Cellular and Molecular Neurobiology最新文献

{"title":"C1-esterase Inhibitor Treatment is Associated with Immune and Vascular Pathway Modulation in PASC with Neurological Symptoms: Longitudinal Plasma Proteomics.","authors":"Noga Orr, Maureen Collins, Shawn Novak, Isaac Melamed, Lawrence Steinman","doi":"10.1007/s10571-026-01736-4","DOIUrl":"10.1007/s10571-026-01736-4","url":null,"abstract":"<p><p>Post-acute sequelae of SARS-CoV-2 infection (PASC), particularly neurological manifestations, remain a significant therapeutic challenge, likely driven by persistent inflammation, immune dysregulation, and endothelial dysfunction. In a randomized, double-blind, placebo-controlled crossover trial, 10 patients with post-COVID-19 neurological symptoms received C1-esterase inhibitor (C1-INH; RUCONEST^®) or placebo over two eight-week phases. Longitudinal plasma proteomics (SomaScan^®) profiled molecular dynamics during and after C1-INH treatment. C1-INH administration was associated with distinct, phase-specific proteomic signatures, including lower levels of inflammatory-associated proteins such as CRP and IL-6, increased levels of neuroimmune and endothelial repair proteins (Neuropilin-2, CD83, C1QTNF5), and modulation of bradykinin-kinin and extracellular matrix pathways. These molecular shifts were evaluated in relation to clinical change scores during the active treatment windows. Several proteomic changes were observed at timepoint 26 after treatment cessation, describing candidate post-treatment molecular trajectories. In conclusion, these results provide exploratory mechanistic insights and support the need for validation in larger, prospective cohorts. Together, these findings prioritize immune and vascular pathways for further investigation in PASC and may have relevance to other post-infectious neuroimmune conditions.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13357479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Expression Analysis of Mitochondria-Associated Membrane (MAM)-Related Genes in ER Stress and Alzheimer's Disease.","authors":"A Anjana Mohan, Priti Talwar","doi":"10.1007/s10571-026-01726-6","DOIUrl":"10.1007/s10571-026-01726-6","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is a devastating neurodegenerative disease, strongly linked to cellular stress originating from the accumulation of the Amyloid-beta (Aβ) peptide and phosphorylated tau protein. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) are reported as early events in the AD pathology. Mitochondria-Associated Membrane (MAM) is a proteinaceous tethering between the ER and mitochondria that plays a role in regulating ER stress and related responses. A high level of ER-mitochondria tethering, thereby mitochondrial Calcium (Ca²⁺) overload and cell death, has been reported in AD brain cells. Despite the independent recognition of these pathways, a precise mechanism that integrates MAM activity, ER stress response, and AD pathogenesis remains elusive. We used three transcriptomic datasets collected from the NCBI-Gene Expression Omnibus (GEO) database, which deal with AD, ER stress, and MAM, and processed them with a multi-layered bioinformatics approach combining differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), protein interaction network construction, and identification of hub genes using different cytoHubba topological algorithms. Four hub genes, namely Calreticulin (CALR), Calnexin (CANX), Heat Shock Protein 90 Beta Family Member 1 (HSP90B1), and Valosin-Containing Protein (VCP), were identified. CALR, CANX, and HSP90B1 are known chaperones that regulate proteostasis. VCP is an ER ATPase that induces autophagy. These genes are not only associated with MAM regulation and ER stress but also with AD pathology. The results suggest hub genes as a new set of biomarkers and the likely existence of a 'three-component system' among MAM, ER stress, and Neurodegeneration. The study highlights the potential of MAM-related genes as therapeutic targets of AD.