Brain Research Bulletin最新文献

{"title":"Treadmill exercise attenuates CUMS-induced depressive behaviors by modulating the UPRmt via the Nrf2/Keap1 pathway","authors":"Yang Wang ,&nbsp;Mingshi Peng ,&nbsp;Tongxi Zhou ,&nbsp;Juncheng Si ,&nbsp;Yuwen Shangguan ,&nbsp;Jingfeng Wang ,&nbsp;Siyun Lei ,&nbsp;Li Li","doi":"10.1016/j.brainresbull.2026.111738","DOIUrl":"10.1016/j.brainresbull.2026.111738","url":null,"abstract":"<div><h3>Introduction</h3><div>Depression is a very common brain disorder worldwide. It is associated with damaging behaviors such as self-harm and suicide that hurt the brain and body. Mitochondrial dysfunction and dysregulation of the mitochondrial unfolded protein response (UPRmt) are increasingly seen as playing a key role in chronic stress-induced pathophysiology of depression. Aerobic exercise is a very effective non-pharmacological intervention, however, the specific mechanisms of how it modifies hippocampal UPRmt is poorly understood. This effect may be attributed to the Nrf2/Keap1 pathway, a master regulator of cellular antioxidant defense that mediates exercise-induced neuroprotection. This study aimed to investigate whether treadmill exercise modulates UPRmt dysregulation in CUMS-induced depressive mice by activating the hippocampal Nrf2/Keap1 signaling pathway, thereby ameliorating mitochondrial dysfunction and depression-like behaviors.</div></div><div><h3>Methods</h3><div>Male C57BL/6 J mice were subjected to a chronic unpredictable model of stress for the induction of a depression model which through exercise on a treadmill for 6 weeks was tested for therapeutic effects. Behaviors consistent with a model of depressive behavior were assessed by OFT, SPT, and TST. Hippocampal mitochondrial function was assessed by transmission electron microscopy, flow cytometry, biochemical, and ELISA. Oxidative stress markers were assessed with biochemical kits and ELISA. The mRNA and protein levels of key markers in the Nrf2/Keap1 pathway and UPRmt were analyzed using RT-qPCR, Western blotting, and immunofluorescence. Pathway dependence was determined using the Nrf2 inhibitor, ML385 and the Nrf2 activator Bardoxolone methyl.</div></div><div><h3>Results</h3><div>The six-week treadmill exercise program significantly reduced depression-like behaviors (e.g., anxiety-like behaviors, anhedonia, and behavioral despair), restored mitochondrial functions (mitochondrial cristae morphology, Δψm, ATP, and ROS levels) and eliminated oxidative stress (SOD, T-AOC, and MDA levels). Moreover, treadmill exercise significantly increased the expression of proteins in the Nrf2/Keap1 pathway (Nrf2, Keap1, NQO1, and HO-1), which attenuated CUMS-induced UPRmt markers (HSP60, ClpP, HSP70, LONP1, and ATF5) and the associated stress transcription factor CHOP.</div></div><div><h3>Conclusion</h3><div>The treadmill exercise activates the Nrf2/Keap1 pathway in the hippocampus, thereby reducing CUMS-induced excessive and dysregulated endoplasmic reticulum stress (UPRmt) in an Nrf2-dependent manner, which leads to a recovery of mitochondrial function, suppression of oxidative stress, and improvement of depressive-like behaviors.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111738"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the serotonin-1A receptor promotes neural regeneration in the rat model of neonatal hypoxic–ischemic brain damage","authors":"Xing Zhu ,&nbsp;Mingrui Shi ,&nbsp;Changyang Ma ,&nbsp;Jie Yu ,&nbsp;Juan Du ,&nbsp;Mingyan Hei","doi":"10.1016/j.brainresbull.2026.111739","DOIUrl":"10.1016/j.brainresbull.2026.111739","url":null,"abstract":"<div><div>Perinatal hypoxic–ischemic brain damage (HIBD) is a leading cause of lifelong neurodevelopmental disability, and effective therapies remain limited. Activation of the postsynaptic serotonin-1A receptor (5-HT_1A-R) has neuroprotective potential against acute and chronic brain injuries. The present study evaluated whether activation of postsynaptic 5-HT_1A-R enhances neural regeneration and improves long-term outcomes after neonatal