Pub Date : 2026-01-08DOI: 10.1016/j.brainresbull.2025.111712
Anping Ouyang , Xinxin Lin , Tian Zhang , Jiayao Li , Chenxi Li , Lingling Wang , Zhiyuan Cao , Xuqian Diao , Wei He , Qianqian Dong , Jun Jiang , Peng Fang
Sleep deprivation (SD) impairs mood and cognition, yet its dynamic neural mechanisms remain unclear. Forty healthy adults (30-h SD) completed mood assessments, resting-state fMRI (rs-fMRI), and psychomotor vigilance task (PVT) tests at baseline and post-SD. Using dynamic functional connectivity (dFC) with sliding windows and k-means clustering, we identified two recurrent whole-brain states: (i) an economical state with sparse, weaker global coupling and (ii) a maladaptive compensatory state with globally strengthened synchronization. SD increased both the fraction of windows and mean dwell time (MDT) of the maladaptive state. Across participants, PVT lapses correlated positively with the maladaptive state’s MDT and fraction of windows and negatively with those of the economical state. Finally, we built an interpretable predictive model of PVT lapses using competitive adaptive reweighted sampling partial least-squares regression (CARS-PLSR), which highlighted connections within the dorsal attention network (DAN) as key predictors. These findings link behavioral impairment to altered brain-state dynamics and provide a sparse, testable feature set that can support early risk stratification and intervention for SD-related cognitive decline.
{"title":"The impact of sleep deprivation on dynamic functional connectivity of the brain: Based on alertness task performance","authors":"Anping Ouyang , Xinxin Lin , Tian Zhang , Jiayao Li , Chenxi Li , Lingling Wang , Zhiyuan Cao , Xuqian Diao , Wei He , Qianqian Dong , Jun Jiang , Peng Fang","doi":"10.1016/j.brainresbull.2025.111712","DOIUrl":"10.1016/j.brainresbull.2025.111712","url":null,"abstract":"<div><div>Sleep deprivation (SD) impairs mood and cognition, yet its dynamic neural mechanisms remain unclear. Forty healthy adults (30-h SD) completed mood assessments, resting-state fMRI (rs-fMRI), and psychomotor vigilance task (PVT) tests at baseline and post-SD. Using dynamic functional connectivity (dFC) with sliding windows and k-means clustering, we identified two recurrent whole-brain states: (i) an economical state with sparse, weaker global coupling and (ii) a maladaptive compensatory state with globally strengthened synchronization. SD increased both the fraction of windows and mean dwell time (MDT) of the maladaptive state. Across participants, PVT lapses correlated positively with the maladaptive state’s MDT and fraction of windows and negatively with those of the economical state. Finally, we built an interpretable predictive model of PVT lapses using competitive adaptive reweighted sampling partial least-squares regression (CARS-PLSR), which highlighted connections within the dorsal attention network (DAN) as key predictors. These findings link behavioral impairment to altered brain-state dynamics and provide a sparse, testable feature set that can support early risk stratification and intervention for SD-related cognitive decline.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111712"},"PeriodicalIF":3.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948025","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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2025.111702
Cai-bao Yue , Wei-wei Luan , Di Qiu , Xin Ding , Han-Wen Gu , Pan-Miao Liu , Kenji Hashimoto , Jian-Jun Yang , Xing-Ming Wang
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.
{"title":"A vagus-dependent gut microbiota–metabolite axis drives chronic inflammatory pain and working-memory deficits in mice","authors":"Cai-bao Yue , Wei-wei Luan , Di Qiu , Xin Ding , Han-Wen Gu , Pan-Miao Liu , Kenji Hashimoto , Jian-Jun Yang , 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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2025.111699
Jingming Shi , Yandong Ma , Lei Gao , Yuting Dai , Qian Chen , Xudong Li , Hang Liu , Ruotong Li , Jie Zhang , Chaoren Yan
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.
{"title":"The uptake of β-amyloid by various brain cells exhibits heterogeneity and correlates with the CD14 expression","authors":"Jingming Shi , Yandong Ma , Lei Gao , Yuting Dai , Qian Chen , Xudong Li , Hang Liu , Ruotong Li , Jie Zhang , 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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2026.111725
Mengzhe Zhang , Bohui Mei , Longyao Ma , Kaixin Li , Mengzhu Wang , Weijian Wang , Yong Zhang
Background
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.
Methods
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.
Results
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.
