CNS Neuroscience & Therapeutics最新文献

{"title":"Modulation of Endoplasmic Reticulum Stress via CEBPB: A Potential Molecular Link to Therapeutic Action in Substance Use Disorders","authors":"Cheng Zhang,&nbsp;Hu Li,&nbsp;Ming-Fen Ho","doi":"10.1002/cns.71183","DOIUrl":"https://doi.org/10.1002/cns.71183","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Opioid use disorder remains a major public health crisis in the United States, driven largely by rising overdose deaths from synthetic opioids, such as fentanyl. Emerging population-level evidence suggests that GLP-1 receptor agonists (GLP-1RAs) may reduce overdose risk. However, their underlying molecular mechanisms are not well understood. We investigated the transcriptional effects of fentanyl and GLP-1RAs using human induced pluripotent stem cell (iPSC)-derived forebrain organoids and neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Organoids were treated with fentanyl, liraglutide, or exenatide, followed by RNA sequencing. We extended these analyses to iPSC-derived neurons exposed to additional therapeutic candidates, including the anticonvulsants topiramate and gabapentin, and the metabolic modulator β-hydroxybutyrate. All compounds were tested at clinically relevant concentrations, and transcriptomic and functional genomic assays were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Across models and drug classes, we identified modulation of endoplasmic reticulum (ER) stress signaling as a shared molecular mechanism. Fentanyl and GLP-1RAs consistently downregulated ER stress-related genes, with TRIB3 as the most strongly suppressed target. We further identified CEBPB as a key upstream regulator and confirmed reduced CEBPB DNA-binding activity in ER stress-related genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight ER stress modulation as a convergent pathway with potential therapeutic relevance for substance use disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Method for Obtaining Patient-Derived Glioblastoma Organoid and Primary Cells: A Generic and Simplified Approach for Intracranial Tumor With Minimized Input","authors":"Siyuan Wang,&nbsp;Zhonggang Shi,&nbsp;Chihao Zhu,&nbsp;Dawei Dai,&nbsp;Xi Yang,&nbsp;Zhiyi Zhou,&nbsp;Qianying Qiu,&nbsp;Wenhua Sun,&nbsp;Yifeng Miao,&nbsp;Yongming Qiu","doi":"10.1002/cns.71024","DOIUrl":"https://doi.org/10.1002/cns.71024","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Glioblastoma is one of the most malignant primary tumors in adults. The shortages of the traditional tumor models obstruct the development of basic research and therapeutic modes. Application of organoid is critical to keep tumoral heterogeneity and microenvironment. The current method for generating glioblastoma organoid is sophisticated, laborious, and inconvenient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We collected glioblastoma tissue samples from patients and used an improved methodology to generate organoids. Subsequently, the collected suspension during the process was used to isolate primary tumor cells. Organoid were used to assess its drug susceptibility. Finally, we generated organoids of other CNS tumors with the same method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The improved method took less time and lowered technical requirements. Glioblastoma organoids generated with our improved method can be cultured for further research. Primary glioblastoma cells isolated from collected medium were proved with immunofluorescence. Patient-derived glioblastoma organoids showed consistent drug susceptibility with the patients. Tumor organoids were also generated successfully from patient's lymphoma and low-grade glioma samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We improved an easier and rapider method to generate glioma organoids from tissue samples and avoided wasting primary tumor cells in used medium. This method established a technical foundation for the widely application of organoids in neuro-oncology tumor research and clinical decision-making.