HIBD. Seven-day-old rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0 % O₂). NLX-101 (0.16 mg/kg), a selective postsynaptic 5-HT_1A-R agonist, was intraperitoneally injected at 0, 24, and 48 h after hypoxic ischemia. Brain damage in adolescent rats was quantified by magnetic resonance imaging (MRI) and hematoxylin and eosin (H&amp;E) staining. Cognitive, social, and emotional behavioral outcomes were evaluated. Hippocampal neural regeneration was analyzed by RNA sequencing and validated by immunofluorescence. We found that the activation of 5-HT_1A-R was amplified by NLX-101 administration, which attenuated HI-induced brain tissue damage in MRI and H&amp;E staining and improved cognitive, social, and emotional behaviors in adolescence. Gene Ontology enrichment revealed significant clustering within neural regeneration-related gene sets, corroborated by immunofluorescence, which showed 5-HT_1A-R activation enhanced neural stem/progenitor cell generation and promoted the long-term survival of regenerated neurons. Kyoto Encyclopedia of Genes and Genomes pathway enrichment indicated that 5-HT_1A-R activation was associated with the MAPK/ERK cascade, and western blotting further confirmed that it enhanced ERK phosphorylation. In conclusion, our findings demonstrate that activation of postsynaptic 5-HT_1A-R amplifies dentate gyrus neural regeneration, attenuates brain damage, and normalizes long-term cognitive, social, and affective deficits in neonatal HIBD, primarily through the MAPK/ERK pathway.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111739"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “miR-669f-5p targeting Dctd contributes to sevoflurane-induced cognitive impairments in aged mice via TLR2/4-MyD88-NF κB pathway” [Brain Res. Bull. 228 (2025) 111381]","authors":"Yuanping Zhong ,&nbsp;Chao Zhang ,&nbsp;Yuan Li ,&nbsp;Dongqin Chen ,&nbsp;Chunchun Tang ,&nbsp;Xue Zheng ,&nbsp;Zhaoqiong Zhu","doi":"10.1016/j.brainresbull.2025.111695","DOIUrl":"10.1016/j.brainresbull.2025.111695","url":null,"abstract":"","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111695"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydroxysafflor yellow A protects against ischemic stroke-associated Weber syndrome by inhibiting oxidative stress and alleviating DNA damage","authors":"Miaolin Zeng ,&nbsp;Huifen Zhou ,&nbsp;Lian Zeng ,&nbsp;Man zhang ,&nbsp;Jiehong Yang ,&nbsp;Wujun Geng ,&nbsp;Haitong Wan","doi":"10.1016/j.brainresbull.2026.111747","DOIUrl":"10.1016/j.brainresbull.2026.111747","url":null,"abstract":"<div><div>Weber syndrome, characterized by ipsilateral oculomotor palsy and contralateral hemiplegia, frequently occurs in ischemic stroke cases and is difficult to recover from. Hydroxysafflor yellow A (HSYA), a bioactive component present in <em>Carthamus tinctorius</em> L. and the standardized preparation Danhong injection, has shown protective effects in animal models of various neurological diseases. This research was conducted to evaluate the therapeutic potential of HSYA in ischemic stroke-associated Weber syndrome, while elucidating its mechanistic basis. A rat MCAO model was induced to detect the effects of HSYA on motor dysfunction, ipsilateral ptosis and neuronal death in the right cerebral peduncle. By western blot, immunohistochemistry staining and immunofluorescence staining, we explored the involvement of oxidative stress and DNA damage in HSYA's neuroprotective action. HSYA treatment for consecutive 7 days significantly improved neurological function, grip strength, and asymmetry of bilateral eye clefts in CI/R-injured rats. HSYA also reduced cerebral infarction, preserved neuronal survival, and mitigated histopathological damage in the cerebral peduncle. Mechanistically, HSYA alleviated oxidative stress by preserving CAT, GSH, and SODM levels while inhibiting iNOS overexpression. Furthermore, CI/R injury triggered substantial DNA damage in the cerebral peduncle, as indicated by upregulated levels of 53BP1 and γ-H2A.X. Contents of PARP1, AIF, and MIF were also significantly elevated, accompanied by obvious upregulation of apoptotic cell death, while HSYA treatment effectively attenuated these deleterious effects. HSYA protects against CI/R injury and associated Weber syndrome, and the mechanism involves suppressing oxidative stress and limiting DNA injury.