Brain Research Bulletin最新文献

{"title":"Alkaloids and flavonoids of Solanaceae: Mechanisms of action in neurodegenerative diseases","authors":"Qiushi Yin ,&nbsp;Mingzhen Hu ,&nbsp;Wei Li ,&nbsp;Peng Cheng ,&nbsp;Yuqing Liu ,&nbsp;Long Liu ,&nbsp;Lin Chen ,&nbsp;Qin Ru ,&nbsp;Yuxiang Wu","doi":"10.1016/j.brainresbull.2026.111716","DOIUrl":"10.1016/j.brainresbull.2026.111716","url":null,"abstract":"<div><div>Neurodegenerative diseases (e.g., Alzheimer's disease [AD], Parkinson's disease [PD], Huntington's disease [HD]) pose a serious threat to human health. Current therapeutic approaches have limitations such as significant side effects and limited efficacy, making natural plant active ingredients an emerging research focus in this field. Solanaceae plants are widely distributed worldwide, rich in secondary metabolites such as alkaloids and flavonoids, and have long been used in traditional medicine. This review systematically summarizes the structural characteristics of Solanaceae-derived alkaloids (e.g., nicotine[NI], atropine[ATP], scopolamine[SCO]) and flavonoids (e.g., quercetin[QR], luteolin[LUT], kaempferol[KAE], anthocyanidin[ACN]), as well as their therapeutic potential and core mechanisms of action against the three major neurodegenerative diseases — including multi-target regulatory pathways such as antioxidative stress, inhibiting neuroinflammation, regulating neurotransmitter balance, preventing abnormal protein aggregation, and suppressing neuronal apoptosis. Additionally, this review analyzes the challenges faced by these natural products in extraction and purification, bioavailability, target selectivity, and clinical translation, and prospects the potential of promoting their clinical application through technological breakthroughs such as synthetic biology and nanodelivery systems. This review indicates that Solanaceae-derived secondary metabolites provide an important resource for the development of safe and effective therapeutic drugs for neurodegenerative diseases, with broad application value.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111716"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976335","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":"Altered cerebellar morphological similarity network correlates with cognitive decline and cerebrospinal fluid biomarkers in mild Alzheimer’s disease: a 7 T MRI study","authors":"Weiwei Zhang ,&nbsp;Haokun Liu ,&nbsp;Long Qian ,&nbsp;Cong Zhang ,&nbsp;Dongcui Wang ,&nbsp;Keying Fang ,&nbsp;Ruiting Chen ,&nbsp;Bin Jiao ,&nbsp;Lu Shen ,&nbsp;Weihua Liao","doi":"10.1016/j.brainresbull.2026.111731","DOIUrl":"10.1016/j.brainresbull.2026.111731","url":null,"abstract":"<div><h3>Backgroud</h3><div>Recent neuroimaging research emphasized cerebellar atrophy and alternation of functional connections in Alzheimer’s disease (AD), fewer studies have focus on the cerebellar subfield and its structural network reorganization. This study aimed to explore the utility of 7 T MRI in assessing cerebellar subfield volumes, morphological similarity network (MSN) and their correlation with cognitive decline and cerebrospinal fluid (CSF) biomarkers in mild AD.</div></div><div><h3>Methods</h3><div>Cerebellar subfield segmentation and individual level MSNs construction were performed using high-resolution structural 7 T MRI data in 30 AD of mild stage and 30 healthy normal controls (NCs). Subfield volumes and topological parameters of the resulting graphs were compared between groups. Correlations between altered MSN metrics and cognitive measurement, CSF biomarkers were further analyzed in AD group.</div></div><div><h3>Results</h3><div>Compared to NCs, AD patients exhibited salient vermis VIIb and vermis VIIIa atrophy and significantly large-scale topological alterations of nodal properties of cerebellar MSN, predominantly in the posterior lobes (lobe VI-IX). The global network metrics were relatively preserved, despite the increased global assortativity. Altered structural network properties of lobule VIII, vermis IX and crus II were significantly associated with cognitive decline and CSF Aβ42 and p-tau181 levels in AD.