Brain Research Bulletin最新文献

{"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}

{"title":"The uptake of β-amyloid by various brain cells exhibits heterogeneity and correlates with the CD14 expression","authors":"Jingming Shi ,&nbsp;Yandong Ma ,&nbsp;Lei Gao ,&nbsp;Yuting Dai ,&nbsp;Qian Chen ,&nbsp;Xudong Li ,&nbsp;Hang Liu ,&nbsp;Ruotong Li ,&nbsp;Jie Zhang ,&nbsp;Chaoren Yan","doi":"10.1016/j.brainresbull.2025.111699","DOIUrl":"10.1016/j.brainresbull.2025.111699","url":null,"abstract":"<div><div>The involvement of β-amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD) remains a contentious topic within the scientific community. For a long time, many studies have been highly interested in the topic of brain cells internalizing Aβ. Nonetheless, the precise processes and mechanisms underlying Aβ internalization by neurons, astrocytes, and microglia under AD settings have yet to be clarified. This study investigated primary neurons and glial cells cultured in vitro, as well as APP/PS1 mouse models. Laser confocal microscopy, frozen brain sections, and intraventricular injection in mice and other methods were employed to evaluate the uptake of Aβ42 monomers and oligomers (ADDL) by neurons, microglia, astrocytes. The results revealed that both microglia and neurons internalized Aβ oligomers. In the experiment, the Aβ that adhered to the cells, as visible using the laser confocal microscope, likely comprised two components: the portion that attached to the cells and the portion that was internalized by them. Contrary to prior observations, astrocytes exhibited limited in ability to internalize Aβ oligomers. The disparities in internalization across the three cell types were probably associated with CD14. This work elucidated the intricacies of several different types of cells internalization of Aβ processes and support a crucial role for CD14 in regulating Aβ internalization.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111699"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910515","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":"Bile acid profile and white matter microstructural changes in early Alzheimer’s disease","authors":"Ye Mo ,&nbsp;Yifeng Peng ,&nbsp;Alzheimer's disease Neuroimaging Initiative (ADNI)","doi":"10.1016/j.brainresbull.2025.111642","DOIUrl":"10.1016/j.brainresbull.2025.111642","url":null,"abstract":"<div><h3>Background</h3><div>Although recent disease-modifying treatments such as Lecanemab have shown promise in reducing amyloid burden and modestly slowing cognitive decline in early Alzheimer’s disease (AD), effective long-term interventions remain limited. Emerging evidence links dysregulated gut-liver bile-acid (BA) metabolism to AD pathology. We examined whether peripheral BA signatures correspond to early white-matter microstructure changes in prodromal AD.</div></div><div><h3>Methods</h3><div>Baseline data were drawn from the Alzheimer’s Disease Neuroimaging Initiative. One-hundred-twenty-seven participants (46 cognitively normal controls, 81 amnestic mild cognitive impairment [MCI]; 55–90 y) contributed serum concentrations of 33 BAs plus three predefined BA ratios, cerebrospinal-fluid biomarkers, and diffusion-tensor MRI. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AxD) diffusivities were derived using tract-based spatial statistics and atlas-based regions of interest.</div></div><div><h3>Results</h3><div>Higher FA was associated with greater taurochenodeoxycholic acid, <span>L</span>-aspartate and <span>L</span>-asparagine, and with lower apocholic and 12-ketolithocholic acids. Elevated AxD, MD and RD tracked with reduced dehydrolithocholic acid and the glycolithocholic acid to chenodeoxycholic acid (GLCA/CDCA) ratio, and with higher palmitic acid. Participants with high cholic acid to chenodeoxycholic acid (CA/CDCA) ratio exhibited greater AxD in the left hippocampal cingulum; high GLCA/CDCA related to diffusivity increases in the right hippocampal cingulum and uncinate fasciculus. The glycodeoxycholic acid to taurodeoxycholic acid (GDCA/TDCA) ratio showed the strongest pattern, producing widespread AxD, MD and RD elevations in the uncinate fasciculus and cerebral peduncles and reduced FA in the fornix (p ≤ 0.0068).</div></div><div><h3>Conclusion</h3><div>Specific peripheral BA profiles—especially the gut-derived GDCA/TDCA ratio—mirror limbic and motor white-matter degeneration in amnestic MCI, independent of demographic and genetic risk. These findings implicate disrupted hepatic–microbial BA metabolism as a modifiable contributor to prodromal AD and highlight BA-targeted gut interventions as potential disease-modifying strategies.