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic Accumulation at the Choroid Plexus Attachment Region.","authors":"Katerina Manzhula, Theresa Greiner, Louise Baumann, Hannes Kaddatz, Vladislav Yakimov, Marcus Frank, Björn Schneider, Markus Kipp, Sarah Joost","doi":"10.1007/s10571-026-01742-6","DOIUrl":"10.1007/s10571-026-01742-6","url":null,"abstract":"<p><p>Immune cell entry into the central nervous system (CNS) under neuroinflammatory conditions is commonly discussed in relation to established barrier interfaces, including the blood-brain barrier and the choroid plexus epithelium. In addition, an alternative anatomical route at the choroid plexus attachment region has been proposed, yet its structural organization remains poorly defined. Here, we provide a detailed descriptive analysis of the choroid plexus attachment region and identify glial structures reminiscent of a glia limitans. We analyzed the morphology of the choroid plexus attachment region in control mice using immunohistochemical and ultrastructural techniques. Immune cell accumulation under neuroinflammatory conditions was examined in the CupEAE mouse model, and human post-mortem sections were analyzed for comparative insights. Our results show that the murine choroid plexus attachment region contains an astrocytic accumulation in close proximity to a continuous basal lamina facing the choroid plexus stroma. Ultrastructural analyses indicate the presence of components associated with junctional complexes. In the CupEAE model, CD3-positive immune cells were more frequently observed in the choroid plexus base than in the brain parenchyma adjacent to the attachment region. In humans, choroid plexus attachment regions also exhibit astrocytic accumulation, though with a different basal lamina pattern. These results underline the complex organization of the choroid plexus attachment region. This anatomical description might be the basis for further studies to evaluate the relevance of the choroid plexus attachment region in immune cell migration to the brain parenchyma.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Serotonin in Brain Development: From Molecular Pathways to Neurodevelopmental Risk.","authors":"Wing Ki Chan, Sofia Rasmusson, Seyedeh Marziyeh Jabbari Shiadeh, Rebecka Wilhelmsson, Maria E Johansson, Betina Elfving, Heidi Kaastrup Müller, Carina Mallard, Maryam Ardalan","doi":"10.1007/s10571-026-01746-2","DOIUrl":"10.1007/s10571-026-01746-2","url":null,"abstract":"<p><p>Serotonin (5-hydroxytryptamine, 5-HT) is a multifaceted neuromodulator involved in processes from early embryogenesis to postnatal brain maturation. During pregnancy, 5-HT plays critical roles not only in maternal mood and behavior but also in placental function and fetal brain development. Beyond its classical role in mood regulation, 5-HT acts as a developmental signal influencing neuronal proliferation, migration, and synaptic organization within precisely timed critical windows. This narrative review provides an integrative framework linking molecular, cellular, and systems-level 5-HT mechanisms to neurodevelopmental outcomes, emphasizing how maternal, placental, and fetal sources of 5-HT dynamically interact with genetic, environmental, and pharmacological factors during gestation. By considering recent advances from developmental neurobiology, genetics, and psychopharmacology, we propose that disrupted 5-HTergic homeostasis represents a convergent mechanism underlying neurodevelopmental risk, particularly in autism spectrum disorder (ASD). We further highlight emerging evidence for sex-dependent 5-HTergic signaling and its role in differential susceptibility across offspring. These results collectively indicate the key role of 5-HT in neurodevelopment and highlight its promise as a biomarker and therapeutic target in neurodevelopmental disorders.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adapted Smart-seq3xpress Facilitates Selective Microglial Transcriptomic Profiling From Frozen Brain Tissue.","authors":"Dominika Dostalova, Pavel Abaffy, Eva Rohlova, Jan Kriska, Tomas Knotek, Jana Tureckova, Denisa Kirdajova, Miroslava Anderova, Lukas Valihrach","doi":"10.1007/s10571-026-01743-5","DOIUrl":"10.1007/s10571-026-01743-5","url":null,"abstract":"<p><p>Single-cell transcriptomics has revealed the central role of microglia in brain development, homeostasis, and disease, particularly in the context of neuroinflammation. While single-cell RNA-sequencing enables targeted microglial analysis from fresh tissue, studying these cells in cryopreserved or archival samples remains challenging due to the lack of a protocol for their specific enrichment and RNA-sequencing. In this study, we developed a method for profiling microglial nuclei from fresh-frozen tissue using Smart-seq3xpress. This approach relies on PU.1-based enrichment, made possible by a brief formaldehyde fixation step to preserve the antigen. To ensure compatibility with Smart-seq3xpress, we utilized a Thermolabile Proteinase K treatment to reverse cross-links, thereby maintaining high