduced ischemic brain damage and neuroinflammation in diabetic cerebral ischemia, offering a promising therapeutic strategy.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115588"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741808","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":"The phenotypic transformation of astrocytes after AIS can be regulated by microglial GSDMD-mediated pyroptosis","authors":"Yige Zhang ,&nbsp;Yifang Zhou ,&nbsp;Wan Zhang ,&nbsp;Yiwei Qian ,&nbsp;Zixin Chen ,&nbsp;Lulu Pei ,&nbsp;Ding Zhang ,&nbsp;Wanxuan Cheng ,&nbsp;Mengke Tian ,&nbsp;Ce Zong ,&nbsp;Xin Wang ,&nbsp;Yamin Wang ,&nbsp;Jiaxin Wang ,&nbsp;MingMing Ning ,&nbsp;Jun Tan ,&nbsp;Zongping Xia ,&nbsp;Yuming Xu ,&nbsp;Yuan Cao ,&nbsp;Bo Song","doi":"10.1016/j.expneurol.2025.115595","DOIUrl":"10.1016/j.expneurol.2025.115595","url":null,"abstract":"<div><h3>Background</h3><div>Microglial pyroptosis contributes to the pathogenesis of ischemic stroke through multiple pathways. However, it is unclear how it contributes to the phenotype switching of neuroinflammatory/ neuroprotective astrocytes.</div></div><div><h3>Methods</h3><div>This study established a mouse MCAO model and utilized microglial <em>Gsdmd</em> gene knockout mice to examine neuroinflammatory/neuroprotective astrocyte-related protein expression, infarct volume, mNSS scores, and other metrics. Additionally, a transwell co-culture model of microglia and astrocytes was constructed, followed by treatment with IL-1β, pyroptosis inhibitor DSF, and IL-1R1 inhibitor IL-1RA.</div></div><div><h3>Results</h3><div>The findings confirm that microglial GSDMD protein-mediated pyroptosis influences the phenotypic transformation of neuroinflammatory/neuroprotective astrocytes. Specifically, GSDMD-mediated pyroptosis in microglia releases IL-1β, which binds to the IL-1R1 receptor, reversing neuroinflammatory / neuroprotective astrocyte polarization.</div></div><div><h3>Conclusion</h3><div>This mechanism improves AIS prognosis and may serve as a promising therapeutic candidate in AIS.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115595"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751907","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":"Axon guidance deficits in a human sensory-like neuron model of Fabry disease","authors":"Christoph Erbacher ,&nbsp;Aneeta Andrews ,&nbsp;Till Sauerwein ,&nbsp;Maximilian Breyer ,&nbsp;Panagiota Arampatzi ,&nbsp;Maximilian Koch ,&nbsp;Stephanie Lamer ,&nbsp;Tom Gräfenhan ,&nbsp;Andreas Schlosser ,&nbsp;Nurcan Üçeyler","doi":"10.1016/j.expneurol.2025.115564","DOIUrl":"10.1016/j.expneurol.2025.115564","url":null,"abstract":"<div><div>Fabry disease (FD) is a rare genetic galactosidase alpha (<em>GLA</em>) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health-related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic <em>GLA</em> knockout line (p.S364del, hemizygous) and its healthy control into sensory-like neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5 A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory neuron model, with potential implications for early central and peripheral innervation in small fiber neuropathy.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115564"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581900","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":"Excitation–inhibition imbalance as a common thread linking early Alzheimer's disease with temporal lobe epilepsy","authors":"Nwife Getrude Okechukwu ,&nbsp;Claudio Zaccone ,&nbsp;Livia La Barbera ,&nbsp;Annalisa Nobili ,&nbsp;Marcello D'Amelio","doi":"10.1016/j.expneurol.2025.115581","DOIUrl":"10.1016/j.expneurol.2025.115581","url":null,"abstract":"<div><div>Growing evidence suggests that network hyperexcitability is a pivotal yet under-recognized pathology linking early Alzheimer's disease (AD) with mesial Temporal Lobe Epilepsy (mTLE). This narrative review synthesises pre-clinical and clinical data showing how disruption of excitation–inhibition balance, driven chiefly by the loss or dysfunction of parvalbumin- and somatostatin-positive GABAergic interneurons (INs), emerges early in AD and fosters subclinical epileptiform activity that hastens cognitive decline. We integrate findings that degeneration of Ventral Tegmental Area dopaminergic projections further destabilises hippocampal circuits by diminishing D2-mediated restraint of pyramidal firing and attenuating anti-inflammatory signalling. Convergent co-pathologies, soluble amyloid-β oligomers, tau