Pub Date : 2026-05-01Epub Date: 2026-01-23DOI: 10.1016/j.expneurol.2026.115667
Zhaosi Zhang , Fuming Liang , Daochen Wen , Hong Chen , Nina Gu , Zhao Li , Lin Wang , Yingwen Wang , Qiuling Pan , Yajun Zhu , Dan Xu , Xiaochuan Sun , Chongjie Cheng , Jin Yan
White matter injury (WMI) is a critical factor contributing to poor neurological outcomes following subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are key regulators of WMI-related pathology and can be delivered via exosomes, yet their mechanisms and therapeutic potential remain largely unexplored. In this study, miRNA sequencing revealed a significant upregulation of miR-27a-3p in peripheral blood exosomes after SAH, which was further confirmed in white matter tissue. BV2 cell–derived exosomes loaded with miR-27a-3p antagomir were administered intranasally and effectively targeted oligodendrocytes. Treatment with these exosomes alleviated WMI by reducing oligodendrocyte apoptosis and promoting the proliferation and differentiation of oligodendrocyte precursor cells, leading to improved neurological and electrophysiological recovery. Mechanistically, miR-27a-3p inhibited PPARγ, resulting in downregulation of PRDX1 and activation of the JNK pathway, which triggered oligodendrocyte apoptosis. These findings demonstrate that exosome-mediated delivery of miR-27a-3p antagomir mitigates SAH-induced WMI through modulation of the PPARγ/PRDX1/JNK axis, providing a promising noninvasive therapeutic approach for enhancing white matter repair and functional recovery after SAH.
{"title":"Exosomes-mediated delivery of miR-27a-3p antagomir alleviates white matter injury by regulating PPARγ/PRDX1/JNK pathway after subarachnoid hemorrhage in rats","authors":"Zhaosi Zhang , Fuming Liang , Daochen Wen , Hong Chen , Nina Gu , Zhao Li , Lin Wang , Yingwen Wang , Qiuling Pan , Yajun Zhu , Dan Xu , Xiaochuan Sun , Chongjie Cheng , Jin Yan","doi":"10.1016/j.expneurol.2026.115667","DOIUrl":"10.1016/j.expneurol.2026.115667","url":null,"abstract":"<div><div>White matter injury (WMI) is a critical factor contributing to poor neurological outcomes following subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are key regulators of WMI-related pathology and can be delivered via exosomes, yet their mechanisms and therapeutic potential remain largely unexplored. In this study, miRNA sequencing revealed a significant upregulation of miR-27a-3p in peripheral blood exosomes after SAH, which was further confirmed in white matter tissue. BV2 cell–derived exosomes loaded with miR-27a-3p antagomir were administered intranasally and effectively targeted oligodendrocytes. Treatment with these exosomes alleviated WMI by reducing oligodendrocyte apoptosis and promoting the proliferation and differentiation of oligodendrocyte precursor cells, leading to improved neurological and electrophysiological recovery. Mechanistically, miR-27a-3p inhibited PPARγ, resulting in downregulation of PRDX1 and activation of the JNK pathway, which triggered oligodendrocyte apoptosis. These findings demonstrate that exosome-mediated delivery of miR-27a-3p antagomir mitigates SAH-induced WMI through modulation of the PPARγ/PRDX1/JNK axis, providing a promising noninvasive therapeutic approach for enhancing white matter repair and functional recovery after SAH.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115667"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-05-01Epub Date: 2026-01-29DOI: 10.1016/j.expneurol.2026.115675
Siva Reddy Challa , Isidra M. Baker , Casimir A. Fornal , Sahil Reddy Mada , Nabeeha Khan , Samantha N. Jackson , Erick Saldes , Jeffrey D. Klopfenstein , Swapna Asuthkar , Krishna Kumar Veeravalli