transcriptomic sensitivity. We benchmarked the method in a mouse model of ischemic stroke, evaluating both technical performance and its ability to capture biologically meaningful microglial states. Compared to standard single-nucleus protocols, our approach yielded higher gene and UMI counts and a greater proportion of coding reads. Transcriptomic profiles closely matched those from whole-cell RNA-sequencing, including the detection of activation markers and diverse microglial subpopulations. This approach enables high-resolution transcriptomic analysis of microglia from fresh-frozen or archival brain samples, overcoming major limitations of single-nucleus RNA sequencing. It broadens access to cellular insights from biobanked material, supporting both basic research and translational studies of neuroinflammatory disease.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13357468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147940057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fecal miRNome and Proteome Profiling Uncovers Stage-Specific Biomarkers of Alzheimer's Disease in 3×Tg-AD Mice.","authors":"Roberta Vitali, Barbara Tanno, Arianna Casciati, Francesca Palone, Luisa Pieroni, Marta Morotti, Massimo Santoro, Emiliano Fratini, Simonetta Pazzaglia, Maria Vittoria Podda, Mariateresa Mancuso","doi":"10.1007/s10571-026-01735-5","DOIUrl":"10.1007/s10571-026-01735-5","url":null,"abstract":"<p><p>Reliable, minimally invasive biomarkers for Alzheimer's disease (AD) remain a critical unmet need. Considering mounting evidence for gut-brain interactions in AD, we explored whether fecal samples contain host-derived molecular signals that reflect disease-related changes and could serve as accessible biomarkers. Fecal small RNA sequencing and quantitative proteomics were performed in symptomatic 15-month-old 3×Tg-AD mice and controls. Pathway and network analyses identified key dysregulated molecules. Selected miRNAs and proteins were validated by qPCR or Western blotting in independent pre-symptomatic, early symptomatic, and severe cohorts. To assess whether fecal signals mirrored tissue alterations, colon samples were analyzed for tight-junction proteins, inflammatory markers, epigenetic regulation, and expression of selected miRNAs and proteins. Multi-omics identified 31 miRNAs and 81 proteins modulated in AD fecal sample, revealing a distinct AD-associated fecal signature involving pathways linked to neuroinflammation, synaptic dysfunction, vascular imbalance, and metabolism. Several miRNAs- including miR-322-5p, miR-194-1 and miR-223-3p were significantly altered and validated across disease stages (3-,7-,15-old months mice, respectively). Notably, miR-146b-5p expression is inversely correlated with AD severity, exhibiting a stepwise decline from asymptomatic individuals to those with mild and severe stages. IgKappa and Ela3B emerged as the strongest protein candidates, showing opposite and progressive modulation. Notably, IgKappa and miR-146b showed the most consistent trajectories. Colon analyses uncovered reduced Claudin-7, strong IgKappa upregulation driven by enhancer hypomethylation, and partial overlap between fecal and tissue miRNA profiles, indicating that fecal signals reflect subtle epithelial and immune perturbations associated with AD. Multi-omics at severe stage and a stage specific validation support fecal miRNAs and proteins as promising, host-derived biomarkers for AD. Fecal profiling offers a practical, repeatable, and low-cost approach with translational potential for early detection and longitudinal monitoring in neurodegeneration.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic-Environmental Programming of Microglial Identity: Shaping Spatiotemporal Dynamics in Neurodevelopment and Neurodevelopmental Diseases.","authors":"YanXiang Zhang, Mengxuan Yang, Simin Yang, Sheng Zhang","doi":"10.1007/s10571-026-01741-7","DOIUrl":"10.1007/s10571-026-01741-7","url":null,"abstract":"<p><p>Microglia, the resident immune cells of the central nervous system, have emerged as dynamic architects of brain development and homeostasis. Here, we propose a unifying framework of \"Genetic-Environmental Programming\" to explain how microglial identity emerges through the bidirectional convergence of lineage-intrinsic factors and spatiotemporally patterned extrinsic signals. This programming process operates through three core principles. First, lineage-determining transcription factors (PU.1, IRF8, RUNX1) establish chromatin accessibility landscapes that confer responsiveness