mis-localisation, glutamate-dependent excitotoxicity and glia-mediated neuroinflammation amplify IN vulnerability and form a self-reinforcing loop of hyperexcitability, plasticity failure and neurodegeneration. Parallels with mTLE, where similar IN and dopaminergic deficits precipitate seizures, provide a mechanistic framework for interpreting EEG abnormalities and seizure susceptibility in prodromal AD. We critically appraise the therapeutic potential of interventions that restore excitation–inhibition balance or neuromodulatory tone, including interneuron-sparing agents, selective D2-like agonists, transcranial stimulation and anti-inflammatory or anti-excitotoxic strategies. By viewing early AD through a circuit-centric lens that bridges neurodegeneration and Epilepsy, we highlight testable biomarkers, propose stage-specific targets and argue that timely suppression of hyperexcitability could slow progression far upstream of irreversible neuronal loss. Such precision approaches may redefine disease modification by stabilizing vulnerable hippocampal networks before cognitive function is irrevocably compromised.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115581"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654157","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":"Amelioration of transcriptional disturbances in female BACHD rats by environmental enrichment","authors":"A. Kilzheimer ,&nbsp;T. Hentrich ,&nbsp;A. Novati ,&nbsp;H. Nguyen ,&nbsp;Z. Wassouf ,&nbsp;J.M. Schulze-Hentrich","doi":"10.1016/j.expneurol.2025.115561","DOIUrl":"10.1016/j.expneurol.2025.115561","url":null,"abstract":"<div><div>Huntington's disease is a devastating neuropsychiatric hereditary illness. While progressive in nature, there is evidence suggesting the disease can be positively modified through lifestyle changes. The influence of putative protective factors can be modelled in animal models by enriched environments. As of today, there is a wide array of different implementations of environmental enrichment with little comparative information regarding their respective effects. Aiming to better understand the connection between environmental stimulation and disease progression, we examined behavioural and striatal gene expression changes in female BACHD transgenic rats exposed to either a standard environment or one of two environmental enrichment protocols differing in temporal onset. Our results show striking transgenic effects on phenotype and gene expression. Both glial and neuronal functions and cellular pathways were affected. When exposed to environmental enrichment, both protocols markedly reduced striatal dysregulation, yet some differences were observed between the two designs, thus inviting future studies to further examine the differential effects of specific paradigms. Our findings highlight the promising potential of lifestyle interventions to lighten disease burden of patients and improving their quality of life.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115561"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556602","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":"Alpha 7 nicotinic acetylcholine receptor contributes to long-term cognitive recovery following ischemic stroke","authors":"Dustin T. Nguyen ,&nbsp;Kate Mendoza ,&nbsp;Cassandra Hall,&nbsp;Chunfeng Tan,&nbsp;Anjali Chauhan","doi":"10.1016/j.expneurol.2025.115562","DOIUrl":"10.1016/j.expneurol.2025.115562","url":null,"abstract":"<div><div>Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n⁰KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance was assessed by novel object recognition (day 10), object location (day 20), and Barnes maze and open field testing (day 28). Mass spectrometry at 24 h quantified brain ACh. Flow cytometry at 24 h, 7 days, and 30 days measured microglial and brain F4/80 macrophages. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. WT mice showed reduced ipsilateral ACh and α7nAChR⁺ microglia with increased TNF-α versus sham. Compared with WT, α7n⁰KO mice exhibited greater myeloid infiltration at 24 h, fewer IL-6⁺microglia and F4/80⁺macrophages with impaired STAT3/SOCS3 signaling at day 7, and by day 30, reduced reparative microglia, fewer F4/80⁺ macrophages, greater tissue loss, demyelination, gliosis, reduced SVZ neurogenesis, and impaired cognitive recovery. GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115562"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573036","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}