</div></div><div><h3>Conclusions</h3><div>Our study emphasizes the crucial role of alterations in morphological connectivity beyond cerebellar atrophy in early AD using 7 T MRI. Structural network alterations in lobule VIII, vermis IX and crus II demonstrated significantly correlation with clinical variables, indicating their potential as sensitive imaging markers and therapeutic targets for AD.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111731"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035650","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":"Brain functional connectivity initiates structured reorganization at a critical oxygen threshold during hypoxia","authors":"Daehun Kang ,&nbsp;Koji Uchida ,&nbsp;Clifton R. Haider ,&nbsp;Norbert G. Campeau ,&nbsp;Myung-Ho In ,&nbsp;Erin M. Gray ,&nbsp;Joshua D. Trzasko ,&nbsp;Kirk M. Welker ,&nbsp;Matt A. Bernstein ,&nbsp;Max R. Trenerry ,&nbsp;David R. Holmes III ,&nbsp;Michael J. Joyner ,&nbsp;Timothy B. Curry ,&nbsp;John Huston III ,&nbsp;Yunhong Shu","doi":"10.1016/j.brainresbull.2026.111748","DOIUrl":"10.1016/j.brainresbull.2026.111748","url":null,"abstract":"<div><div>The human brain, one of the most energy-demanding organs, continuously adapts to internal and external challenges. Hypoxia, a reduction in oxygen availability, poses a substantial threat to brain function. Despite its importance, the nature of the brain’s adaptive response to hypoxia remains poorly understood. In this study, we investigated dynamic functional connectivity (FC) under acute hypoxic conditions (FiO₂ = 7.7 % and 11.8 %) in healthy adults using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and concurrent advanced physiological monitoring, including partial pressures of end-tidal oxygen (PetO₂) and carbon dioxide (PetCO₂) and peripheral oxygen saturation (SpO₂), and a Go/No-Go cognitive task to assess behavioral performance. Principal component analysis identified a hypoxia-responsive component in dynamic FCs across 400 cerebral parcels. This component captured hypoxia-specific FC changes that coincided with a critical drop in PetO₂ (∼53 mmHg), preceding subsequent changes in SpO₂, bulk BOLD signals, and behavioral performance. These FC changes were network-specific, with a marked increase primarily centered on the default mode network (DMN), which selectively synchronized with other high-level cognitive networks. In contrast, hypoxia-responsive connectivity showed limited involvement of visual networks, including connectivity with the DMN. These findings suggest that the brain engages in proactive and structured FC adaptations in anticipation of oxygen decline, rather than in response to it. FC-based metrics offer new insights into the temporal dynamics of brain resilience and may hold translational value for the early detection of vulnerability in neurological or neurodegenerative disorders.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111748"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050399","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":"Exploring the mechanism by which puerarin inhibits neuroinflammation and alleviates lipopolysaccharide-induced anxiety-like behavior in mice via modulating gut microbiota based on the brain-gut axis theory","authors":"Ge Wang ,&nbsp;Qisheng Tang ,&nbsp;Dan Wang","doi":"10.1016/j.brainresbull.2025.111698","DOIUrl":"10.1016/j.brainresbull.2025.111698","url":null,"abstract":"<div><h3>Background</h3><div>The gut-brain axis (GBA) has been increasingly recognized as a potential contributor to anxiety pathophysiology. Puerarin possesses anti-inflammatory, antioxidant, and neuroprotective properties, but its anxiolytic mechanism via the GBA remains unclear. The intervention of puerarin on lipopolysaccharide (LPS)-induced anxiety-like behavior (ALB) in mice was investigated based on the GBA theory.</div></div><div><h3>Methods</h3><div>Forty mice were allocated at random: control, LPS, LPS+PueL (low-dose puerarin), and LPS+PueH (high-dose puerarin) groups (n = 10 each). ALB was evaluated by the elevated plus maze (EPM). Inflammatory cytokines were measured by ELISA. Tight junction proteins were detected by qPCR and Western blot. Gut microbiota (GM) was analyzed by 16S rRNA sequencing.