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breath Signatures of Antiseizure Medication Response and Tolerability in Adults With Epilepsy","authors":"Kai Fricke,&nbsp;Diego Manuel Baur,&nbsp;Kapil Dev Singh,&nbsp;Felix Schmidt,&nbsp;Kathrin Müsch,&nbsp;Noriane Andrina Sievi,&nbsp;Marco Di Donato,&nbsp;Anton Schmick,&nbsp;Silvia Ulrich,&nbsp;Pablo Sinues,&nbsp;Marian Galovic,&nbsp;Malcolm Kohler","doi":"10.1002/cns.71169","DOIUrl":"https://doi.org/10.1002/cns.71169","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Achieving seizure control without intolerable adverse effects remains a major challenge in adult epilepsy, and serum concentrations of antiseizure medications correlate poorly with clinical outcomes. Metabolic processes influencing treatment response are not captured by blood monitoring. This study evaluates whether exhaled breath metabolomic profiles reflect treatment response and adverse effects in adults receiving antiseizure therapy, using epilepsy as a model for pharmacodynamic phenotyping.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>A single-center observational cohort of 117 adults provided 127 breath samples during stable antiseizure treatment. Exhaled breath samples were analyzed using secondary electrospray ionization high-resolution mass spectrometry. Machine-learning models with nested cross-validation were used to classify treatment response and adverse effects, and pathway-level analyses were performed to provide biological context. Findings were compared with an independent, predominantly pediatric cohort analyzed using the same workflow.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Breath metabolomic profiles distinguished responders from nonresponders and individuals with and without adverse effects, whereas serum drug concentrations showed no meaningful association. Classification models achieved areas under the curve of 0.84 for treatment response and 0.88 for adverse effects, with good calibration. Pathway-level alterations were directionally consistent across cohorts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Breath metabolomics supports a non-invasive approach to pharmacodynamic phenotyping that captures treatment-related metabolic states not reflected by serum drug concentrations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ER Stress Regulates HIV Tat and Alcohol-Induced NLRP6 Activation in Astrocytes","authors":"Seema Singh,&nbsp;Elias Horanieh,&nbsp;Shilpa Buch,&nbsp;Palsamy Periyasamy","doi":"10.1002/cns.71184","DOIUrl":"https://doi.org/10.1002/cns.71184","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Chronic alcohol consumption is common among people living with HIV (PLWH) and exacerbates HIV-associated neurocognitive disorders (HAND). HIV-1 transactivator of transcription (Tat) and ethanol synergistically promote neuroinflammation, but the underlying molecular mechanisms remain unclear. This study aimed to determine whether endoplasmic reticulum (ER) stress regulates astrocytic NLRP6 inflammasome activation in response to HIV Tat and ethanol coexposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mouse primary astrocytes were exposed to HIV Tat (50 ng/mL) and ethanol (50 mM), individually or in combination. Astrocyte activation, NLRP6 inflammasome signaling, proinflammatory cytokine production, and ER stress responses were assessed using western blotting, immunocytochemistry, qPCR, and ELISA. ER stress was inhibited using 4-phenylbutyric acid (4-PBA), and NLRP6 was silenced using siRNA to define pathway hierarchy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Combined HIV Tat and ethanol exposure markedly increased astrocytic activation, NLRP6 expression, caspase-1 cleavage, and IL-1β and IL-18 production compared with individual treatments. Coexposure also significantly induced ER stress markers BiP, ATF6, and phosphorylated eIF2α. Pharmacological inhibition of ER stress suppressed NLRP6 inflammasome activation and astrocytic reactivity, whereas NLRP6 knockdown attenuated inflammatory signaling without affecting ER stress markers, indicating ER stress acts upstream of NLRP6.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings identify an ER stress–NLRP6 inflammasome axis as a potential mechanism underlying HIV Tat and ethanol-induced astrocytic neuroinflammation, providing mechanistic insight into alcohol-associated neuroinflammatory processes relevant to HAND.