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111642"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534314","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 deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia","authors":"Lauren N. Miterko-Myers ,&nbsp;Lauren E. Peacoe ,&nbsp;Lita Duraine ,&nbsp;Zhongyuan Zuo ,&nbsp;Roy V. Sillitoe","doi":"10.1016/j.brainresbull.2025.111704","DOIUrl":"10.1016/j.brainresbull.2025.111704","url":null,"abstract":"<div><div>Deep brain stimulation (DBS) improves motor function in a growing list of movement diseases including Parkinson’s disease, dystonia, and tremor. There is evidence that DBS may also be effective in ataxia. It is not known why DBS is effective, but modulating cell activity and conferring neuroprotection are hypothesized to underlie its benefits. Understanding the effects of DBS on neurons is paramount to extending its clinical use in the treatment of various motor and non-motor diseases. Here, we stimulated the cerebellum of <em>Car8 waddles</em> (<em>Car8</em>^<em>wdl</em>) mice, given the cerebellum’s important role in ataxia pathophysiology. Using transmission electron microscopy, we tested the effects of therapeutic neuromodulation on Purkinje cell subcellular structures, including the mitochondria and their proximity to the endoplasmic reticulum (ER). In the absence of stimulation, we found increased putative mitochondria-ER contacts in <em>Car8</em>^<em>wdl</em> Purkinje cells as well as mitochondrial size and density alterations. Low-frequency cerebellar DBS rescued mitochondrial density, but not size or putative contacts in <em>Car8</em>^<em>wdl</em> Purkinje cells. Although increased mitochondrial density and sustained ER contact are specific to DBS treatment, they do not determine efficaciousness. These data uncover a mode of intracellular plasticity in Purkinje cells after stimulation, enhancing our mechanistic understanding of DBS for cerebellar disorders.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111704"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843219","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":"Investigation of dipyridamole-elicited signaling in the brain of Niemann Pick type C mice: A multi-omic study","authors":"Sabrina Tait ,&nbsp;Federica Fratini ,&nbsp;Zaira Boussadia ,&nbsp;Lucia Gaddini ,&nbsp;Manuela Marra ,&nbsp;Loredana Le Pera ,&nbsp;Gloria Venturini ,&nbsp;Antonella Ferrante","doi":"10.1016/j.brainresbull.2025.111708","DOIUrl":"10.1016/j.brainresbull.2025.111708","url":null,"abstract":"<div><div>Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endo-lysosomal (EL) lipid accumulation that leads to damage of both peripheral organs and central nervous system, with cerebellum and hippocampus being particularly affected. Currently very few therapeutic options exist in Europe for NPC. In fact, miglustat is the only approved drug and <span>L</span>-acetylleucine was recently granted for marketing authorization by European Medicine Agency. Thus, the identification of new treatments is mandatory. We have previously demonstrated that dipyridamole (DIP), an approved medicine that is clinically employed as an antiplatelet agent, could rescue recognition memory and increase hippocampal expression of calbindin. On the contrary, the drug was unable to improve cerebellar-dependent motor function. In order to elucidate the mechanism of these region-specific changes induced by DIP, in this work we performed a multi-omic analysis of genes and proteins modulated by the treatment in the hippocampus and cerebellum of a mouse model of NPC1 (Npc1^-/-). Our results revealed that DIP significantly affected various pathways in the hippocampus at protein level, but it had no significant impact on pathways in the cerebellum (either at gene or protein level). Interestingly, the most affected pathways in the hippocampus of Npc1^-/- mice administered with DIP were those related to cGMP-PKG activation and to mitochondrial function. Our results paved the way to test DIP in experimental models of other neurodegenerative disorders, such as Alzheimer’s disease that is similarly marked by hippocampal and mitochondrial dysfunctions.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111708"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848839","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 multimodal fusion framework reveals the heterogeneity of basal ganglia atrophy and its molecular mechanisms in temporal lobe epilepsy","authors":"Guiming Weng ,&nbsp;Xiaochuan Fu ,&nbsp;Cuimi Luo ,&nbsp;Qin Zhou ,&nbsp;Huoyou Hu ,&nbsp;Bailing Qin ,&nbsp;Binghua Lv ,&nbsp;Zirong Chen ,&nbsp;Jinou Zheng","doi":"10.1016/j.brainresbull.2025.111682","DOIUrl":"10.1016/j.brainresbull.2025.111682","url":null,"abstract":"<div><div>The heterogeneity of basal ganglia (BG) atrophy in temporal lobe epilepsy (TLE) has not been fully elucidated. This study employed a multimodal fusion framework to examine the potential heterogeneity of BG atrophy among TLE patients. 89 patients diagnosed with TLE were recruited. Structural magnetic resonance imaging (sMRI), resting - state functional magnetic resonance imaging (fMRI), consensus clustering (CC), and neuroimaging - transcriptomic approaches were integrated to explore the structural and functional alterations in the BG and their molecular mechanisms. Canonical correlation analysis (CCA) was employed to investigate the associations between MRI features and clinical characteristics. An individualized prediction model was constructed to facilitate clinical decision-making. CC identified a significant subgroups of BG atrophy in TLE: widespread BG atrophy (TLE-Cluster1, TLE-C1). In TLE-C1, the functional connectivity between the BG and cortical regions associated with sensation, emotion, and memory was notably enhanced. These patients additionally exhibited more severe cognitive impairment as well as higher degrees of anxiety and depression. Transcriptomic analysis established a connection between the heterogeneity of BG atrophy and specific gene expression patterns that were enriched in biological processes such as synaptic function, neurostructural development, and learning and memory. Further analyses uncovered a positive correlation between the gray matter volume of BG and cognitive performance. A classifier based on a Neural Network (NNET) predicted cognitive function with an area under curve (AUC) of 0.983. This study characterizes BG atrophy heterogeneity in TLE, its molecular mechanisms, and clinical relevance, offering insights for personalized diagnosis and management.