</div></div><div><h3>Results</h3><div>Compared with the Control, open arm entries (OAE) and open arm time (OAT) were decreased, inflammatory cytokine levels were elevated, intestinal tight junction protein expression was down-regulated, microbial diversity was reduced, and the abundance of pro-inflammatory bacterial genera was obviously increased in the LPS. In the LPS+PueH, OAE and OAT, inflammatory cytokine levels, tight junction protein expression, microbial diversity, and abundance of beneficial bacterial genera were evidently improved (<em>P</em> &lt; 0.05). Correlation analysis revealed that <em>Lactobacillus</em> and <em>Akkermansia</em> were positively correlated with OAE and OAT, whereas <em>Escherichia-Shigella</em> was negatively correlated (<em>P</em> &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>Puerarin alleviated LPS-induced ALB in mice by suppressing neuroinflammation, restoring intestinal barrier integrity, and modulating GM balance, which was closely associated with GBA regulation.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111698"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803070","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":"Functional connectivity-based searchlight multivariate pattern analysis for discriminating Parkinson’s disease patients and predicting clinical variables","authors":"Jingjing Xu ,&nbsp;Sijia Tan ,&nbsp;Jiaqi Wen,&nbsp;Weijin Yuan,&nbsp;Minming Zhang,&nbsp;Xiaojun Xu","doi":"10.1016/j.brainresbull.2026.111723","DOIUrl":"10.1016/j.brainresbull.2026.111723","url":null,"abstract":"<div><h3>Objectives</h3><div>Disruptions in brain functional connectivity (FC) have been verified to be one of the characteristics of Parkinson’s disease (PD) and PD patients with mild cognitive impairment (MCI). This study aims to differentiate PD patients from healthy controls (HCs), distinguish PD-MCI from PD patients with normal cognition (PD-NC), and evaluate the extent to which connectivity-based searchlight multivariate pattern analysis (CBS-MVPA) could provide predictive information on clinical severity.</div></div><div><h3>Methods</h3><div>A cohort of 261 participants from the Parkinson’s Progression Markers Initiative (PPMI) was included (98 PD-MCI patients, 98 PD-NC patients, and 65 HCs). Resting-state functional magnetic resonance imaging was used to examine whole-brain FC subnetworks. CBS-MVPA, a novel unbiased whole-brain analysis capable of capturing distributed predictive signals, was applied to identify subnetworks that contributed to group discrimination, and to assess their predictive effects on clinical measures.</div></div><div><h3>Result</h3><div>CBS-MVPA identified 20 FC subnetworks that reliably differentiated PD patients from HCs. Classification accuracy was moderate for PD vs HC (71.25 % to 75.48 %) and modest for PD-MCI vs PD-NC (57.21 % to 62.74 %). Specifically, four subnetworks centered on the posterior cingulate cortex, hippocampus, pallidum, and central postcentral gyrus showed modest predictive value for motor severity (MDS-UPDRS I-III scores). Additional subnetworks involving the paracentral lobule, lingual gyrus, and medial orbital superior frontal gyrus showed modest associations with cognitive performance. It should be noted, however, that this accuracy is only modestly above chance level, reflecting the complexity and heterogeneity of PD.</div></div><div><h3>Conclusion</h3><div>This study introduces a novel approach for identifying distributed FC subnetworks patterns relevant to PD and PD-MCI. While predictive performance was modest, the detected subnetworks nonetheless contained measurable predictive signals related to both diagnostic status and clinical severity, highlighting the potential utility of whole-brain multivariate FC analyses for future mechanistic research and therapeutic interventions in PD.