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction","authors":"Yang Zou,&nbsp;Jun Yang,&nbsp;Yang Li,&nbsp;Guodong Wang,&nbsp;Wen Lu,&nbsp;Xiaoping Chen,&nbsp;Xingxing Ma,&nbsp;Kehan Chen,&nbsp;Peng Liang,&nbsp;Yinghui Wu,&nbsp;Tao Zhuo","doi":"10.1002/cns.71174","DOIUrl":"https://doi.org/10.1002/cns.71174","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Although depression is a potent risk factor for Alzheimer's disease (AD), the underlying causal mechanisms remain unclear. This study investigated the molecular and circuit-level mechanisms linking chronic stress to accelerated AD pathogenesis and evaluated the therapeutic potential of precise mTORC1 targeting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A chronic restraint stress (CRS) paradigm was established in 5xFAD mice. Multi-scale neurofunctional and histopathological alterations were deconstructed using behavioral profiling, wide-field and two-photon calcium imaging, immunofluorescence, and bulk RNA-sequencing. Pharmacological intervention was conducted using the specific mTORC1 inhibitor EN6.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CRS severely impaired cortical slow-wave oscillations and induced aberrant prefrontal single-neuron hyperactivity, exacerbating cognitive decline. These network deficits were accompanied by accelerated AD hallmarks, including elevated Aβ deposition, dystrophic neurite aggravation, and reactive gliosis. Mechanistically, transcriptomic profiling and biochemical validation revealed that chronic stress suppresses autophagic pathways via selective hyperactivation of mTORC1 signaling rather than the AMPK pathway. Time-course analysis showed that mTORC1 activation and autophagy-related abnormalities preceded overt Aβ accumulation, while pharmacological mTOR activation with MHY1485 further aggravated autophagic impairment and increased Aβ42 levels. Crucially, targeted mTORC1 inhibition with EN6 ameliorated autophagy-related abnormalities and was associated with reduced BACE1 abundance and CTFβ generation, together with a diminished global Aβ burden. This microenvironmental stabilization attenuated neuroinflammation, realigned neural networks, and rescued both cognitive and emotional deficits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Chronic stress-induced mTORC1 hyperactivation is associated with autophagic impairment, contributing to macro-circuit desynchronization and accelerated amyloid accumulation. Targeting the mTORC1–autophagy axis represents a potential therapeutic approach to mitigate neural network breakdown and neuropathology in stress-related neurodegenerative conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Multimodal MRI Habitat and Transformer-Based Pathomics to Predict High-Risk Molecular Subtypes and Explore Biological Mechanisms in Adult Diffuse Gliomas","authors":"Wenju Niu,&nbsp;Xin Duan,&nbsp;Xuan Li,&nbsp;Zehui Li,&nbsp;Qian Liang,&nbsp;Xiangli Yang,&nbsp;Yan Tan,&nbsp;Xiaochun Wang,&nbsp;Guoqiang Yang,&nbsp;Hui Zhang","doi":"10.1002/cns.71171","DOIUrl":"https://doi.org/10.1002/cns.71171","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study aims to achieve accurate prediction of high-risk molecular subtypes of gliomas through a cross-scale Combined model, matching the model's classification metrics with patient risk stratification and exploring the underlying biological mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study retrospectively collected preoperative MRI, postoperative whole-slide pathological images, molecular markers, and clinical data from 456 adult diffuse glioma patients. We separately constructed an MRI habitat prediction model, a WSI Transformer-based deep learning pathomics (PDL) model, and a Combined model. A dynamic nomogram web page for predicting high-risk molecular subtypes was developed based on the Combined model. Patients were stratified into risk groups according to the output scores of the Combined model, and Kaplan–Meier survival analysis and the Log-rank test were employed to evaluate survival differences between the groups. Additionally, differential expression and GO/KEGG enrichment analyses were further performed in the test set with available RNA-seq data to explore transcriptional features and biological processes associated with model-based risk stratification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The Combined model demonstrated the highest AUC (Training set: 0.888, Test set: 