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111682"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734693","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":"VPS25 alleviates depression-like behavior in rats by inhibiting apoptosis in the hippocampus","authors":"Lili Yuan ,&nbsp;Xiaofang Huang ,&nbsp;Qi Wang ,&nbsp;Beibei Hou ,&nbsp;Sifan Xu ,&nbsp;Zhiming Zhou ,&nbsp;Yigao Wu ,&nbsp;Jiucui Tong","doi":"10.1016/j.brainresbull.2025.111705","DOIUrl":"10.1016/j.brainresbull.2025.111705","url":null,"abstract":"<div><h3>Background</h3><div>Depression is a psychiatric disorder manifested by significant and persistent depressive symptoms. In recent years, autophagy has been identified with a key role in neuronal survival, synaptic plasticity, and depression. We previously observed that vacuolar protein sorting 25 (VPS25) was up-regulated in the hippocampus of depressive rats, but the mechanisms were unclear.</div></div><div><h3>Methods</h3><div>In chronic unpredictable mild stress (CUMS)-stimulated rats, lateral ventricles were injected with adeno-associated virus (AAV) to silence <em>VPS25</em>. Depression status in rats was evaluated using behavioral tests. In the corticosterone (CORT)-induced PC12 cell apoptosis model, Cell Counting Kit-8 (CCK-8) assays were used to determine cell viability. We next investigated the effects of CORT and VPS25 on PC12 apoptosis and proliferation using flow cytometry and cell proliferation assays. <em>VPS25</em> mRNA expression was determined using qRT-PCR, while VPS25, Bax, Bcl-2, cleaved-caspase3, P62, Beclin-1, LC3, JAK1, p-JAK1, STAT1, and p-STAT1 levels of expression were assessed using western blotting.</div></div><div><h3>Results</h3><div>Our data demonstrate that in CORT-induced PC12 cells or a CUMS-induced rat depression model, <em>VPS25</em> silencing not only alleviated CUMS-induced neuronal apoptosis in rats but also reduced CORT-induced apoptosis in PC12 cells. Notably, <em>VPS25</em> silencing alleviated CUMS-provoked depression-like behaviors, reduced neuronal apoptosis (as evidenced by TUNEL staining), and promoted autophagy flux by increasing the LC3-II/LC3-I ratio. These effects were associated with the blockade of JAK/STAT signaling.</div></div><div><h3>Conclusion</h3><div>These results indicate that silencing <em>VPS25</em> alleviates depression symptoms by promoting autophagy and inhibiting neuronal apoptosis, partly through the JAK/STAT signaling pathway.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111705"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833324","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":"CAF-derived exosomes promote the proliferation and invasion of pituitary adenoma cells via miR-184 transfer","authors":"Qiu Du ,&nbsp;Zhiyong Chen ,&nbsp;Weiyu Zhang ,&nbsp;Mengchao Zhu ,&nbsp;Zhichao Yang ,&nbsp;Yaru Li ,&nbsp;Lei Xu ,&nbsp;Jianmin Zhang ,&nbsp;Aijun Peng ,&nbsp;Qingling Feng","doi":"10.1016/j.brainresbull.2025.111678","DOIUrl":"10.1016/j.brainresbull.2025.111678","url":null,"abstract":"<div><div>Pituitary adenomas (PAs) are common intracranial tumors whose mass effects and endocrine dysfunction pose serious threats to patient health. However, the mechanisms underlying their progression, particularly the role of the tumor microenvironment (TME), remain insufficiently studied. Within this context, cancer-associated fibroblasts (CAFs) have been shown to drive tumor development via extracellular matrix remodeling and extracellular vesicle release, but their specific contributions to PA progression remain unclear. In this study, we observed a correlation between PA invasiveness and fibroblast density in the TME. Functionally, both CAFs and CAF-derived exosomes significantly enhanced the proliferation and invasion of PA cells compared to normal fibroblasts. Small RNA sequencing identified 16 upregulated and 8 downregulated miRNAs in CAF-derived exosomes, with KEGG analysis indicating enrichment in MAPK signaling, regulation of actin cytoskeleton, and lysosome-related pathways. Among these, miR-184 was notably upregulated in both CAF-derived exosomes and PA specimens. We further demonstrated that exosomal miR-184 from CAFs could be transferred into PA cells, promoting their proliferation and invasion, while miR-184 knockdown attenuated the tumor-promoting effects of CAF-derived exosomes. Mechanistically, TLE1 was validated as a direct functional target of miR-184. In summary, our study reveals exosomal miR-184 as a key mediator of CAF-driven PA progression, highlighting its potential as a therapeutic target for PAs.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111678"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695852","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}