to environmental cues. Second, brain-derived trophic factors (CSF1, IL-34, TGF-β) and peripheral inputs (microbiota metabolites, adaptive immune signals) stabilize or redirect these intrinsic programs through cooperative transcriptional complexes-notably, TGF-β signaling through SMADs converges with the microglia-specific transcription factor SALL1 to sustain homeostatic identity. Third, programming outcomes are state-dependent, with early configurations constraining but not absolutely determining later states. This framework enables context-specific microglial specialization for neurodevelopmental tasks while maintaining developmental plasticity. Importantly, this programming is vulnerable during sensitive developmental windows; environmental insults-including maternal immune activation, prenatal stress, and postnatal inflammation-can disrupt normal programming through lasting epigenetic modifications, impairing microglial immune and synaptic functions. Such misprogramming establishes a developmentally encoded vulnerability to neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and schizophrenia. Understanding microglial identity as a programmed continuum-rather than a predetermined fate-shifts therapeutic strategies from broad immunomodulation toward precise reprogramming of developmental checkpoints.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cycloastragenol Protects Against Cisplatin-Induced Cochlear Hair Cell Apoptosis via the PI3K/Akt/mTOR Pathway.","authors":"Tan Wang, Zhemeng Chen, Daquan Wu, Zhengjie Zhu, Kanglun Jiang, Li Gao, Tianyu Gong, Jingrong Lv, Xinsheng Huang","doi":"10.1007/s10571-026-01737-3","DOIUrl":"10.1007/s10571-026-01737-3","url":null,"abstract":"<p><strong>Conclusion: </strong>Cycloastragenol protects cochlear hair cells against cisplatin-induced ototoxicity by preserving mitochondrial function, suppressing apoptosis, and activating the PI3K/Akt/mTOR signaling pathway. These findings highlight the potential of CAG as a therapeutic candidate for preventing cisplatin-induced hearing loss.</p><p><strong>Results: </strong>CAG significantly improved cell viability and reduced cisplatin-induced apoptosis in cochlear hair cells, as demonstrated by decreased TUNEL positivity, reduced apoptotic rates, and modulation of apoptosis-related proteins. CAG also preserved hair-cell marker expression and maintained cochlear hair-cell morphology. Furthermore, CAG restored mitochondrial function by increasing ATP production, maintaining ΔΨm, reducing ROS accumulation, and enhancing respiratory chain complex activities, while preventing mitochondrial fragmentation. In vivo, CAG markedly attenuated cisplatin-induced hearing loss, as indicated by improved ABR thresholds. Mechanistically, CAG activated the PI3K/Akt/mTOR signaling pathway, and inhibition of this pathway abolished its protective effects.</p><p><strong>Background: </strong>Cisplatin-induced ototoxicity, a major adverse effect of chemotherapy, results in irreversible sensorineural hearing loss primarily due to apoptotic loss of cochlear sensory hair cells. Cycloastragenol (CAG), a naturally occurring triterpenoid saponin derived from Astragalus, possesses antioxidant and anti-apoptotic properties. However, its potential protective effects against cisplatin-induced cochlear injury and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>HEI-OC1 cells, cochlear explant cultures (including the ex vivo cochlear explant model), and a mouse model were used to evaluate the protective effects of CAG against cisplatin-induced ototoxicity. Cell viability was assessed using the CCK-8 assay, while apoptosis was evaluated by TUNEL staining, flow cytometry, and Western blotting of apoptosis-related proteins. Hair-cell markers (Myo7a and Prestin) and cochlear hair-cell morphology were examined by immunofluorescence staining. Mitochondrial function was assessed by measuring ATP levels, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), and respiratory chain complex activities, along with mitochondrial morphology analysis using immunofluorescence and transmission electron microscopy. Auditory function in mice was evaluated by auditory brainstem response (ABR) measurements. The involvement of the PI3K/Akt/mTOR pathway was analyzed by Western blotting and inhibition assays using the PI3K inhibitor LY294002.