0.836) compared to the Habitat model (Training set: 0.832, Test set: 0.798) and the PDL model (Training set: 0.852, Test set: 0.821). The high-risk and low-risk groups, stratified based on the cutoff value derived from the Combined model output scores, exhibited significant survival differences. Exploratory transcriptomic analysis showed that differentially expressed genes between the high- and low-risk groups were mainly enriched in biological processes and pathways related to the extracellular matrix and cell–matrix interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The cross-scale Combined model not only enabled identification of high-risk molecular subtypes and risk stratification but also showed associations with biologically relevant transcriptional features.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Anterior Insular Parvalbumin GABAergic Interneurons in Impulsivity-Related and Alcohol-Seeking Behaviors","authors":"F. Bezerra,&nbsp;G. J. D. Fernandes,&nbsp;A. Anjos-Santos,&nbsp;C. A. Favoretto,&nbsp;B. T. Rodolpho,&nbsp;P. Palombo,&nbsp;V. Vialou,&nbsp;K. P. Abrahao,&nbsp;F. C. Cruz","doi":"10.1002/cns.71138","DOIUrl":"https://doi.org/10.1002/cns.71138","url":null,"abstract":"&lt;p&gt;Alcohol use remains one of the most widespread forms of psychoactive substance misuse worldwide and continues to represent a major public health challenge [&lt;span&gt;1-3&lt;/span&gt;]. Alcohol use disorder (AUD) is characterized by compulsive intake, impaired behavioral control, and persistent consumption despite adverse consequences [&lt;span&gt;4-6&lt;/span&gt;]. Importantly, alcohol use often begins during adolescence, a developmental period marked by substantial neurobiological remodeling and heightened vulnerability to maladaptive behaviors [&lt;span&gt;7&lt;/span&gt;]. Adolescence is associated with increased risk-taking, emotional reactivity, and impulsivity, reflected by a preference for immediate rewards and reduced inhibitory control [&lt;span&gt;8-10&lt;/span&gt;]. Exposure to alcohol during this critical window may exacerbate these vulnerabilities, reinforcing reward-driven behaviors and increasing the risk for the development of AUD [&lt;span&gt;11, 12&lt;/span&gt;]. Consistent with this, impulsivity has been strongly associated with the initiation and escalation of alcohol use, with more impulsive adolescents showing a greater likelihood of hazardous drinking later in life [&lt;span&gt;13-16&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;At the neural level, the insular cortex acts as an integrative hub for interoceptive, affective, and cognitive processing, playing a central role in decision-making and behavioral control. Its extensive connectivity with cortical and subcortical regions supports its involvement in impulsivity-related behaviors [&lt;span&gt;17-19&lt;/span&gt;]. Clinical and preclinical evidence indicate that functional alterations in the insular cortex are associated with impulsivity and impaired behavioral regulation [&lt;span&gt;20, 21&lt;/span&gt;]. During adolescence, ongoing structural and functional maturation of the insula has been linked to individual differences in impulsivity, with reduced neuronal excitability in the anterior insula associated with increased impulsive and compulsive behaviors [&lt;span&gt;22-24&lt;/span&gt;]. In contrast, experimental activation of this region has been shown to attenuate such behaviors [&lt;span&gt;25&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The insular cortex has emerged as a critical cortical hub in the regulation of alcohol-related behaviors, integrating interoceptive, emotional, and motivational signals that influence both alcohol consumption and relapse vulnerability [&lt;span&gt;26&lt;/span&gt;]. Growing evidence indicates that the anterior insular cortex, in particular, plays a central role in compulsive alcohol seeking, as pharmacological or chemogenetic manipulations of this region significantly alter the propensity to relapse following punishment-imposed abstinence, highlighting its importance in alcohol seeking, despite adverse consequences [&lt;span&gt;27&lt;/span&gt;]. In parallel, structural adaptations within insular microcircuits have also been implicated in compulsive drinking, as repeated binge-like ethanol exposure increases