Brain Research最新文献_第10页

Tongqiao huoxue decoction and its components promote angiogenesis and treat ischemic stroke via glycolysis-enhanced VEGF-A/VEGFR2 pathway 通窍活血汤及其组方通过糖酵解增强VEGF-A/VEGFR2通路促进血管生成，治疗缺血性脑卒中。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-21 DOI: 10.1016/j.brainres.2025.150069

Gongda Li , Zhongyu Liu , Wenwen Li , Rui Zhang , Hua Han , Peiliang Dong

Background

Tongqiao Huoxue Decoction (TQHXD), a representative Traditional Chinese Medicine (TCM) formula, is known for its effects in revitalizing the brain, opening the orifices, promoting blood circulation, and resolving stasis. It is widely used to treat stroke and related disorders.

Objective

This study aimed to investigate the effects of TQHXD and its component groups on post-ischemic angiogenesis in rats and to elucidate the underlying mechanisms.

Methods

Permanent middle cerebral artery occlusion (pMCAO) was performed in rats. Therapeutic effects of TQHXD were observed on days 1, 3, 5, and 7 post-surgery. Neurological deficits, infarct volume, cerebral edema, cortical cell morphology, and neuronal damage were assessed. Microvascular endothelial cells (CD31 + ) in the ischemic cortex were also evaluated. TQHXD was separated into two sub-formulas: Tongqiao Tongyang Group (TQTY) and Huoxue Huayu Group (HXHY). Drug efficacy was assessed using laser speckle contrast imaging for cerebral blood flow, and glycolysis-related markers were measured. Immunostaining was used to assess endothelial cell proliferation and vascular maturation. Protein levels were evaluated by Western blotting.

Results

TQHXD alleviated neurological deficits, reduced infarct volume, and improved the cellular morphology in the infarcted cortex of rats with MCAO rats on days 1, 3, 5, and 7. It promotes angiogenesis, manifested as a significant increase in CD31 + endothelial cells on day 7. TQHXD and its components markedly improved cerebral blood flow, increased blood perfusion velocity, and restored perfusion homogeneity in the MCAO rats. What’s more, TQHXD and HXHY enhanced glycolytic activity in endothelial cells, and promoted angiogenesis and vascular maturation. These effects were associated with the upregulation of key signaling molecules, including VEGF-A/VEGFR2, p-PI3K/PI3K, p-AKT/AKT, p-PLCγ1/PLCγ1, and p-ERK1/2/ERK1/2.

Conclusion

TQHXD and HXHY promote angiogenesis and treat ischemic stroke (IS) by activating the VEGF-A/VEGFR2-PI3K/AKT and VEGF-A/VEGFR2-PLCγ1/ERK1/2 pathways through enhanced glycolysis.

背景：通窍活血汤（TQHXD）是一种代表性的中药方剂，具有活脑、通窍、活血、化瘀的功效。它被广泛用于治疗中风和相关疾病。目的：本研究旨在探讨通络通络合剂及其各组分对大鼠缺血后血管生成的影响，并探讨其作用机制。方法：采用大鼠永久性大脑中动脉闭塞术。于术后第1、3、5、7天观察TQHXD的治疗效果。评估神经功能缺损、梗死体积、脑水肿、皮质细胞形态和神经元损伤。同时对缺血皮质微血管内皮细胞（CD31 + ）进行检测。TQHXD分为两个子配方：通桥通阳组（TQTY）和活血化瘀组（HXHY）。采用激光散斑对比成像评估脑血流的疗效，并测量糖酵解相关标志物。免疫染色用于评估内皮细胞增殖和血管成熟。Western blotting检测蛋白水平。结果：TQHXD可减轻MCAO大鼠1、3、5、7天的神经功能缺损，减少梗死体积，改善梗死皮质细胞形态。它促进血管生成，表现为在第7天CD31 + 内皮细胞显著增加。TQHXD及其组分明显改善MCAO大鼠脑血流量，增加血流灌注速度，恢复血流均匀性。TQHXD和HXHY增强内皮细胞糖酵解活性，促进血管生成和血管成熟。这些作用与关键信号分子的上调有关，包括VEGF-A/VEGFR2、p-PI3K/PI3K、p-AKT/AKT、p- plc - γ1/ plc - γ1和p-ERK1/2/ERK1/2。结论：TQHXD和HXHY通过增强糖酵解，激活VEGF-A/VEGFR2-PI3K/AKT和VEGF-A/ vegfr2 - plc - γ1/ERK1/2通路，促进血管生成，治疗缺血性卒中。