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111747"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting IGF2BP2 alleviates high fat diet aggravated Alzheimer’s disease by inhibiting ferroptosis","authors":"Duobin Zhang ,&nbsp;Lingyun Shao ,&nbsp;Min He ,&nbsp;Shen Yang ,&nbsp;Zhongwu Sun","doi":"10.1016/j.brainresbull.2026.111749","DOIUrl":"10.1016/j.brainresbull.2026.111749","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose development is increasingly recognized to be influenced by metabolic factors such as high-fat diet (HFD). HFD can accelerate cognitive decline and exacerbate AD pathology by promoting oxidative stress, neuroinflammation, and lipid dysregulation. Meanwhile, ferroptosis—an iron-dependent form of regulated cell death—has emerged as a key mechanism contributing to neuronal damage in AD. However, the upstream regulators that link HFD-induced stress to ferroptosis and AD progression remain unclear. IGF2BP2, an m⁶A RNA-binding protein, has been implicated in both metabolic regulation and mRNA stability, but its role in AD under HFD conditions has not been fully elucidated.</div></div><div><h3>Methods</h3><div>We established AD models both in vivo and in vitro and subjected them to HFD exposure. Behavioral and biochemical assessments—including Morris water maze, H&amp;E staining, serum triglyceride (TG) and total cholesterol (TC) levels, and ELISA for Aβ and m6A—were conducted. Transcriptomic sequencing identified IGF2BP2 as a differentially expressed gene associated with AD progression under HFD. IGF2BP2 expression was silenced using siRNA in cells and adeno-associated virus (AAV) in rats. Apoptosis, Aβ, TNF-α, IL-1β, and m6A levels were evaluated post-knockdown. Ferroptosis markers (ROS, SOD, GSH, MDA, and SLC7A11) and mitochondrial ultrastructure were also assessed.</div></div><div><h3>Results</h3><div>HFD exacerbated cognitive dysfunction, neuronal damage, lipid metabolism disorder, Aβ accumulation, and m6A hypomodification in AD models. IGF2BP2 expression was significantly elevated in HFD-induced AD, and its knockdown alleviated neuroinflammation, apoptosis, and restored m6A modification. Notably, silencing IGF2BP2 enhanced SLC7A11 expression and reduced ferroptosis-related oxidative stress, mimicking the effects of the ferroptosis inhibitor Fer-1. Moreover, IGF2BP2 knockdown lowered serum TG and TC levels and improved cognitive performance in the Morris water maze.</div></div><div><h3>Conclusion</h3><div>Our findings identify IGF2BP2 as a key mediator linking HFD-induced metabolic dysfunction to AD progression via m6A modification and ferroptosis. Targeting IGF2BP2 may represent a promising therapeutic strategy for AD patients with metabolic comorbidities.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111749"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic GSK-3β targeting stabilizes multifunctional β-catenin to rescue neuronal and behavioral deficits in fragile X messenger ribonucleoprotein 1 knockout mice","authors":"Siming Zhang ,&nbsp;Peng Xiang ,&nbsp;Mingjiao Suo,&nbsp;Ziyu Yi,&nbsp;Zhen Wei,&nbsp;Jinquan Li,&nbsp;Yan Zeng,&nbsp;Yushan Chen","doi":"10.1016/j.brainresbull.2025.111710","DOIUrl":"10.1016/j.brainresbull.2025.111710","url":null,"abstract":"<div><div>Fragile X syndrome (FXS) is the predominant singlegene cause of inherited intellectual disability and is strongly associated with autism spectrum disorder (ASD). FXS results from the disruption of fragile X messenger ribonucleoprotein 1 gene (FMR1) and is characterized by synaptic dysfunction manifesting as impaired cognitive function and social communication. The Wnt/β-catenin pathway plays a pivotal role in regulating synaptic structural remodeling and functional homeostasis, critically contributing