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal Cord Stimulation Alleviates Neuropathic Pain Involves Regulation of the Ca²⁺/CaN/NFAT4 Pathway in Spinal Dorsal Horn Astrocytes.","authors":"Xiangmiao Li, Zhen Wu, Rongrong Wang, Jinzhu Bai","doi":"10.1007/s10571-026-01739-1","DOIUrl":"10.1007/s10571-026-01739-1","url":null,"abstract":"<p><p>Spinal cord stimulation (SCS) represents an established neuromodulatory intervention for refractory neuropathic pain (NP), yet the cellular mechanisms underlying its anti-inflammatory effects remain incompletely defined. The activation of astrocytes, especially polarization into the A1-like phenotype, is crucial for the persistence of central sensitization. This study aimed to investigate whether the analgesic effects of SCS are associated with modulation of astrocyte activation and calcium ions (Ca²⁺) / calcineurin (CaN) / nuclear factors of activated T cells 4 (NFAT4) pathway signaling in the spinal dorsal horn. In a rat model of chronic constriction injury (CCI), the present study found that SCS significantly ameliorated mechanical allodynia and reduced spinal levels of proinflammatory cytokines. Furthermore, SCS suppressed spinal dorsal horn astrocyte activation and attenuated their polarization toward the A1-like phenotype. In association with these changes, SCS reduced CCI-induced spinal Ca²⁺ elevation, downregulated CaN and NFAT4 expression, and decreased NFAT4 nuclear translocation. In vitro experiments further demonstrated that inhibition of CaN or NFAT4 similarly attenuated astrocyte activation, A1-like polarization, and proinflammatory cytokine release. The findings suggest that the analgesic effect of SCS in NP is associated with suppression of Ca²⁺/CaN/NFAT4 pathway signaling and attenuation of neurotoxic A1-like astrocyte polarization and neuroinflammation. This study supports the involvement of an astrocyte-related Ca²⁺/CaN/NFAT4 signaling axis in the biological effects of SCS and provides a potential therapeutic target for improving neuromodulation-based pain management. Graphical Abstract. Spinal cord stimulation alleviates neuropathic pain and is associated with reduced Ca²⁺/CaN/NFAT4 pathway signaling, astrocyte activation, and A1-like polarization in the spinal dorsal horn. Spinal cord stimulation reverses the activation of the Ca²⁺/CaN/NFAT4 signaling pathway in spinal dorsal horn caused by peripheral nerve injury, thereby inhibiting NFAT4 nuclear translocation. This suppresses A1-like astrocyte polarization and proinflammatory cytokine release, alleviating neuropathic pain.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optogenetic Strategies for Motor Recovery After Ischemic Stroke: Mechanisms and Therapeutic Implications.","authors":"Ping-Xuan Shen, Pei Wang, Hong-Xing Wang","doi":"10.1007/s10571-026-01740-8","DOIUrl":"10.1007/s10571-026-01740-8","url":null,"abstract":"<p><p>Ischemic stroke frequently results in persistent motor impairment, which highlights the need for effective strategies for neural repair. Functional recovery relies fundamentally on neurobehavioral remodeling, yet traditional physical and electrical stimulation therapies often lack the necessary cell-type and spatial specificity. Optogenetics overcomes these limitations by enabling the selective activation or inhibition of specific neuronal subpopulations with millisecond-level spatiotemporal precision, offering a powerful approach to modulate post-injury plasticity. This review synthesizes recent evidence regarding optogenetic interventions for motor rehabilitation in rodent models of ischemic stroke. We detail the multi-level neurobiological mechanisms that drive functional recovery. At the molecular and cellular levels, targeted optical stimulation enhances neurotrophic factor secretion, regulates neurovascular coupling, and modulates glial cell plasticity to create a reparative microenvironment. Circuit-level analysis demonstrates that specific stimulation protocols promote corticospinal tract remodeling and restore the balance of interhemispheric inhibition. Furthermore, modulation of whole-brain network dynamics, particularly the restoration of gamma oscillation rhythmicity, plays a critical role in coordinating motor output and reducing secondary injury. Optogenetics provides crucial mechanistic insights into the neural substrates of stroke recovery. These findings offer a theoretical basis for optimizing parameter selection in existing brain stimulation therapies. While clinical translation faces challenges related to viral vector safety and deep-brain light delivery, precise neuromodulation represents a promising frontier for restoring motor function after cerebral ischemia.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}