{"title":"Tongqiao huoxue decoction and its components promote angiogenesis and treat ischemic stroke via glycolysis-enhanced VEGF-A/VEGFR2 pathway","authors":"Gongda Li , Zhongyu Liu , Wenwen Li , Rui Zhang , Hua Han , Peiliang Dong","doi":"10.1016/j.brainres.2025.150069","DOIUrl":"10.1016/j.brainres.2025.150069","url":null,"abstract":"<div><h3>Background</h3><div>Tongqiao Huoxue Decoction (TQHXD), a representative Traditional Chinese Medicine (TCM) formula, is known for its effects in revitalizing the brain, opening the orifices, promoting blood circulation, and resolving stasis. It is widely used to treat stroke and related disorders.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the effects of TQHXD and its component groups on post-ischemic angiogenesis in rats and to elucidate the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Permanent middle cerebral artery occlusion (pMCAO) was performed in rats. Therapeutic effects of TQHXD were observed on days 1, 3, 5, and 7 post-surgery. Neurological deficits, infarct volume, cerebral edema, cortical cell morphology, and neuronal damage were assessed. Microvascular endothelial cells (CD31 + ) in the ischemic cortex were also evaluated. TQHXD was separated into two sub-formulas: Tongqiao Tongyang Group (TQTY) and Huoxue Huayu Group (HXHY). Drug efficacy was assessed using laser speckle contrast imaging for cerebral blood flow, and glycolysis-related markers were measured. Immunostaining was used to assess endothelial cell proliferation and vascular maturation. Protein levels were evaluated by Western blotting.</div></div><div><h3>Results</h3><div>TQHXD alleviated neurological deficits, reduced infarct volume, and improved the cellular morphology in the infarcted cortex of rats with MCAO rats on days 1, 3, 5, and 7. It promotes angiogenesis, manifested as a significant increase in CD31 + endothelial cells on day 7. TQHXD and its components markedly improved cerebral blood flow, increased blood perfusion velocity, and restored perfusion homogeneity in the MCAO rats. What’s more, TQHXD and HXHY enhanced glycolytic activity in endothelial cells, and promoted angiogenesis and vascular maturation. These effects were associated with the upregulation of key signaling molecules, including VEGF-A/VEGFR2, p-PI3K/PI3K, p-AKT/AKT, p-PLCγ1/PLCγ1, and p-ERK1/2/ERK1/2.</div></div><div><h3>Conclusion</h3><div>TQHXD and HXHY promote angiogenesis and treat ischemic stroke (IS) by activating the VEGF-A/VEGFR2-PI3K/AKT and VEGF-A/VEGFR2-PLCγ1/ERK1/2 pathways through enhanced glycolysis.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150069"},"PeriodicalIF":2.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer’s disease 线粒体在阿尔茨海默病的发展过程中是神经元-胶质细胞串扰的重要组成部分。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-19 DOI: 10.1016/j.brainres.2025.150040

Maryam Sardari , Oveis Hosseinzadeh Sahafi , Ameneh Rezayof

Alzheimer’s disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.

阿尔茨海默病（AD）是一种多发性进行性神经退行性疾病，通常以淀粉样蛋白-β (a β)斑块的积累、神经原纤维缠结（nft）以及胆碱能和谷氨酸能系统的功能障碍为特征。在阿尔茨海默病的早期阶段，线粒体通过补偿能量波动在神经元和胶质细胞中起神经保护细胞器的作用。随着疾病的进展，神经元和神经胶质细胞的线粒体功能恶化，最终导致细胞代谢受损和神经胶质过度激活。这种时间依赖性的小胶质细胞和星形胶质细胞的过度激活依次促进促炎细胞因子的释放，升高活性氧，破坏钙稳态，增加氧化应激。总之，这些过程驱动神经炎症，而神经炎症既影响线粒体活动，又受线粒体活动的影响。此外，线粒体功能障碍阻碍了神经元和神经胶质细胞之间的交流，促进了神经元的兴奋性毒性。这篇综述强调了线粒体动力学在不同阶段阿尔茨海默病病理生理中的重要作用，并探讨了细胞特异性靶向线粒体活性如何减轻神经炎症，恢复神经元功能，并提供潜在的治疗益处。增强健康神经元和神经胶质细胞（尤其是小胶质细胞）的线粒体功能，作为一种代偿机制，特别是在疾病早期或在后期恢复存活神经元的线粒体功能，可能促进神经保护并改善神经元-神经胶质相互作用，从而为阿尔茨海默病的治疗提供了一种潜在的策略。

{"title":"Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer’s disease","authors":"Maryam Sardari , Oveis Hosseinzadeh Sahafi , Ameneh Rezayof","doi":"10.1016/j.brainres.2025.150040","DOIUrl":"10.1016/j.brainres.2025.150040","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150040"},"PeriodicalIF":2.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trait hostility modulates the impact of cathodal tDCS on frustration-induced aggression 特质敌意调节负性tDCS对挫折攻击的影响。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-19 DOI: 10.1016/j.brainres.2025.150062

Takeshi Hirono , Hiyori Horii , Sean Draine , Ryusuke Suzuki , Rika Yano , Inaho Shishido , Yuji Inagaki , Taisuke Miyazaki , Daisuke Sawamura

Aggression, particularly reactive aggression, is a key contributor to violence and public health burdens. The left ventrolateral prefrontal cortex (VLPFC) is central to downregulating and eliciting aggression, and its influence varies with trait hostility, a dispositional tendency toward mistrust and resentment. We aimed to examine whether transcranial direct current stimulation (tDCS) of the left VLPFC alters frustration-induced aggression and whether its impact is moderated by trait hostility. Ninety-nine healthy right-handed men were randomized in a double-blind, sham-controlled trial to receive anodal, cathodal, or sham tDCS while completing an unsolvable number-sequence task. Aggression was quantified using a competitive reaction time task and physiological measurements. Although frustration induction was successful across all groups, no significant group-level differences were observed in aggression or physiological responses. However, trait hostility moderated the effect of stimulation on aggressive behavior: aggression was suppressed among individuals with low hostility but was enhanced among those with high hostility, particularly under cathodal stimulation. These findings suggest that trait hostility critically influences the behavioral impact of tDCS on aggression. Taken together, these findings underscore the dual function of the left VLPFC in anger regulation and highlight the importance of tailoring neuromodulatory interventions to individual hostility levels.