to higher-order neural processes such as learning and memory. Studies have identified glycogen synthase kinase 3 beta (GSK3β), a key negative regulator of Wnt signal transduction, is abnormally activated in the pathophysiology of FXS, and demonstrated that GSK3β inhibition partially rescues cognitive and behavioral deficiencies in FXS mice. However, the spatiotemporal dysregulation of β-catenin dynamics and its synaptic consequences remain poorly understood. Here, we investigated the role and molecular mechanism of Wnt/β-catenin pathway during developmental stages in FXS using <em>Fmr1</em> gene knockout (<em>Fmr1</em> KO) mice. We systematically explored β-catenin homeostasis across subcellular compartments. Our results showed increased phosphorylation of β-catenin at Ser^33,37, Thr⁴¹ and Ser⁵⁵² residues, which fosters its degradation. This was accompanied by reduced levels of active β-catenin in the membrane, cytoplasm and nucleus within the hippocampus (Hipp) and prefrontal cortex (PFC) of <em>Fmr1</em> KO mice. Confocal microscopy further demonstrated diminished co-localization of β-catenin with N-cadherin, leading to compromised intercellular adhesion in both <em>Fmr1</em> KO neurons. Moreover, FXS mice showed impaired neuronal morphology and deficiencies in social and cognitive functions, which were associated with the downregulation of pre- and postsynaptic proteins targeted by Wnt pathway. Strikingly, pharmacological activation of Wnt signal transduction restored β-catenin nuclear translocation and synaptic protein expression, rescued neuronal ultrastructural abnormalities and improvd cognitive and social behaviors. Our findings establish hypoactivity of canonical Wnt signaling as a central mechanism underlying synaptic pathology in FXS, linking β-catenin destabilization to altered neuronal morphology, aberrant synaptic protein networks, and behavioral phenotypes. Consequently, bolstering Wnt pathway may represent a promising neuroprotective strategy for precision intervention in FXS.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111710"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A vagus-dependent gut microbiota–metabolite axis drives chronic inflammatory pain and working-memory deficits in mice","authors":"Cai-bao Yue ,&nbsp;Wei-wei Luan ,&nbsp;Di Qiu ,&nbsp;Xin Ding ,&nbsp;Han-Wen Gu ,&nbsp;Pan-Miao Liu ,&nbsp;Kenji Hashimoto ,&nbsp;Jian-Jun Yang ,&nbsp;Xing-Ming Wang","doi":"10.1016/j.brainresbull.2025.111702","DOIUrl":"10.1016/j.brainresbull.2025.111702","url":null,"abstract":"<div><div>Chronic inflammatory pain (CIP) has been increasingly linked to gut microbiota (GM)–brain interactions, yet whether these effects rely on vagal signaling remains unclear. Here, we investigated whether GM from CIP mice is sufficient to transfer pain-like behaviors to healthy recipients and whether this process depends on the vagus nerve. Fecal microbiota transplantation (FMT) from mice treated with complete Freund’s adjuvant induced mechanical and thermal hypersensitivity and impaired working memory in recipients, accompanied by hippocampal neuroinflammation and GM dysbiosis. Subdiaphragmatic vagotomy (SDV) performed prior to FMT attenuated these behavioral and neuroinflammatory alterations and partially normalized microbial community structure. Plasma metabolomics further showed that SDV restored phosphatidylcholines while reducing pro-inflammatory lipid classes, with several metabolites and bacterial taxa correlating significantly with pain sensitivity and hippocampal cytokine levels. Collectively, these findings demonstrate that a vagus-dependent GM–metabolite–brain axis contributes to CIP-like behaviors and neuroinflammation. Targeting vagal pathways and GM-regulated lipid metabolism may offer therapeutic strategies and pharmacodynamic biomarkers for inflammatory pain.