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111723"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948024","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":"The role of optic flow on reactive brain processing in cognitive tasks during locomotion","authors":"BiancaMaria Di Bello ,&nbsp;Natalie Ferrulli ,&nbsp;Camilla Panacci ,&nbsp;Margherita Filosa ,&nbsp;Sabrina Pitzalis ,&nbsp;Francesco Di Russo","doi":"10.1016/j.brainresbull.2026.111722","DOIUrl":"10.1016/j.brainresbull.2026.111722","url":null,"abstract":"<div><div>Perception and action share neural resources that must be flexibly allocated across simultaneous tasks. In this context, the optic flow provides key visual input during locomotion and may interact with concurrent cognitive processing. This study aimed to: 1) examine how walking modulates event-related potential (ERP) components linked to visual, attentional, and sensorimotor processes evoked by a concomitant cognitive task; 2) relate neural changes to behavior; 3) test whether optic flow modifies these locomotion effects; and 4) extend previous findings on anticipatory brain processing to post-stimulus activity. To these aims, forty participants performed a visual discrimination task under four conditions that manipulated locomotion (walking vs. standing) and visual stimulation (with vs. without optic flow). Behavioral measures (response time (RT), accuracy, RT variability) and ERP components indexing distinct brain processing stages were recorded. Behaviorally, walking improved performance by increasing accuracy and reducing RT variability, while optic flow reduced accuracy without affecting RT. At the brain level, walking decreased the prefrontal N1 (pN1), indicating lower visual awareness, but increased the N1 (enhanced visual attention). Walking with the optic flow also increased the prefrontal P1 (pP1), indicating greater sensorimotor awareness. The presence of the optic flow independently reduced P1 (associated with early visual processing) and increased the pN1 and the N1. The P3 varied only with stimulus type, indicating no walking or optic flow effects on post-perceptual evaluation. Overall, walking facilitated early cognitive processing, whereas the optic flow added sensory-attentional load, reducing accuracy via competition for visual resources. These results support multiple-resource allocation dual-task theories, highlighting how ecological multisensory environments may dynamically reallocate cognitive resources and shape neural processing during action. In addition, present data can be used to design immersive environments, motor-cognitive dual-task training, and real-world cognition studies.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111722"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948648","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":"Inhibiting H3K18 lactylation in microglia aggravates white matter injury after intracerebral hemorrhage in mice","authors":"Bing Jiang ,&nbsp;Lin Li ,&nbsp;Ye Yuan ,&nbsp;Zhongyi Zhang ,&nbsp;Yuxin Xie ,&nbsp;Linhui Zhang ,&nbsp;Yihao Tao ,&nbsp;Zongyi Xie","doi":"10.1016/j.brainresbull.2026.111744","DOIUrl":"10.1016/j.brainresbull.2026.111744","url":null,"abstract":"<div><h3>Background</h3><div>White matter injury (WMI) is a key contributor to long-term cognitive deficits following intracerebral hemorrhage (ICH), yet its underlying mechanisms remain incompletely understood.</div></div><div><h3>Aims</h3><div>This study aims to investigate the role of histone H3K18 lactylation (H3K18la) and microglial function in post-ICH WMI and cognitive impairment.</div></div><div><h3>Methods</h3><div>Utilizing a collagenase-induced ICH mouse model, we assessed H3K18la expression dynamics (days 3, 7, 14, 21 post-ICH) and the effects of inhibiting lactate dehydrogenase (using Oxamate) or p300/CBP histone acetyltransferase (using A-485) on WMI and cognitive function. Furthermore, we employed PLX5622 (a colony-stimulating factor 1 receptor inhibitor) to deplete microglia (MG), alone or combined with A-485, to examine the role of p300/CBP inhibition in the context of MG absence. WMI was evaluated using myelin basic protein (MBP), neurofilament H (non-phosphorylated; SMI32) immunostaining, and transmission electron microscopy. Oligodendrocyte precursor cell (OPC) accumulation around the hematoma was quantified, and microglial depletion was verified by cell counting. Cognitive function was assessed up to 28 days post-ICH using the Morris Water Maze test.