侵略，特别是反应性侵略，是造成暴力和公共卫生负担的一个主要因素。左腹外侧前额叶皮层（VLPFC）是下调和引发攻击的核心，其影响随敌意（不信任和怨恨的性格倾向）的特征而变化。我们的目的是研究经颅直流电刺激（tDCS）是否会改变左侧VLPFC的挫折性攻击，以及其影响是否会被特质性敌意所调节。在一项双盲、假对照试验中，99名健康的右撇子男性被随机分配接受阳极、阴极或假tDCS，同时完成一项无法解决的数字序列任务。通过竞争性反应时间任务和生理测量对攻击性进行量化。虽然挫折诱导在所有组中都是成功的，但在攻击或生理反应方面没有观察到显著的组水平差异。然而，特质敌意调节刺激对攻击行为的影响：低敌意个体的攻击行为被抑制，而高敌意个体的攻击行为被增强，尤其是在阴极刺激下。这些研究结果表明，敌意特质对tDCS对攻击行为的影响至关重要。综上所述，这些发现强调了左侧VLPFC在愤怒调节中的双重功能，并强调了针对个体敌意水平量身定制神经调节干预的重要性。

{"title":"Trait hostility modulates the impact of cathodal tDCS on frustration-induced aggression","authors":"Takeshi Hirono , Hiyori Horii , Sean Draine , Ryusuke Suzuki , Rika Yano , Inaho Shishido , Yuji Inagaki , Taisuke Miyazaki , Daisuke Sawamura","doi":"10.1016/j.brainres.2025.150062","DOIUrl":"10.1016/j.brainres.2025.150062","url":null,"abstract":"<div><div>Aggression, particularly reactive aggression, is a key contributor to violence and public health burdens. The left ventrolateral prefrontal cortex (VLPFC) is central to downregulating and eliciting aggression, and its influence varies with trait hostility, a dispositional tendency toward mistrust and resentment. We aimed to examine whether transcranial direct current stimulation (tDCS) of the left VLPFC alters frustration-induced aggression and whether its impact is moderated by trait hostility. Ninety-nine healthy right-handed men were randomized in a double-blind, sham-controlled trial to receive anodal, cathodal, or sham tDCS while completing an unsolvable number-sequence task. Aggression was quantified using a competitive reaction time task and physiological measurements. Although frustration induction was successful across all groups, no significant group-level differences were observed in aggression or physiological responses. However, trait hostility moderated the effect of stimulation on aggressive behavior: aggression was suppressed among individuals with low hostility but was enhanced among those with high hostility, particularly under cathodal stimulation. These findings suggest that trait hostility critically influences the behavioral impact of tDCS on aggression. Taken together, these findings underscore the dual function of the left VLPFC in anger regulation and highlight the importance of tailoring neuromodulatory interventions to individual hostility levels.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1871 ","pages":"Article 150062"},"PeriodicalIF":2.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure, Function, Pathomechanisms and Targeting of TDP-43 in Neurodegeneration TDP-43在神经退行性变中的结构、功能、病理机制及靶向作用。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-19 DOI: 10.1016/j.brainres.2025.150063

Xudong Zhang , Baiwen Zhang , Yaxin Shang , Li Zou

The TDP-43 protein has a significant relationship to the aetiology of neurodegenerative disorders. Based on its protein structure, protein modification and RNA function, this study analysed its various biological effects and the pathological effects of these biological effects in neurodegenerative diseases. It was found that TDP-43 protein undergoes conformational changes and functional alterations through protein phosphorylation, ubiquitination, SUMOylation, and acetylation, promoting its removal from the nucleus and transforming it from a normal, functional protein to an abnormally aggregated, pathological protein. It is involved in oxidative stress, inflammatory response, autophagy, angiogenesis and other biological effects. Furthermore, investigations have demonstrated that the TDP-43 protein is directly associated with neuronal growth, axon guidance, and synaptic activity, suggesting it may potentially play a significant role in the onset of degenerative neurological conditions. Based on this, the treatment strategy and future research direction are outlined to provide some insights into understanding the pathogenic mechanisms of neurodegenerative disorders and potential treatment approaches.

TDP-43蛋白与神经退行性疾病的病因学有重要关系。本研究从其蛋白结构、蛋白修饰和RNA功能等方面分析了其各种生物学效应以及这些生物学效应在神经退行性疾病中的病理作用。研究发现，TDP-43蛋白通过磷酸化、泛素化、sumo化和乙酰化发生构象改变和功能改变，促进其从细胞核中移除，使其从正常的功能蛋白转变为异常聚集的病理蛋白。它参与氧化应激、炎症反应、自噬、血管生成等生物效应。此外，研究表明，TDP-43蛋白与神经元生长、轴突引导和突触活动直接相关，这表明它可能在神经退行性疾病的发病中发挥重要作用。在此基础上，概述了神经退行性疾病的治疗策略和未来的研究方向，为了解神经退行性疾病的发病机制和潜在的治疗途径提供一些见解。

{"title":"Structure, Function, Pathomechanisms and Targeting of TDP-43 in Neurodegeneration","authors":"Xudong Zhang , Baiwen Zhang , Yaxin Shang , Li Zou","doi":"10.1016/j.brainres.2025.150063","DOIUrl":"10.1016/j.brainres.2025.150063","url":null,"abstract":"<div><div>The TDP-43 protein has a significant relationship to the aetiology of neurodegenerative disorders. Based on its protein structure, protein modification and RNA function, this study analysed its various biological effects and the pathological effects of these biological effects in neurodegenerative diseases. It was found that TDP-43 protein undergoes conformational changes and functional alterations through protein phosphorylation, ubiquitination, SUMOylation, and acetylation, promoting its removal from the nucleus and transforming it from a normal, functional protein to an abnormally aggregated, pathological protein. It is involved in oxidative stress, inflammatory response, autophagy, angiogenesis and other biological effects. Furthermore, investigations have demonstrated that the TDP-43 protein is directly associated with neuronal growth, axon guidance, and synaptic activity, suggesting it may potentially play a significant role in the onset of degenerative neurological conditions. Based on this, the treatment strategy and future research direction are outlined to provide some insights into understanding the pathogenic mechanisms of neurodegenerative disorders and potential treatment approaches.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150063"},"PeriodicalIF":2.6,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synaptic function of descending projections from the insular cortex to the nucleus solitary tract in the rat 大鼠岛叶皮层向孤立核束下降投射的突触功能。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-17 DOI: 10.1016/j.brainres.2025.150061