B7-H3 (CD276) is an immune checkpoint co-signaling molecule expressed on immune and non-immune cells. It is best known for suppressing T-cell responses but can also promote inflammation depending on the microenvironment. In neuroinflammatory models such as experimental autoimmune encephalomyelitis, B7-H3 expression increases concomitantly with the inflammatory response, and its inhibition is associated with reduced disease progression. Although its role in ischemic stroke remains unclear, we hypothesized that cerebral ischemia/reperfusion (I/R) would upregulate B7-H3 expression in the ischemic brain and that increased B7-H3 expression would positively correlate with pro-inflammatory cytokine expression. Young and aged male and female rodents, including normotensive and spontaneously hypertensive rats to model comorbid hypertension, underwent transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Brain tissue was collected on post-MCAO days 1, 3, 5, or 7. B7-H3 mRNA was analyzed by real-time PCR, whereas protein expression was assessed by Western blotting and immunohistochemistry at selected time points. B7-H3 expression was significantly upregulated in the ischemic brain across sexes, age groups, and species. The extent of B7-H3 degradation was influenced by species, sex, age, and time after cerebral I/R. Upregulation of B7-H3 was observed at both the mRNA and protein levels and was localized primarily to the somatosensory cortex and caudate putamen in the ipsilateral (ischemic) hemisphere, the main regions affected in this MCAO model. Elevated B7-H3 expression in the ischemic brain positively correlated with the pro-inflammatory mediator TNFα. In rats, the temporal profile of B7-H3 expression paralleled the early inflammatory phase associated with secondary tissue damage after ischemic stroke. These findings identify B7-H3 as an ischemia-induced immune checkpoint molecule in the brain that may modulate post-stroke immune responses and support further investigation into its beneficial versus detrimental roles in neuroinflammation and its potential as a therapeutic target following cerebral I/R.
B7-H3 （CD276）是免疫和非免疫细胞上表达的免疫检查点共信号分子。它以抑制t细胞反应而闻名，但也可以根据微环境促进炎症。在神经炎症模型（如实验性自身免疫性脑脊髓炎）中，B7-H3表达随着炎症反应而增加，其抑制与疾病进展减少有关。尽管其在缺血性脑卒中中的作用尚不清楚，但我们假设脑缺血/再灌注（I/R）会上调缺血性脑中B7-H3的表达，并且B7-H3表达的增加与促炎细胞因子的表达呈正相关。年轻和年老的雄性和雌性啮齿动物，包括正常血压和自发性高血压大鼠来模拟合并症高血压，进行短暂性大脑中动脉闭塞（MCAO）后再灌注。在mcao后第1、3、5、7天采集脑组织。实时荧光定量PCR分析B7-H3 mRNA， Western blotting和免疫组织化学在选定时间点检测蛋白表达。B7-H3在缺血性脑中的表达在不同性别、年龄组和物种中均显著上调。脑I/R后B7-H3降解程度受物种、性别、年龄和时间的影响。B7-H3在mRNA和蛋白水平上均出现上调，并主要定位于同侧（缺血）半球的体感觉皮层和尾状壳核，这是MCAO模型中受影响的主要区域。缺血脑组织B7-H3表达升高与促炎介质TNFα呈正相关。在大鼠中，B7-H3表达的时间谱与缺血性脑卒中后继发性组织损伤相关的早期炎症期相似。这些发现确定B7-H3是脑缺血诱导的免疫检查点分子，可能调节脑卒中后免疫反应，并支持进一步研究其在神经炎症中的有益与有害作用及其作为脑I/R后治疗靶点的潜力。
{"title":"B7-H3 upregulation in ischemic stroke: friend or foe?","authors":"Siva Reddy Challa , Isidra M. Baker , Casimir A. Fornal , Sahil Reddy Mada , Nabeeha Khan , Samantha N. Jackson , Erick Saldes , Jeffrey D. Klopfenstein , Swapna Asuthkar , Krishna Kumar Veeravalli","doi":"10.1016/j.expneurol.2026.115675","DOIUrl":"10.1016/j.expneurol.2026.115675","url":null,"abstract":"<div><div>B7-H3 (CD276) is an immune checkpoint co-signaling molecule expressed on immune and non-immune cells. It is best known for suppressing T-cell responses but can also promote inflammation depending on the microenvironment. In neuroinflammatory models such as experimental autoimmune encephalomyelitis, B7-H3 expression increases concomitantly with the inflammatory response, and its inhibition is associated with reduced disease progression. Although its role in ischemic stroke remains unclear, we hypothesized that cerebral ischemia/reperfusion (I/R) would upregulate B7-H3 expression in the ischemic brain and that increased B7-H3 expression would positively correlate with pro-inflammatory cytokine expression. Young and aged male and female rodents, including normotensive and spontaneously hypertensive rats to model comorbid hypertension, underwent transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Brain tissue was collected on post-MCAO days 1, 3, 5, or 7. B7-H3 mRNA was analyzed by real-time PCR, whereas protein expression was assessed by Western blotting and immunohistochemistry at selected time points. B7-H3 expression was significantly upregulated in the ischemic brain across sexes, age groups, and species. The extent of B7-H3 degradation was influenced by species, sex, age, and time after cerebral I/R. Upregulation of B7-H3 was observed at both the mRNA and protein levels and was localized primarily to the somatosensory cortex and caudate putamen in the ipsilateral (ischemic) hemisphere, the main regions affected in this MCAO model. Elevated B7-H3 expression in the ischemic brain positively correlated with the pro-inflammatory mediator TNFα. In rats, the temporal profile of B7-H3 expression paralleled the early inflammatory phase associated with secondary tissue damage after ischemic stroke. These findings identify B7-H3 as an ischemia-induced immune checkpoint molecule in the brain that may modulate post-stroke immune responses and support further investigation into its beneficial versus detrimental roles in neuroinflammation and its potential as a therapeutic target following cerebral I/R.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115675"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traumatic cervical spinal cord injury (cSCI) causes severe neurological deficits and long-term disability. Preclinical models such as cervical vertebrate level 2 (C2) hemisection (C2HS), which disrupts communication between respiratory centers and the phrenic motoneurons pool, have been used for decades to study respiratory dysfunction and neuroinflammation after cSCI. Recently, contusive injuries such as cervical vertebrate level 3 hemicontusion (C3HC) have been increasingly employed, as they induce phrenic motoneuron damage and offer a more clinically relevant model of SCI. However, these two different models may engage distinct pathophysiological cascades, raising concerns about the generalizability of findings across injury paradigms. In this study, we compared neuroimmune responses following C2HS or C3HC in mice. Animals underwent either lesion, and spinal cord segments (C1-C8) were collected seven days post-injury for immuno-histological analyses around the lesion level and flow cytometry analyses at the lesion level. We observed that C2HS preserved more neurons accompanied by an upregulation of CD86 and F4/80 in macroglia, markers of activated macrophages, suggesting a response oriented toward phagocytic and reparative functions. This phenotype was associated with limited pro-inflammatory cell infiltration and normalized level of systemic IL-6 level. Conversely, C3HC induced more extensive tissue damage, heightened microglial activation, a trend toward increased astrocytic reactivity, and significantly elevated CSPG levels on the contralateral side. Moreover, a persistent NK cell, neutrophil, and CD43+ infiltrating cells, along with sustained elevation of circulating IL-6 These findings demonstrate distinct neuroinflammatory signatures and repairing mechanisms between models. This study underscores, for the first time, how injury type shapes neuroimmune mechanisms, reinforcing the need for lesion-specific therapeutic strategies in cervical spinal cord injury.