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111702"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How tobacco use disorder affects gray matter aberrance: The mediating effect of glymphatic system function","authors":"Mengzhe Zhang ,&nbsp;Bohui Mei ,&nbsp;Longyao Ma ,&nbsp;Kaixin Li ,&nbsp;Mengzhu Wang ,&nbsp;Weijian Wang ,&nbsp;Yong Zhang","doi":"10.1016/j.brainresbull.2026.111725","DOIUrl":"10.1016/j.brainresbull.2026.111725","url":null,"abstract":"<div><h3>Background</h3><div>The glymphatic system (GS) represents a newly identified biological pathway, but its possible involvement in the pathophysiology of tobacco use disorder (TUD) remains unclear. We aimed to assess the GS function in TUD individuals and to establish the connections among GS, brain structure and clinical features of disease.</div></div><div><h3>Methods</h3><div>We recruited 149 male subjects, including 92 TUD individuals and 57 controls, then obtained their 3D-T1 weighted image scans, diffusion tensor image scans and clinical scales. Diffusion tensor imaging along the perivascular space (DTI-ALPS) index was calculated to evaluate glymphatic function changes between the groups. Gray matter (GM) regions associated with the DTI-ALPS index were identified by voxel-based morphometry analysis (VBM). Finally, the relationships between DTI-ALPS index, GM and smoking behaviors were assessed through a mediation model.</div></div><div><h3>Results</h3><div>Compared to control group, TUD group displayed notably lower DTI-ALPS index in the whole brain and both bilateral hemispheres, which displayed negatively correlations with the severity of disease. The GMV alterations in left thalamus and right inferior temporal gyrus were positively correlated with the mean DTI-ALPS index. Moreover, the DTI-ALPS index partially mediated the relationship between GMV alterations and pack-year in TUD.</div></div><div><h3>Conclusions</h3><div>The current study revealed abnormalities of DTI-ALPS index in TUD and identified that abnormal GS function in TUD individuals could be the potential mechanism underlying the effects of tobacco exposure on GMV changes. These findings provided further evidence for understanding the pathogenesis of TUD and suggested GS function could serve as a new target for clinical therapeutic strategies.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111725"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding neurotransmitter and genetic contributions to abnormal neuronal signal variability in Anti‑N‑Methyl‑D‑Aspartate receptor encephalitis: Implications for targeted therapies","authors":"Rong Guo ,&nbsp;Wenjia Wang ,&nbsp;Rui Qian ,&nbsp;Yang Ji ,&nbsp;Wei Li ,&nbsp;Meidan Zu ,&nbsp;Qianqian Li ,&nbsp;Jiayun Wu ,&nbsp;Wentao Dai ,&nbsp;Si Xu ,&nbsp;Juanjuan Zhang ,&nbsp;Ling Wei ,&nbsp;Yuanyuan Guo ,&nbsp;Yanghua Tian ,&nbsp;Kai Wang","doi":"10.1016/j.brainresbull.2026.111717","DOIUrl":"10.1016/j.brainresbull.2026.111717","url":null,"abstract":"<div><h3>Background</h3><div>The molecular mechanisms linking brain function alterations to gene expression in anti-N-methyl-<span>D</span>-aspartate receptor (NMDAR) encephalitis remain unclear.</div></div><div><h3>Methods</h3><div>We analyzed the coefficient of variation of blood oxygenation level dependent signal (CV_BOLD) and functional connectivity (FC) in 30 healthy controls and 42 patients, with classification via 5 machine learning models. Transcriptomic profiles from the Allen Human Brain Atlas and neurotransmitter density maps from positron emission tomography were integrated. Partial least squares (PLS) regression determined gene expression relevant to the CV_BOLD/FC changes. Multivariate linear regression evaluated neurotransmitter contributions.</div></div><div><h3>Results</h3><div>Anti-NMDAR encephalitis patients exhibited increased CV_BOLD in the right superior parietal gyrus, right fusiform gyrus, right lingual gyrus, left fusiform gyrus and left paracentral lobule meanwhile disrupted FC mainly in default mode and salience networks. PLS analysis revealed 2320 genes significantly associated with CV_BOLD/FC (<em>p</em>_bonferrni &lt; 0.05), enriched in synaptic signaling (MAPK, cAMP), metabolic regulation (insulin resistance), and neurodegeneration pathways. Hub genes PPARGC1A (positive correlation with CV_BOLD/FC) and UBA52 (negative correlation) were validated in key brain regions. Neurotransmitter analysis showed norepinephrine (NAT) strongly contributed to CV_BOLD (weight = 0.57, <em>p</em>_<em>FDR</em> &lt; 0.001), meanwhile serotonin (5HT4), cannabinoid (CB1), noradrenaline (NAT), and glutamate (NMDA) influenced FC.