Ami Wakabayashi , Yuka Nakaya , Kiyofumi Yamamoto , Yumi Tsutsumi , Fumihiko Sato , Atsushi Yoshida , Takashi Kikuiri , Masayuki Kobayashi

The rostral part of the nucleus of the solitary tract (rNST) receives gustatory inputs via the facial, glossopharyngeal, and vagus nerves. In addition to these ascending pathways, the rNST receives descending projections from higher brain regions, including the insular cortex (IC). Neurons in the dysgranular and granular IC around the middle cerebral artery (MCA) respond to gustatory stimulation; therefore, descending IC projections to the rNST are thought to regulate gustatory information processing. However, little is known about how IC inputs modulate rNST neuronal activity at the synaptic level, which comprises both glutamatergic and GABAergic neurons. In this study, we examined the synaptic strength of IC → rNST projections in glutamatergic and GABAergic neurons using vesicular GABA transporter–Venus transgenic rats. We first confirmed that the IC subregion around the MCA, a region where gustatory information converges, projects axons to the rNST. Whole-cell patch-clamp recordings revealed that rNST neurons could be classified into three groups: regular-spiking (68.2 %), late-spiking (22.7 %), and burst-spiking (9.1 %). Among glutamatergic neurons, 58.8 % were regular-spiking, 23.5 % were late-spiking, and 17.6 % were burst-spiking, whereas GABAergic neurons were predominantly regular-spiking (77.8 %), with fewer late-spiking (18.5 %) and burst-spiking (3.7 %) neurons. In rats injected with AAV5-CAG-ChR2(H134R)-mCherry into the IC subregion, both glutamatergic and GABAergic rNST neurons exhibited photostimulation-induced monosynaptic excitatory postsynaptic currents with comparable amplitudes and latencies. Paired whole-cell recordings further demonstrated that glutamatergic neurons receive inhibitory inputs from rNST GABAergic neurons with a high failure rate. These findings suggest that IC projections to the rNST primarily enhance excitatory output from the rNST neurons. (250/250 words)

孤立束核的吻侧部通过面神经、舌咽神经和迷走神经接受味觉输入。除了这些上升通路外，rNST还接收来自包括岛叶皮质（IC）在内的大脑高级区域的下降投射。大脑中动脉（MCA）周围的非颗粒状和颗粒状IC中的神经元对味觉刺激有反应；因此，向下的IC投射到rNST被认为调节了味觉信息的处理。然而，对于IC输入如何在突触水平上调节rNST神经元的活动知之甚少，其中包括谷氨酸能神经元和gaba能神经元。在这项研究中，我们用泡状GABA转运体- venus转基因大鼠检测了IC → rNST在谷氨酸能和GABA能神经元中的突触强度。我们首先证实，在MCA周围的IC子区域，一个味觉信息聚集的区域，将轴突投射到rNST。全细胞膜片钳记录显示，rNST神经元可分为三组：正常尖峰（68.2% %）、晚尖峰（22.7% %）和突发尖峰（9.1% %）。在谷氨酸能神经元中，58.8% %为常规峰值，23.5% %为晚峰值，17.6% %为突发峰值，而gaba能神经元以常规峰值为主（77.8% %），晚峰值较少（18.5% %）和突发峰值较少（3.7 %）。在大鼠IC亚区注射AAV5-CAG-ChR2(H134R)-mCherry后，谷氨酸能和gaba能rNST神经元均表现出光刺激诱导的单突触兴奋性突触后电流，其振幅和潜伏期相似。配对全细胞记录进一步证明，谷氨酸能神经元接受来自rNST gaba能神经元的抑制性输入，失败率高。这些发现表明，IC对rNST的投射主要是增强rNST神经元的兴奋输出。(250/250的话)。

{"title":"Synaptic function of descending projections from the insular cortex to the nucleus solitary tract in the rat","authors":"Ami Wakabayashi , Yuka Nakaya , Kiyofumi Yamamoto , Yumi Tsutsumi , Fumihiko Sato , Atsushi Yoshida , Takashi Kikuiri , Masayuki Kobayashi","doi":"10.1016/j.brainres.2025.150061","DOIUrl":"10.1016/j.brainres.2025.150061","url":null,"abstract":"<div><div>The rostral part of the nucleus of the solitary tract (rNST) receives gustatory inputs via the facial, glossopharyngeal, and vagus nerves. In addition to these ascending pathways, the rNST receives descending projections from higher brain regions, including the insular cortex (IC). Neurons in the dysgranular and granular IC around the middle cerebral artery (MCA) respond to gustatory stimulation; therefore, descending IC projections to the rNST are thought to regulate gustatory information processing. However, little is known about how IC inputs modulate rNST neuronal activity at the synaptic level, which comprises both glutamatergic and GABAergic neurons. In this study, we examined the synaptic strength of IC → rNST projections in glutamatergic and GABAergic neurons using vesicular GABA transporter–Venus transgenic rats. We first confirmed that the IC subregion around the MCA, a region where gustatory information converges, projects axons to the rNST. Whole-cell patch-clamp recordings revealed that rNST neurons could be classified into three groups: regular-spiking (68.2 %), late-spiking (22.7 %), and burst-spiking (9.1 %). Among glutamatergic neurons, 58.8 % were regular-spiking, 23.5 % were late-spiking, and 17.6 % were burst-spiking, whereas GABAergic neurons were predominantly regular-spiking (77.8 %), with fewer late-spiking (18.5 %) and burst-spiking (3.7 %) neurons. In rats injected with AAV5-CAG-ChR2(H134R)-mCherry into the IC subregion, both glutamatergic and GABAergic rNST neurons exhibited photostimulation-induced monosynaptic excitatory postsynaptic currents with comparable amplitudes and latencies. Paired whole-cell recordings further demonstrated that glutamatergic neurons receive inhibitory inputs from rNST GABAergic neurons with a high failure rate. These findings suggest that IC projections to the rNST primarily enhance excitatory output from the rNST neurons. (250/250 words)</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150061"},"PeriodicalIF":2.6,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigating the impact of resveratrol and quercetin on glymphatic function, blood-brain barrier, and neuroglial health: A systematic review 研究白藜芦醇和槲皮素对淋巴功能、血脑屏障和神经胶质健康的影响：一项系统综述。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-13 DOI: 10.1016/j.brainres.2025.150046

Renee Grandi , Vandana Gulati , Md Shahidul Islam , Okobi Ekpo , Nitin Chitranshi

Objective

This systematic review evaluates the therapeutic potential of quercetin (QUE) and resveratrol (RSV) in Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), focusing on their effects on glymphatic function, cerebrospinal fluid (CSF) dynamics, neuroglial health, and blood–brain barrier (BBB) permeability.