Conclusions
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.
glymphatic system （GS）是一种新发现的生物学途径，但其在烟草使用障碍（TUD）病理生理中的可能参与尚不清楚。我们的目的是评估TUD个体的GS功能，并建立GS与大脑结构和疾病临床特征之间的联系。方法招募男性受试者149例，其中TUD组92例，对照组57例，获取其3D-T1加权图像扫描、弥散张量图像扫描和临床量表。计算沿血管周围间隙弥散张量成像（DTI-ALPS）指数，评价各组间淋巴功能的变化。通过基于体素的形态分析（VBM），确定与DTI-ALPS指数相关的灰质（GM）区域。最后，通过中介模型评估DTI-ALPS指数、GM与吸烟行为之间的关系。结果与对照组相比，TUD组全脑及双侧半脑DTI-ALPS指数明显降低，且与疾病严重程度呈负相关。左侧丘脑和右侧颞下回GMV变化与DTI-ALPS平均指数呈正相关。此外，DTI-ALPS指数部分介导了TUD GMV变化与包年之间的关系。结论本研究揭示了TUD患者DTI-ALPS指数异常，认为TUD患者GS功能异常可能是烟草暴露影响GMV变化的潜在机制。这些发现为了解TUD的发病机制提供了进一步的证据，并提示GS功能可作为临床治疗策略的新靶点。
{"title":"How tobacco use disorder affects gray matter aberrance: The mediating effect of glymphatic system function","authors":"Mengzhe Zhang , Bohui Mei , Longyao Ma , Kaixin Li , Mengzhu Wang , Weijian Wang , 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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2026.111717
Rong Guo , Wenjia Wang , Rui Qian , Yang Ji , Wei Li , Meidan Zu , Qianqian Li , Jiayun Wu , Wentao Dai , Si Xu , Juanjuan Zhang , Ling Wei , Yuanyuan Guo , Yanghua Tian , Kai Wang
Background
The molecular mechanisms linking brain function alterations to gene expression in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remain unclear.
Methods
We analyzed the coefficient of variation of blood oxygenation level dependent signal (CVBOLD) 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 CVBOLD/FC changes. Multivariate linear regression evaluated neurotransmitter contributions.
Results
Anti-NMDAR encephalitis patients exhibited increased CVBOLD 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 CVBOLD/FC (pbonferrni < 0.05), enriched in synaptic signaling (MAPK, cAMP), metabolic regulation (insulin resistance), and neurodegeneration pathways. Hub genes PPARGC1A (positive correlation with CVBOLD/FC) and UBA52 (negative correlation) were validated in key brain regions. Neurotransmitter analysis showed norepinephrine (NAT) strongly contributed to CVBOLD (weight = 0.57, pFDR < 0.001), meanwhile serotonin (5HT4), cannabinoid (CB1), noradrenaline (NAT), and glutamate (NMDA) influenced FC.
Conclusion
This study identifies a transcriptional signature that is spatially associated with CVBOLD/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.
{"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 , Wenjia Wang , Rui Qian , Yang Ji , Wei Li , Meidan Zu , Qianqian Li , Jiayun Wu , Wentao Dai , Si Xu , Juanjuan Zhang , Ling Wei , Yuanyuan Guo , Yanghua Tian , 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<sub>BOLD</sub>) 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<sub>BOLD</sub>/FC changes. Multivariate linear regression evaluated neurotransmitter contributions.</div></div><div><h3>Results</h3><div>Anti-NMDAR encephalitis patients exhibited increased CV<sub>BOLD</sub> 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<sub>BOLD</sub>/FC (<em>p</em><sub>bonferrni</sub> < 0.05), enriched in synaptic signaling (MAPK, cAMP), metabolic regulation (insulin resistance), and neurodegeneration pathways. Hub genes PPARGC1A (positive correlation with CV<sub>BOLD</sub>/FC) and UBA52 (negative correlation) were validated in key brain regions. Neurotransmitter analysis showed norepinephrine (NAT) strongly contributed to CV<sub>BOLD</sub> (weight = 0.57, <em>p</em><sub><em>FDR</em></sub> < 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<sub>BOLD</sub>/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}
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.
Methods
In chronic unpredictable mild stress (CUMS)-stimulated rats, lateral ventricles were injected with adeno-associated virus (AAV) to silence VPS25. 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. VPS25 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.
Results
Our data demonstrate that in CORT-induced PC12 cells or a CUMS-induced rat depression model, VPS25 silencing not only alleviated CUMS-induced neuronal apoptosis in rats but also reduced CORT-induced apoptosis in PC12 cells. Notably, VPS25 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.
Conclusion
These results indicate that silencing VPS25 alleviates depression symptoms by promoting autophagy and inhibiting neuronal apoptosis, partly through the JAK/STAT signaling pathway.
{"title":"VPS25 alleviates depression-like behavior in rats by inhibiting apoptosis in the hippocampus","authors":"Lili Yuan , Xiaofang Huang , Qi Wang , Beibei Hou , Sifan Xu , Zhiming Zhou , Yigao Wu , 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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2025.111704
Lauren N. Miterko-Myers , Lauren E. Peacoe , Lita Duraine , Zhongyuan Zuo , Roy V. Sillitoe
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 Car8 waddles (Car8wdl) 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 Car8wdl Purkinje cells as well as mitochondrial size and density alterations. Low-frequency cerebellar DBS rescued mitochondrial density, but not size or putative contacts in Car8wdl 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.