</div></div><div><h3>Conclusion</h3><div>This study identifies a transcriptional signature that is spatially associated with CV_BOLD/FC abnormalities and neurotransmitter distributions in anti-NMDAR encephalitis, thereby generating hypotheses about molecular targets that may be relevant for future mechanistic studies and precision medicine.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111717"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebellar subregional atrophy in relapsing-remitting multiple sclerosis: Stage-dependent dynamics and pharmacological modulation","authors":"Xiaohui Zhang ,&nbsp;Jinzhou Feng ,&nbsp;Zhiwei Zhang ,&nbsp;Bin Yu ,&nbsp;Silin Du ,&nbsp;Kai Zhang ,&nbsp;Xiaoya Chen ,&nbsp;Yongmei Li","doi":"10.1016/j.brainresbull.2025.111679","DOIUrl":"10.1016/j.brainresbull.2025.111679","url":null,"abstract":"<div><h3>Background</h3><div>Cerebellar atrophy is increasingly recognized as an important pathological feature of multiple sclerosis (MS). However, the specific patterns at different stages and their alteration by disease-modifying therapies (DMTs) are not well comprehended.</div></div><div><h3>Objective</h3><div>This study aimed to investigate stage-dependent cerebellar subregional volume changes in relapsing-remitting MS (RRMS) and evaluate the effects of different DMT classes on cerebellar atrophy and clinical outcomes.</div></div><div><h3>Methods</h3><div>A total of 181 patients with RRMS and 99 healthy controls were recruited for this study. Patients were stratified by lesion activity into acute-active, chronic-active, and chronic-inactive subgroups, and by pharmacological mechanism into untreated, sphingosine-1-phosphate (S1P)_T (siponimod, fingolimod, and ozanimod) and not_S1P_DMT (dimethyl fumarate and teriflunomide). Cerebellar subregional volumes were quantified using the deep learning-based tool, CerebNet. Group comparisons were conducted, and interaction effects were examined. The correlations between the cerebellar subregions and cognition were subsequently analyzed.</div></div><div><h3>Results</h3><div>In the lesion-activity subgroups, significant volume loss was detected in several posterior cerebellar lobules, including Crus II, VIIIa/b, VIIb, X, Crus I, and IX (all <em>p</em> &lt; 0.05). The acute-active subgroup exhibited additional atrophy in anterior lobules I–IV and vermis IX compared with the chronic-active subgroup (all <em>p</em> &lt; 0.05). In the treatment subgroups, widespread reductions were observed in the posterior lobules Crus I/II, V, VIIb, VIIIb, IX, and X, with most decreases appearing in the untreated groups (all <em>p</em> &lt; 0.05). Pairwise com<em>p</em>arisons displayed region-specific patterns: left VIIIa volume was reduced in the MS_noDrug and MS_not_S1P_DMT groups but increased in the S1P_DMT group, whereas right lobule V in the S1P_DMT and vermis VI in the MS_not_S1P_DMT were both higher (all <em>p</em> &lt; 0.05). The interaction effects of disease stage and treatment were mainly localized to lobules IX and VIIIb, and the volumes of bilateral IX lobules showed a weak positive correlated with cognitive performance.</div></div><div><h3>Conclusion</h3><div>This study demonstrated stage-specific patterns of cerebellar atrophy in RRMS and the heterogeneous, stage-dependent effects of DMTs on posterior cerebellar subregions. Lobules IX and VIIIb emerged as critical loci linking pharmacological modulation with cognitive outcomes. These findings suggest that these regions may serve as potential imaging biomarkers of therapeutic response and prognosis in MS.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111679"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}