Methods

A systematic search was conducted across PubMed, ScienceDirect, and ProQuest following PRISMA guidelines for studies published between 2019 and 2024. Thirty-six studies, including experimental models and clinical trials, were identified and assessed for outcomes relating to antioxidant, anti-inflammatory, and neuroprotective effects of QUE and RSV.

Results

Across 36 studies, both QUE and RSV significantly enhanced antioxidant defences (upregulation of SOD, GSH, GPx, CAT) and downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB). BBB integrity improved via increased claudin‑5/occludin/ZO‑1 expression and reduced Evans blue/sodium fluorescein extravasation; cerebrovascular reactivity and cerebral blood flow (CBF) were frequently restored. Glymphatic outcomes demonstrated enhanced AQP4 polarisation at end feet and accelerated clearance of fluorescent tracers and β-amyloid in vivo, with preserved astrocyte–pericyte coupling. Neuroglial health improved (reduced microglial M1 markers, increased M2/Arg‑1 and astrocytic homeostatic markers), alongside neuronal survival, remyelination markers, and synaptic proteins. Nanoparticle/liposomal formulations of QUE/RSV increased BBB penetration and brain concentrations relative to free compounds.

Conclusion

QUE and RSV demonstrate significant potential as adjunctive therapies for mitigating neuroinflammation, oxidative stress, and neurodegenerative progression through glymphatic and BBB modulation. However, further high-quality, long-term clinical trials are needed to validate these findings, optimise delivery systems, and establish translational relevance to human neurodegenerative conditions.

目的：本系统评价槲皮素（QUE）和白藜芦醇（RSV）在阿尔茨海默病（AD）、帕金森病（PD）和多发性硬化症（MS）中的治疗潜力，重点关注它们对淋巴功能、脑脊液（CSF）动力学、神经胶质健康和血脑屏障（BBB）通透性的影响。方法：根据PRISMA指南，对2019年至2024年间发表的研究进行了PubMed、ScienceDirect和ProQuest的系统检索。包括实验模型和临床试验在内的36项研究被确定并评估了QUE和RSV的抗氧化、抗炎和神经保护作用。结果：在56项研究中，QUE和RSV均显著增强抗氧化防御（SOD、GSH、GPx、CAT上调），下调促炎细胞因子（IL-1β、IL-6、TNF-α、NF-κB）。一些研究也报道了Nrf2/HO-1和SIRT1/AMPK的激活。通过增加claudin - 5/occludin/ZO - 1表达和减少埃文斯蓝/荧光素钠外渗，血脑屏障完整性得到改善；脑血管反应性和脑血流量（CBF）经常恢复。glymatic结果显示末端足AQP4极化增强，荧光示踪剂和β-淀粉样蛋白在体内的清除加速，并保留星形细胞-周细胞偶联。神经胶质健康得到改善（小胶质M1标记物减少，M2/Arg - 1和星形细胞稳态标记物增加），同时神经元存活和突触蛋白也得到改善。相对于游离化合物，QUE/RSV的纳米颗粒/脂质体制剂增加血脑屏障渗透和脑浓度。结论：QUE和RSV作为辅助疗法具有显著的潜力，可通过淋巴和血脑屏障调节缓解神经炎症、氧化应激和神经退行性进展。然而，需要进一步的高质量、长期的临床试验来验证这些发现，优化给药系统，并建立与人类神经退行性疾病的转化相关性。

{"title":"Investigating the impact of resveratrol and quercetin on glymphatic function, blood-brain barrier, and neuroglial health: A systematic review","authors":"Renee Grandi , Vandana Gulati , Md Shahidul Islam , Okobi Ekpo , Nitin Chitranshi","doi":"10.1016/j.brainres.2025.150046","DOIUrl":"10.1016/j.brainres.2025.150046","url":null,"abstract":"<div><h3>Objective</h3><div>This systematic review evaluates the therapeutic potential of quercetin (QUE) and resveratrol (RSV) in Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), focusing on their effects on glymphatic function, cerebrospinal fluid (CSF) dynamics, neuroglial health, and blood–brain barrier (BBB) permeability.</div></div><div><h3>Methods</h3><div>A systematic search was conducted across PubMed, ScienceDirect, and ProQuest following PRISMA guidelines for studies published between 2019 and 2024. Thirty-six studies, including experimental models and clinical trials, were identified and assessed for outcomes relating to antioxidant, anti-inflammatory, and neuroprotective effects of QUE and RSV.</div></div><div><h3>Results</h3><div>Across 36 studies, both QUE and RSV significantly enhanced antioxidant defences (upregulation of SOD, GSH, GPx, CAT) and downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB). BBB integrity improved via increased claudin‑5/occludin/ZO‑1 expression and reduced Evans blue/sodium fluorescein extravasation; cerebrovascular reactivity and cerebral blood flow (CBF) were frequently restored. Glymphatic outcomes demonstrated enhanced AQP4 polarisation at end feet and accelerated clearance of fluorescent tracers and β-amyloid <em>in vivo</em>, with preserved astrocyte–pericyte coupling. Neuroglial health improved (reduced microglial M1 markers, increased M2/Arg‑1 and astrocytic homeostatic markers), alongside neuronal survival, remyelination markers, and synaptic proteins. Nanoparticle/liposomal formulations of QUE/RSV increased BBB penetration and brain concentrations relative to free compounds.</div></div><div><h3>Conclusion</h3><div>QUE and RSV demonstrate significant potential as adjunctive therapies for mitigating neuroinflammation, oxidative stress, and neurodegenerative progression through glymphatic and BBB modulation. However, further high-quality, long-term clinical trials are needed to validate these findings, optimise delivery systems, and establish translational relevance to human neurodegenerative conditions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150046"},"PeriodicalIF":2.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer’s disease 下一代神经疗法：阿尔茨海默病单克隆抗体的机制见解。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-13 DOI: 10.1016/j.brainres.2025.150047