{"title":"Cerebellar deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia","authors":"Lauren N. Miterko-Myers , Lauren E. Peacoe , Lita Duraine , Zhongyuan Zuo , 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><sup><em>wdl</em></sup>) 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><sup><em>wdl</em></sup> 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><sup><em>wdl</em></sup> 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}
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 L-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.
Niemann Pick type C1 （NPC1）是一种罕见的致死性疾病，其特征是内溶酶体（EL）脂质积聚，可导致外周器官和中枢神经系统损害，小脑和海马尤其受影响。目前在欧洲针对鼻咽癌的治疗方案很少。事实上，米卢司他是唯一被批准的药物，l -乙酰亮氨酸最近被欧洲药品管理局批准上市。因此，确定新的治疗方法是必须的。我们之前已经证明，临床上被批准用作抗血小板药物的双嘧达莫（DIP）可以恢复识别记忆并增加海马calbindin的表达。相反，该药物不能改善小脑依赖性运动功能。为了阐明DIP诱导的这些区域特异性变化的机制，本研究对NPC1小鼠模型（NPC1 -/-）海马和小脑中的基因和蛋白进行了多组学分析。我们的研究结果显示，DIP在蛋白质水平上显著影响海马的各种通路，但在基因或蛋白质水平上对小脑的通路没有显著影响。有趣的是，给予DIP的Npc1-/-小鼠海马中受影响最大的通路是与cGMP-PKG激活和线粒体功能相关的通路。我们的结果为在其他神经退行性疾病的实验模型中测试DIP铺平了道路，比如阿尔茨海默病，它同样以海马和线粒体功能障碍为特征。
{"title":"Investigation of dipyridamole-elicited signaling in the brain of Niemann Pick type C mice: A multi-omic study","authors":"Sabrina Tait , Federica Fratini , Zaira Boussadia , Lucia Gaddini , Manuela Marra , Loredana Le Pera , Gloria Venturini , 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<sup>-/-</sup>). 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<sup>-/-</sup> 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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2025.111694
Fang Yang , Yujia Zhong , Xuhong Yang , Weihong Li , Yang Zhang
Background
Ischemic stroke (IS) is a common subtype of stroke in China, accounting for 60 %-80 % of all stroke cases. Shen-Xiong-Tong-Mai granule (SXTMG) is one of the commonly used herbal medicine formulas in TCM. The present work aimed to explore the predominant active substances and molecular mechanisms underlying SXTMG against IS.
Methods
IS animal model and cell model were constructed using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) methods, respectively. The SXTMG and IS targets were predicted using four databases. UPLC/MS analysis was employed to identify the active compounds of SXTMG. The pathway changes were detected using western blot and immunofluorescence staining.
Results
Firstly, SXTMG significantly reduced the ischemic area, brain edema, and nerve function injury of MCAO rats, exhibiting crucial anti-IS effects. Totally 22 active compounds were identified in SXTMG based on HPLC-MS/MS results. After bioinformatics analysis, 89 common targets were identified, which were significantly enriched in pathways including apoptosis pathway and PI3K/Akt signaling. Finally, in vitro experiments indicated that SXTMG treatment significantly inhibited the OGD/R HT22 cell apoptosis and activated the PI3K/Akt signaling in OGD/R HT22 cells.
Conclusion
SXTMG possessed promising protective effects against IS through triggering PI3K/Akt signaling to suppress nerve cell apoptosis.