</div></div><div><h3>Results</h3><div>H3K18la levels were elevated and oligodendrocyte precursor cells (OPCs) increased in the perihematomal region post-ICH. A-485 administration significantly reduced microglial H3K18la, concomitantly suppressed OPC recruitment to the injury site, and exacerbated both WMI and long-term cognitive impairment. In contrast, oxamate administration did not significantly reduce microglial H3K18la or exacerbate cognitive deficits, but it did significantly aggravate WMI. PLX5622-induced MG depletion similarly aggravated WMI and cognitive deficits. However, combined PLX5622 and A-485 treatment did not produce additive worsening compared to MG depletion alone.</div></div><div><h3>Conclusion</h3><div>These results demonstrated that lactate-derived H3K18 lactylation (H3K18la), orchestrated by p300/CBP-mediated epigenetic reprogramming, serves as a critical endogenous neuroprotective axis of WMI following ICH. Microglia emerge as the cellular executors of this pathway. This lactate-p300/CBP-H3K18la axis thus represents a therapeutically targetable mechanism for enhancing post-hemorrhagic brain repair through microglia-guided myelin regeneration.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111744"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090182","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":"Inhibition of SCD1 attenuates neuroinflammation and brain injury after cerebral ischemia-reperfusion","authors":"Shuangkai Li ,&nbsp;Xiang Li Jr ,&nbsp;Lu Peng ,&nbsp;Haojie Ding ,&nbsp;Xuan Shi ,&nbsp;Jiale Liu ,&nbsp;Haiying Li ,&nbsp;Jianguo Xu ,&nbsp;Qing Sun","doi":"10.1016/j.brainresbull.2025.111693","DOIUrl":"10.1016/j.brainresbull.2025.111693","url":null,"abstract":"<div><div>Neuroinflammation mediated by microglial hyperactivation represents a pivotal pathological mechanism exacerbating neuronal damage following cerebral ischemia. Stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis, plays a crucial regulatory role in metabolic and inflammatory processes. However, its specific function in post-ischemic neuroinflammation remains incompletely understood. This study found that SCD1 was highly expressed in the penumbra region following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Then, we systematically evaluated the role of SCD1 in regulating neuroinflammation after cerebral ischemia–reperfusion and explored its underlying mechanisms through administrating SCD1-specific inhibitor CAY10566. Results showed that CAY10566 significantly reduced level of pro-inflammatory cytokines and infarct volume after cerebral ischemia–reperfusion. Furthermore,suppression of SCD1 also alleviated neuronal apoptosis and improved cognitive and motor functions after ischemic stroke Mechanistically, the modulation of the NF-κB signaling pathway by SCD1 may involve the participation of TNFR1. Collectively, these findings suggested that the SCD1 may serve as a critical checkpoint regulating NF-κB signaling in cerebral ischemia–reperfusion injury. Targeting SCD1 may represent a promising therapeutic strategy for ischemic stroke.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111693"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809987","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":"Time-dependent alterations in brain metabolites and gut microbiota following whole-brain FLASH versus conventional radiotherapy in mice","authors":"Renke He ,&nbsp;Yuhan Liu ,&nbsp;Wenxuan Li ,&nbsp;Shengqiang Xie ,&nbsp;Jiayu Liu ,&nbsp;Gang Cheng ,&nbsp;Jianning Zhang","doi":"10.1016/j.brainresbull.2026.111755","DOIUrl":"10.1016/j.brainresbull.2026.111755","url":null,"abstract":"<div><h3>Purpose</h3><div>This study compared the time-dependent changes in brain metabolites and gut microbiota at early and late post-irradiation stages in mice receiving conventional radiotherapy (CONV-RT) or ultra-high dose-rate FLASH radiotherapy (FLASH-RT).</div></div><div><h3>Methods</h3><div>Male C57BL/6 J mice received whole-brain irradiation using CONV-RT (2 Gy/min) or X-ray-based FLASH-RT (200 Gy/s). Brain tissue and gut contents were collected on days 1, 3, 7, and 21 post-irradiation. Targeted LC–MS metabolomics profiled dynamic brain metabolite changes, and 16S rRNA sequencing characterized gut microbiota trajectories. Neuroinflammation and brain injury were assessed by immunofluorescence (microglia/astrocyte markers) and laser speckle cerebral blood flow imaging, while behavioral assays evaluated cognition and anxiety-like behaviors.