Akhil Sharma, Thakur Gurjeet Singh

Monoclonal antibodies (mAbs) for Alzheimer’s disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation via anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies—especially dual Aβ/tau targeting—demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood–brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.

针对阿尔茨海默病（AD）的单克隆抗体（mab）面临着根本性的转化挑战，正如淀粉样蛋白- β (a β)靶向单克隆抗体所证明的那样，该单克隆抗体成功地利用了片段结晶γ受体(FcγR)/免疫受体酪氨酸激活基序（ITAM）介导的小胶质吞噬，但仅实现了适度的认知改善，同时引入了显著的淀粉样蛋白相关成像异常（ARIA）风险。从而突出了固有的单一疗法的局限性。基于这些发现，tau定向抗体通过靶向病理播种和繁殖显示出临床前的希望，但面临着转化挑战，包括有限的细胞外可及性和不同疾病阶段的不同疗效，需要扩展到单靶点方法之外。因此，翻译领域正朝着创新的多机制策略发展，包括通过抗prp和神经营养受体激动剂提供独立于斑块减少的功能益处的突触恢复，通过抗cd33和补体抑制剂进行神经炎症调节，由于结果不同，需要仔细选择患者，以及新兴的抗trem2和抗apoe4单克隆抗体，实现针对个体基因谱的精准医疗。重要的是，比较研究还表明，联合治疗-特别是双Aβ/tau靶向-显示出卓越的协同效果，推动下一代工程进展，包括降低ARIA风险的Fc修饰，具有增强血脑屏障（BBB）穿透性的纳米体/单链可变片段（scFvs），细胞内tau通路的细胞穿透格式，以及优化组织特异性结合的ph敏感糖工程。最终，成功的临床转化取决于整合生物标志物引导的患者选择、优化的给药策略和适合疾病阶段的时机，以及通过双特异性/多特异性抗体靶向互补途径和个性化生物标志物方法预期的未来进展，共同为阿尔茨海默病患者实现真正的神经保护和有意义的疾病改变提供现实的潜力，而不是对症治疗。

{"title":"Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer’s disease","authors":"Akhil Sharma, Thakur Gurjeet Singh","doi":"10.1016/j.brainres.2025.150047","DOIUrl":"10.1016/j.brainres.2025.150047","url":null,"abstract":"<div><div>Monoclonal antibodies (mAbs) for Alzheimer’s disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation <em>via</em> anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies—especially dual Aβ/tau targeting—demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood–brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150047"},"PeriodicalIF":2.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Brain development and musical skills: A longitudinal twin study on brain developmental trajectories and sensorimotor synchronization 脑发育和音乐技能：脑发育轨迹和感觉运动同步的纵向双胞胎研究。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-13 DOI: 10.1016/j.brainres.2025.150045

L. van Drunen , B.G. Schultz , A.I. Becht , R.S. Schaefer , L.M. Wierenga

There are individual differences in brain developmental patterns, yet it is unknown to what extent these may be driven by enriched experiences. Moreover, it is not well known whether enriched experiences may result in attenuated or accelerated brain development. Studying the relation between music performance and the brain using a large longitudinal twin study provides a framework for better understanding the genetic and environmental effects on brain development in childhood. The present region-of-interest study tested whether individual differences in sensorimotor synchronization with an auditorily cued finger tapping task are related to individual differences in developmental brain trajectories and if this relation was genetically or environmentally driven. The present study included a longitudinal twin design with up to 3 MRI waves of data (7–14 years old; N_t1 = 418, N_T2 = 367, N_T3 = 228). In line with our preregistered hypotheses, results showed that attenuated patterns of brain development in 27 % of motor and affective ROIs were associated with SMS performance independent of socio-economic status effects. Furthermore, brain-behavior associations were at least partly driven by shared and unique environmental/measurement error effects, in addition to genetic influences. Possibly, attenuated brain development may be indicative of prolonged brain plasticity related to enriched environmental experiences, such as musical training, in addition to predisposing genetic factors.

大脑发育模式存在个体差异，但尚不清楚这些差异在多大程度上可能是由丰富的经历驱动的。此外，我们还不清楚丰富的经历是否会导致大脑发育的减弱或加速。通过一项大型纵向双胞胎研究来研究音乐表演与大脑之间的关系，为更好地理解遗传和环境对儿童时期大脑发育的影响提供了一个框架。当前的兴趣区域研究测试了听觉提示的手指敲击任务的感觉运动同步的个体差异是否与大脑发育轨迹的个体差异有关，以及这种关系是遗传还是环境驱动的。本研究包括纵向双胞胎设计，最多3个MRI波的数据（7-14 岁；Nt1 = 418,NT2 = 367,NT3 = 228）。与我们预先登记的假设一致，结果表明，27% %的运动和情感roi的大脑发育减弱模式与SMS表现相关，而不受社会经济地位的影响。此外，除了遗传影响外，大脑-行为关联至少部分是由共同的和独特的环境/测量误差效应驱动的。可能，大脑发育的减弱可能表明，除了易患的遗传因素外，大脑可塑性的延长与丰富的环境体验（如音乐训练）有关。