{"title":"Shen-Xiong-Tong-Mai granule suppresses nerve cell apoptosis to ameliorate ischemic stroke via activating PI3K/Akt signaling pathway","authors":"Fang Yang , Yujia Zhong , Xuhong Yang , Weihong Li , Yang Zhang","doi":"10.1016/j.brainresbull.2025.111694","DOIUrl":"10.1016/j.brainresbull.2025.111694","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic stroke (IS) is a common subtype of stroke in China, accounting for 60 %-80 % of all stroke cases. Shen-Xiong-Tong-Mai granule (SXTMG) is one of the commonly used herbal medicine formulas in TCM. The present work aimed to explore the predominant active substances and molecular mechanisms underlying SXTMG against IS.</div></div><div><h3>Methods</h3><div>IS animal model and cell model were constructed using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) methods, respectively. The SXTMG and IS targets were predicted using four databases. UPLC/MS analysis was employed to identify the active compounds of SXTMG. The pathway changes were detected using western blot and immunofluorescence staining.</div></div><div><h3>Results</h3><div>Firstly, SXTMG significantly reduced the ischemic area, brain edema, and nerve function injury of MCAO rats, exhibiting crucial anti-IS effects. Totally 22 active compounds were identified in SXTMG based on HPLC-MS/MS results. After bioinformatics analysis, 89 common targets were identified, which were significantly enriched in pathways including apoptosis pathway and PI3K/Akt signaling. Finally, in vitro experiments indicated that SXTMG treatment significantly inhibited the OGD/R HT22 cell apoptosis and activated the PI3K/Akt signaling in OGD/R HT22 cells.</div></div><div><h3>Conclusion</h3><div>SXTMG possessed promising protective effects against IS through triggering PI3K/Akt signaling to suppress nerve cell apoptosis.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111694"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833277","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}
Pub Date : 2026-01-01DOI: 10.1016/j.brainresbull.2025.111713
Jiahui Zheng , Xiaoyu Zhou , Jing Yang , Lin Tang , Yu Tang , Jing Zhang , Yong Tan , Hong Yu , Xunrong Luo , Meng Lin , Daihong Liu , Jiuquan Zhang
Background
The hippocampus and amygdala are interconnected structures critical for cognition. Existing whole-region analyses show inconsistent findings, while subregional changes and their interactions remain unclear. Therefore, we aim to investigate subregional abnormalities in breast cancer patients undergoing neoadjuvant chemotherapy, focusing on both regional and network-level alterations.
Methods
A total of 79 breast cancer (BC) patients and 98 healthy controls (HC) were enrolled in our study. The subregional volumes and network measures in BC patients were analyzed at three time points: baseline (B0), following the first cycle of neoadjuvant chemotherapy (NAC) (B1), and at the completion of therapy (B2). These were then compared with those of the HC group at B0. Partial Least Squares Regression (PLSR) identified subregional predictors of chemotherapy-related cognitive dysfunction.
Results
Subregional analysis disclosed significant volume disparities in four hippocampal subregions and one amygdala subregion among BC patients across three time points. Compared to B0, 80 % of these regions exhibited volume increases, and 80 % of these differences were statistically significant during the B1. Network analysis demonstrated significant differences in the nodal measures of the Subregion Interconnected Networks in three hippocampal subregions and one amygdalar subregion across the three time points. Notably, all these subregions are located in the right hemisphere, displaying a lateralized distribution pattern. Eleven PLSR models for multidomain cognitive functions demonstrated predictive validity, identifying key subregions as cognitive impairment biomarkers.
Conclusion
Chemotherapy induces distinct hippocampal-amygdalar subregional volumetric changes, which possess predictive significance for chemotherapy-related multidomain cognitive impairment in BC patients.
{"title":"Hippocampal-amygdala subregional characteristic changes predict heterogeneous post-chemotherapy neuropsychological outcomes","authors":"Jiahui Zheng , Xiaoyu Zhou , Jing Yang , Lin Tang , Yu Tang , Jing Zhang , Yong Tan , Hong Yu , Xunrong Luo , Meng Lin , Daihong Liu , Jiuquan Zhang","doi":"10.1016/j.brainresbull.2025.111713","DOIUrl":"10.1016/j.brainresbull.2025.111713","url":null,"abstract":"<div><h3>Background</h3><div>The hippocampus and amygdala are interconnected structures critical for cognition. Existing whole-region analyses show inconsistent findings, while subregional changes and their interactions remain unclear. Therefore, we aim to investigate subregional abnormalities in breast cancer patients undergoing neoadjuvant chemotherapy, focusing on both regional and network-level alterations.</div></div><div><h3>Methods</h3><div>A total of 79 breast cancer (BC) patients and 98 healthy controls (HC) were enrolled in our study. The subregional volumes and network measures in BC patients were analyzed at three time points: baseline (B0), following the first cycle of neoadjuvant chemotherapy (NAC) (B1), and at the completion of therapy (B2). These were then compared with those of the HC group at B0. Partial Least Squares Regression (PLSR) identified subregional predictors of chemotherapy-related cognitive dysfunction.</div></div><div><h3>Results</h3><div>Subregional analysis disclosed significant volume disparities in four hippocampal subregions and one amygdala subregion among BC patients across three time points. Compared to B0, 80 % of these regions exhibited volume increases, and 80 % of these differences were statistically significant during the B1. Network analysis demonstrated significant differences in the nodal measures of the Subregion Interconnected Networks in three hippocampal subregions and one amygdalar subregion across the three time points. Notably, all these subregions are located in the right hemisphere, displaying a lateralized distribution pattern. Eleven PLSR models for multidomain cognitive functions demonstrated predictive validity, identifying key subregions as cognitive impairment biomarkers.</div></div><div><h3>Conclusion</h3><div>Chemotherapy induces distinct hippocampal-amygdalar subregional volumetric changes, which possess predictive significance for chemotherapy-related multidomain cognitive impairment in BC patients.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"234 ","pages":"Article 111713"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892039","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}
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