</div></div><div><h3>Results</h3><div>Compared with CONV-RT, FLASH-RT was associated with less pronounced hippocampal microglial and astrocytic reactivity, a smaller reduction in cerebral blood flow perfusion, and attenuated radiation-associated cognitive deficits. Metabolomics revealed distinct temporal trajectories: CONV-RT showed sustained late-phase suppression of metabolic programs, whereas FLASH-RT exhibited a coordinated late-stage rebound in pathways related to amino acid/carbohydrate metabolism and synaptic neurotransmission. Mechanistically relevant metabolites linked to antioxidation, energy metabolism, and neural repair were increased under FLASH-RT, consistent with reduced neuroinflammation. Gut microbiota profiling demonstrated that FLASH-RT induced a milder and more transient dysbiosis, with faster restoration toward a Sham-like structure and enrichment of putative beneficial taxa (including <em>Lachnospiraceae</em>, <em>Peptostreptococcaceae</em>, and <em>Dubosiella</em>), while CONV-RT was associated with more persistent <em>Proteobacteria/Enterobacteriaceae</em>-related disruptions and opportunistic signatures.</div></div><div><h3>Conclusion</h3><div>In summary, we have innovatively explored the changes in brain metabolites and gut microbiota induced by FLASH-RT whole-brain irradiation, providing a theoretical foundation for further investigation into the mechanisms underlying FLASH-RT’s effects.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111755"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099788","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":"Cell-type-specific reorganization of VGSCs in auditory cortex and therapeutic potential of Nav1.6 blockade for tinnitus","authors":"Miao Zhao ,&nbsp;Shichu Sun ,&nbsp;Shiqi Jing ,&nbsp;Zifei Ma ,&nbsp;Zihan Zhang ,&nbsp;Yonghua Ji ,&nbsp;Chenchen Xia ,&nbsp;You Zhou","doi":"10.1016/j.brainresbull.2026.111733","DOIUrl":"10.1016/j.brainresbull.2026.111733","url":null,"abstract":"<div><div>Neuronal hyperexcitability resulting from an inhibitory-excitatory imbalance in the primary auditory cortex (A1) is a key pathological feature of tinnitus. Voltage-gated sodium channels (VGSCs) are crucial in regulating neuronal excitability by facilitating action potential generation and propagation. However, the specific involvement of VGSC subtypes in tinnitus-related hyperexcitability within the A1 cortex remains poorly understood. Previous studies have shown that acute and chronic salicylate administration can induce stable tinnitus in rats. In this study, we investigated the distribution and expression profiles of four VGSC subtypes (Nav1.1, Nav1.2, Nav1.3, and Nav1.6) in the A1 cortex of rats following systemic salicylate administration. Immunohistochemical staining and quantitative PCR analyses revealed dynamic and subtype-specific changes in VGSC expression. Notably, while the expression of Nav1.1 and Nav1.2 was significantly reduced in GAD67-immunoreactive GABAergic neurons, both Nav1.3 and Nav1.6 showed substantial upregulation, particularly in VGLUT2-immunoreactive glutamatergic neurons in the A1 cortex. Among these, Nav1.6 exhibited the most pronounced changes, suggesting it could be a key player in the altered excitatory-inhibitory balance observed in tinnitus. Furthermore, Nav1.6 knockout mice displayed reduced central gain enhancement following salicylate administration, further implicating Nav1.6 in tinnitus pathology. Treatment with NBI-921352, a selective Nav1.6 inhibitor, alleviated tinnitus-like behaviors induced by both acute and chronic salicylate treatments, concomitant with a suppression of salicylate-induced central gain enhancement. These findings suggest that the bidirectional regulation of VGSC subtypes contributes to tinnitus-associated excitatory-inhibitory imbalances in the A1 cortex, with Nav1.6 representing a promising therapeutic target for tinnitus.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111733"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975647","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}