{"title":"Brain development and musical skills: A longitudinal twin study on brain developmental trajectories and sensorimotor synchronization","authors":"L. van Drunen , B.G. Schultz , A.I. Becht , R.S. Schaefer , L.M. Wierenga","doi":"10.1016/j.brainres.2025.150045","DOIUrl":"10.1016/j.brainres.2025.150045","url":null,"abstract":"<div><div>There are individual differences in brain developmental patterns, yet it is unknown to what extent these may be driven by enriched experiences. Moreover, it is not well known whether enriched experiences may result in attenuated or accelerated brain development. Studying the relation between music performance and the brain using a large longitudinal twin study provides a framework for better understanding the genetic and environmental effects on brain development in childhood. The present region-of-interest study tested whether individual differences in sensorimotor synchronization with an auditorily cued finger tapping task are related to individual differences in developmental brain trajectories and if this relation was genetically or environmentally driven. The present study included a longitudinal twin design with up to 3 MRI waves of data (7–14 years old; N<sub>t1</sub> = 418, N<sub>T2</sub> = 367, N<sub>T3</sub> = 228). In line with our preregistered hypotheses, results showed that attenuated patterns of brain development in 27 % of motor and affective ROIs were associated with SMS performance independent of socio-economic status effects. Furthermore, brain-behavior associations were at least partly driven by shared and unique environmental/measurement error effects, in addition to genetic influences. Possibly, attenuated brain development may be indicative of prolonged brain plasticity related to enriched environmental experiences, such as musical training, in addition to predisposing genetic factors.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150045"},"PeriodicalIF":2.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inherited and seizure-induced abnormalities in the temporal cortex astroglia of Krushinsky-Molodkina audiogenic rats: A pilot study 克鲁辛斯基-莫洛奇纳听性大鼠颞叶皮层星形胶质细胞的遗传和癫痫诱发异常：一项初步研究。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-12 DOI: 10.1016/j.brainres.2025.150056

Yulia S. Grigorieva, Ksenia A. Ivanova, Elena V. Chernigovskaya, Alexandra A. Naumova, Margarita V. Glazova

The role of astrocytes in the pathogenesis of temporal lobe epilepsy (TLE) is intensively studied. Here, we present a pilot study of astrocytes in the temporal cortex of Krushinsky-Molodkina (KM) rats, which are genetically prone to audiogenic seizures (AGS) and may be used as a model of TLE when exposed to audiogenic kindling. Naïve KM rats (with no AGS) were compared to Wistar rats to disclose the inherited abnormalities, and KM rats after 14-day audiogenic kindling were compared to naïve ones to determine TLE effects. Our results demonstrated that in the temporal cortex of naïve KM rats, the population of ALDH1L1-positive astrocytes was unaltered, while GFAP-positive astrocytes were localized only in the outer layers. Nuclear factor IA (NFIA)-positive astrocytes were distributed evenly, but their number was also lower. In addition, decreased aquaporin 4 and Kir4.1 were revealed indicating defective water and potassium homeostasis. These data point on genetically determined disfunction of cortex astroglia associated with inherited epileptic predisposition. After audiogenic kindling, KM rats still demonstrated no changes in ALDH1L1 expression, however, exhibited increased number of NFIA-positive astrocytes in the temporal cortex and upregulation of GFAP, aldolase C, and glutamine synthetase. Meanwhile, kindling further exacerbated the basal deficits of aquaporin 4 and Kir4.1.

星形胶质细胞在颞叶癫痫（TLE）发病机制中的作用被深入研究。在这里，我们对Krushinsky-Molodkina （KM）大鼠颞叶皮层的星形胶质细胞进行了初步研究，Krushinsky-Molodkina （KM）大鼠在遗传上容易发生听源性癫痫（AGS），可能被用作暴露于听源性点燃时的TLE模型。将未发生AGS的Naïve KM大鼠与Wistar大鼠进行比较，以揭示遗传异常，并将14 d后的KM大鼠与naïve大鼠进行比较，以确定TLE的影响。我们的研究结果表明，在naïve KM大鼠的颞叶皮层中，aldh1l1阳性星形胶质细胞的数量没有改变，而gmap阳性星形胶质细胞仅位于外层。核因子IA （NFIA）阳性星形胶质细胞分布均匀，但数量较少。此外，水通道蛋白4和Kir4.1的减少表明水钾平衡存在缺陷。这些数据表明，大脑皮层星形胶质细胞的功能障碍与遗传性癫痫易感性有关。听原点燃后，KM大鼠ALDH1L1表达未见变化，但颞叶皮层nfia阳性星形胶质细胞数量增加，GFAP、醛缩酶C、谷氨酰胺合成酶表达上调。同时，点燃进一步加剧了水通道蛋白4和Kir4.1的基础缺陷。