perineuronal net expression in the insular cortex, and disruption of these extracellular matrix structures reduc","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Metabolic Reprogramming in Glioma: Mechanisms of Tumorigenesis and Implications for Clinical Therapy","authors":"Liangqi Jiang,&nbsp;Mingrui Li,&nbsp;Zhen Li,&nbsp;Qing Liu,&nbsp;Yang Li","doi":"10.1002/cns.71180","DOIUrl":"https://doi.org/10.1002/cns.71180","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gliomas are metabolically heterogeneous tumors in which mitochondria coordinate bioenergetics, biosynthesis, redox homeostasis, stress adaptation, and treatment responses. This review examines mitochondrial dependencies across glioma subtypes and cell states.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We synthesized evidence on mitochondrial integration of glucose, amino acid and protein, lipid, and nucleotide metabolism, together with mitochondrial genetics, signaling, intercellular transfer, and barriers to therapeutic translation in gliomas.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Glioma glucose metabolism does not follow a uniform Warburg phenotype. IDH-mutant gliomas exhibit D-2-hydroxyglutarate-driven metabolic and epigenetic remodeling, whereas IDH-wild-type glioblastomas contain glycolytic, oxidative phosphorylation-enriched, and adaptable stem-like states. Mitochondrial proteostasis links protein import and translation with PI3K/AKT/mTOR signaling, the ubiquitin–proteasome system, autophagy, and mitophagy. Lipid synthesis, storage, fatty acid oxidation, and cardiolipin homeostasis support metabolic adaptation. Electron transport, aspartate availability, redox balance, and dihydroorotate dehydrogenase connect mitochondria with nucleotide synthesis, DNA repair, and treatment resistance. Mitochondrial DNA alterations, mitonuclear signaling, and intercellular mitochondrial transfer further influence respiratory adaptation and tumorigenicity. Metabolic compensation and intratumoral heterogeneity limit single-target therapies, whereas clinical evidence supports genotype-directed intervention, exemplified by vorasidenib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Effective mitochondrial targeting requires biomarkers that match metabolic dependencies to molecular subtypes and cell states while accounting for brain exposure, compensation, and toxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mast Cell–Microglia Crosstalk Drives Aberrant Synaptic Pruning Through PAR-2/MAPK/NF-κB Signaling in Neonatal Hypoxic–Ischemic Encephalopathy","authors":"Yanping Yang,&nbsp;Dingliang Cai,&nbsp;Jingwen Yu,&nbsp;Yixiao Zhu,&nbsp;Yongxin Huang,&nbsp;Yubing Lin,&nbsp;Chengqian Teng,&nbsp;Jianjie Wei,&nbsp;Ying Lin,&nbsp;Dongsheng Dai,&nbsp;Fushan Xue,&nbsp;Andi Chen,&nbsp;Xiaochun Zheng,&nbsp;Xiaohui Chen","doi":"10.1002/cns.71189","DOIUrl":"https://doi.org/10.1002/cns.71189","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Neonatal hypoxic–ischemic encephalopathy (HIE) causes severe neurodevelopmental impairment, but the upstream immune mechanisms that initiate this process remain unclear. We investigated whether mast cell (MC)-derived tryptase contributes to aberrant microglia-mediated synaptic pruning through PAR-2/MAPK/NF-κB signaling after neonatal hypoxic–ischemic (HI) injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A postnatal Day-7 rat HI model was established using the Rice-Vannucci method. MC abundance, c-Kit and tryptase expression, PAR-2/MAPK/NF-κB signaling, and synaptic integrity were assessed using histological, immunofluorescence, biochemical, ultrastructural, and three-dimensional (3D) reconstruction analyses. Microglia-targeted F2rl1 silencing and pharmacological inhibition with FSLLRY-NH2 or APC366 were used to examine PAR-2 and tryptase-related signaling. Complementary oxygen–glucose deprivation/reperfusion (OGD/R) experiments were performed in BV-2 microglia. Cognitive outcomes were assessed using the Morris water maze and Y maze.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HI increased hippocampal MC abundance and tryptase expression, and these changes were associated with acute neurological deficits. HI insult also increased complement associated synaptic labeling, PAR-2/MAPK/NF-κB signaling, CD68 expression, and engulfment of PSD95 positive synaptic material. Microglia-targeted F2rl1 silencing attenuated pathway activation and synaptic engulfment. FSLLRY-NH2 and APC366 similarly reduced HI associated signaling and microglial synaptic engulfment, while APC366 preserved dendritic spine density and synaptic ultrastructure and improved long-term spatial learning and memory. In BV-2 microglial cells, exogenous tryptase enhanced OGD/R associated CD68 expression and MAPK/NF-κB phosphorylation, which were attenuated by F-NH2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>MC-derived tryptase is an upstream contributor to pathological microglial synaptic pruning and cognitive impairment after neonatal HI, potentially involving the PAR-2/MAPK/NF-κB axis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspectives on Human Cingulate Cortex Functional Organization From Cortical Electrical Stimulation Mapping","authors":"Yun Zhuang,&nbsp;Haoyu Wang","doi":"10.1002/cns.71191","DOIUrl":"https://doi.org/10.1002/cns.71191","url":null,"abstract":"&lt;p&gt;We read with great interest the recent article titled “Function of the Human Cingulate Cortex: A Brainnetome Atlas-Based Study via Cortical Electrical Stimulation in Patients with Epilepsy” by Deng and colleagues [&lt;span&gt;1&lt;/span&gt;], in which the authors established a comprehensive functional atlas of the human cingulate cortex using cortical electrical stimulation (CES) in 234 patients by integrating 1141 stimulation sites with the Brainnetome Atlas. The study provides one of the largest systematic characterizations of cingulate functions to date and represents a valuable resource for both cognitive neuroscience and functional neurosurgery. We congratulate the authors on this important contribution. We would like to offer several considerations that may further strengthen future investigations in this field.&lt;/p&gt;&lt;p&gt;A first consideration concerns the developmental trajectory of cingulate functional organization. The authors noted that their cohort included patients with diverse pathologies and a broad age range, and suggested that future studies in more homogeneous adult cohorts may help refine the functional organization of the cingulate cortex [&lt;span&gt;1&lt;/span&gt;]. However, we suggest that the wide age distribution of the present cohort (mean age 20.0 ± 10.2 years) may also provide an opportunity to investigate developmental changes in cingulate functional organization. The cingulate cortex undergoes protracted structural and functional maturation throughout adolescence and early adulthood, with developmental changes in cortical morphology [&lt;span&gt;2&lt;/span&gt;] and functional connectivity [&lt;span&gt;3&lt;/span&gt;]. Moreover, structural changes in the cingulate cortex continue throughout adulthood, with individual subregions showing distinct trajectories of age-related volume decline [&lt;span&gt;4&lt;/span&gt;]. Given that the present cohort spans from late childhood to mid-adulthood, an initial comparison between adolescent (&lt; 18 years) and adult (≥ 18 years) groups could reveal age-related changes in subregional distribution or stimulation thresholds. If sample sizes permit, modeling age as a continuous variable would further capture the progressive nature of cortical maturation. Given the sampling constraints inherent to clinical electrode placement, integration with functional magnetic resonance imaging (fMRI) developmental studies would further strengthen such analyses.&lt;/p&gt;&lt;p&gt;A second consideration concerns the interpretation of variability in cingulate stimulation responses. The authors adopted a group-level analytical approach by aggregating stimulation responses across 1141 sites from 234 patients. As reviewed by Borchers et al. [&lt;span&gt;5&lt;/span&gt;], CES responses reflect complex interactions between local excitability, axonal activation, and network-level propagation, introducing potential sources of variability that may not directly correspond to functional specialization. The large sample size of the present study is therefore a major strength that enables more rel","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 10","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.71191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}