{"title":"Inherited and seizure-induced abnormalities in the temporal cortex astroglia of Krushinsky-Molodkina audiogenic rats: A pilot study","authors":"Yulia S. Grigorieva, Ksenia A. Ivanova, Elena V. Chernigovskaya, Alexandra A. Naumova, Margarita V. Glazova","doi":"10.1016/j.brainres.2025.150056","DOIUrl":"10.1016/j.brainres.2025.150056","url":null,"abstract":"<div><div>The role of astrocytes in the pathogenesis of temporal lobe epilepsy (TLE) is intensively studied. Here, we present a pilot study of astrocytes in the temporal cortex of Krushinsky-Molodkina (KM) rats, which are genetically prone to audiogenic seizures (AGS) and may be used as a model of TLE when exposed to audiogenic kindling. Naïve KM rats (with no AGS) were compared to Wistar rats to disclose the inherited abnormalities, and KM rats after 14-day audiogenic kindling were compared to naïve ones to determine TLE effects. Our results demonstrated that in the temporal cortex of naïve KM rats, the population of ALDH1L1-positive astrocytes was unaltered, while GFAP-positive astrocytes were localized only in the outer layers. Nuclear factor IA (NFIA)-positive astrocytes were distributed evenly, but their number was also lower. In addition, decreased aquaporin 4 and Kir4.1 were revealed indicating defective water and potassium homeostasis. These data point on genetically determined disfunction of cortex astroglia associated with inherited epileptic predisposition. After audiogenic kindling, KM rats still demonstrated no changes in ALDH1L1 expression, however, exhibited increased number of NFIA-positive astrocytes in the temporal cortex and upregulation of GFAP, aldolase C, and glutamine synthetase. Meanwhile, kindling further exacerbated the basal deficits of aquaporin 4 and Kir4.1.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150056"},"PeriodicalIF":2.6,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcription factors implicated in substance use disorder, from immediate early genes to altered gene expression 涉及物质使用障碍的转录因子，从直接早期基因到改变的基因表达。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-12 DOI: 10.1016/j.brainres.2025.150048

Emily Orr, Jiye Yi, Dustin Baldridge

Transcription factors (TFs) link external stimuli to altered gene expression in all cell types, tissues, and biological processes. Because addiction phenotypes, including substance use disorder (SUD) cause enormous human suffering, significant effort is ongoing to understand the molecular processes that underlie these conditions, including elucidating the genetic drivers of addiction. While immense progress has been made, the combination of complex, multilocus genetics, large numbers of inherited variants of small effect size, and heterogeneous cellular physiology has proved difficult to untangle. Despite these challenges, genome-wide association studies (GWAS) have provided evidence for the likely causative role for some genes and pathways, and neurobiological molecular studies have implicated some cellular and physiological processes. These mechanisms include how the substance itself is processed, the subsequent induced signals that activate neurobiological responses and influence behavioral changes, and corresponding epigenetic and structural alterations of brain circuitry. These mechanisms persist for some users, contributing to the addictive phenotype. Central to this response is the activation of several transcription factors and cofactors that are considered “immediate early genes” (IEGs), which communicate signals through neurotransmitter signaling pathways in the brain. In this review, we aggregate published evidence that links TFs to SUD and summarize the key TFs (such as CREB1, FOSB, E2F3A, and EGR1) involved in shared cellular processes emphasizing the role of IEGs. We also document shared connections across substances and model organisms, with an emphasis on known epigenetic interactions, GWAS links, and relevance to human biology.

转录因子（TFs）将外部刺激与所有细胞类型、组织和生物过程中的基因表达改变联系起来。由于包括物质使用障碍（SUD）在内的成瘾表型给人类带来了巨大的痛苦，人们正在努力了解这些病症背后的分子过程，包括阐明成瘾的遗传驱动因素。虽然已经取得了巨大的进展，但事实证明，复杂的多位点遗传学、大量小效应的遗传变异和异质细胞生理学的结合很难解开。尽管存在这些挑战，全基因组关联研究（GWAS）已经为一些基因和途径可能的致病作用提供了证据，神经生物学分子研究也涉及了一些细胞和生理过程。这些机制包括物质本身是如何被处理的，随后激活神经生物学反应并影响行为变化的诱导信号，以及相应的脑回路的表观遗传和结构改变。这些机制在一些用户中持续存在，导致成瘾表型。这种反应的核心是几个转录因子和辅助因子的激活，这些转录因子和辅助因子被认为是“即时早期基因”（IEGs），它们通过大脑中的神经递质信号传导途径传递信号。在这篇综述中，我们收集了已发表的证据，将tf与SUD联系起来，并总结了参与共享细胞过程的关键tf（如CREB1、FOSB、E2F3A和EGR1），强调了eeg的作用。我们还记录了物质和模式生物之间的共享连接，重点是已知的表观遗传相互作用，GWAS链接以及与人类生物学的相关性。

{"title":"Transcription factors implicated in substance use disorder, from immediate early genes to altered gene expression","authors":"Emily Orr, Jiye Yi, Dustin Baldridge","doi":"10.1016/j.brainres.2025.150048","DOIUrl":"10.1016/j.brainres.2025.150048","url":null,"abstract":"<div><div>Transcription factors (TFs) link external stimuli to altered gene expression in all cell types, tissues, and biological processes. Because addiction phenotypes, including substance use disorder (SUD) cause enormous human suffering, significant effort is ongoing to understand the molecular processes that underlie these conditions, including elucidating the genetic drivers of addiction. While immense progress has been made, the combination of complex, multilocus genetics, large numbers of inherited variants of small effect size, and heterogeneous cellular physiology has proved difficult to untangle. Despite these challenges, genome-wide association studies (GWAS) have provided evidence for the likely causative role for some genes and pathways, and neurobiological molecular studies have implicated some cellular and physiological processes. These mechanisms include how the substance itself is processed, the subsequent induced signals that activate neurobiological responses and influence behavioral changes, and corresponding epigenetic and structural alterations of brain circuitry. These mechanisms persist for some users, contributing to the addictive phenotype. Central to this response is the activation of several transcription factors and cofactors that are considered “immediate early genes” (IEGs), which communicate signals through neurotransmitter signaling pathways in the brain. In this review, we aggregate published evidence that links TFs to SUD and summarize the key TFs (such as CREB1, FOSB, E2F3A, and EGR1) involved in shared cellular processes emphasizing the role of IEGs. We also document shared connections across substances and model organisms, with an emphasis on known epigenetic interactions, GWAS links, and relevance to human biology.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1870 ","pages":"Article 150048"},"PeriodicalIF":2.6,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0