{"title":"Unveiling distinct neuroimmune responses in mouse models of cervical spinal cord injury: Hemisection versus hemicontusion","authors":"Wei Chen , Lucille Adam , Michel-Flutot Pauline , Arnaud Mansart , Stéphane Vinit , Isabelle Vivodtzev","doi":"10.1016/j.expneurol.2026.115661","DOIUrl":"10.1016/j.expneurol.2026.115661","url":null,"abstract":"<div><div>Traumatic cervical spinal cord injury (cSCI) causes severe neurological deficits and long-term disability. Preclinical models such as cervical vertebrate level 2 (C2) hemisection (C2HS), which disrupts communication between respiratory centers and the phrenic motoneurons pool, have been used for decades to study respiratory dysfunction and neuroinflammation after cSCI. Recently, contusive injuries such as cervical vertebrate level 3 hemicontusion (C3HC) have been increasingly employed, as they induce phrenic motoneuron damage and offer a more clinically relevant model of SCI. However, these two different models may engage distinct pathophysiological cascades, raising concerns about the generalizability of findings across injury paradigms. In this study, we compared neuroimmune responses following C2HS or C3HC in mice. Animals underwent either lesion, and spinal cord segments (C1-C8) were collected seven days post-injury for immuno-histological analyses around the lesion level and flow cytometry analyses at the lesion level. We observed that C2HS preserved more neurons accompanied by an upregulation of CD86 and F4/80 in macroglia, markers of activated macrophages, suggesting a response oriented toward phagocytic and reparative functions. This phenotype was associated with limited pro-inflammatory cell infiltration and normalized level of systemic IL-6 level. Conversely, C3HC induced more extensive tissue damage, heightened microglial activation, a trend toward increased astrocytic reactivity, and significantly elevated CSPG levels on the contralateral side. Moreover, a persistent NK cell, neutrophil, and CD43<sup>+</sup> infiltrating cells, along with sustained elevation of circulating IL-6 These findings demonstrate distinct neuroinflammatory signatures and repairing mechanisms between models. This study underscores, for the first time, how injury type shapes neuroimmune mechanisms, reinforcing the need for lesion-specific therapeutic strategies in cervical spinal cord injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"399 ","pages":"Article 115661"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-14DOI: 10.1016/j.expneurol.2026.115647
Judith R.A. van Rooij , Monica van den Berg , Manoy Van Vosselen , Elke Calus , Tamara Vasilkovska , Lauren Kosten , Ignace Van Spilbeeck , Johan Van Audekerke , Debby Van Dam , Daniele Bertoglio , Mohit H. Adhikari , Marleen Verhoye
Short-term caloric restriction (CR) and resveratrol (Rsv) supplementation have shown potential in preserving brain function in aging and neurodegenerative diseases such as AD. However, there is a lack of knowledge regarding the potential benefits of long-term CR or Rsv on brain health in context of AD. Therefore, we aimed to assess the effects of short-term (1 month) CR and Rsv administration on resting-state functional connectivity (rs-FC), as well as the effect of long-term (8 months) CR or Rsv supplementation on rs-FC, spatial memory, amyloid burden, and neuroinflammation in male and female TgF344-AD (Tg) and wild-type (WT) rats. In Tg rats, short-term CR decreased rs-FC in female rats, while long-term CR decreased rs-FC and modestly improved spatial memory in male rats. Long-term CR and Rsv altered regional amyloid burden, and CR decreased IBA-1 in males without affecting GFAP. Overall, long-term CR and Rsv failed to mitigate FC loss and cognition, underscoring the potentially limited impact of these dietary interventions in AD.
{"title":"Long-term dietary interventions fail to mitigate functional connectivity loss and cognitive decline in the TgF344-AD rat model of Alzheimer's disease","authors":"Judith R.A. van Rooij , Monica van den Berg , Manoy Van Vosselen , Elke Calus , Tamara Vasilkovska , Lauren Kosten , Ignace Van Spilbeeck , Johan Van Audekerke , Debby Van Dam , Daniele Bertoglio , Mohit H. Adhikari , Marleen Verhoye","doi":"10.1016/j.expneurol.2026.115647","DOIUrl":"10.1016/j.expneurol.2026.115647","url":null,"abstract":"<div><div>Short-term caloric restriction (CR) and resveratrol (Rsv) supplementation have shown potential in preserving brain function in aging and neurodegenerative diseases such as AD. However, there is a lack of knowledge regarding the potential benefits of long-term CR or Rsv on brain health in context of AD. Therefore, we aimed to assess the effects of short-term (1 month) CR and Rsv administration on resting-state functional connectivity (rs-FC), as well as the effect of long-term (8 months) CR or Rsv supplementation on rs-FC, spatial memory, amyloid burden, and neuroinflammation in male and female TgF344-AD (Tg) and wild-type (WT) rats. In Tg rats, short-term CR decreased rs-FC in female rats, while long-term CR decreased rs-FC and modestly improved spatial memory in male rats. Long-term CR and Rsv altered regional amyloid burden, and CR decreased IBA-1 in males without affecting GFAP. Overall, long-term CR and Rsv failed to mitigate FC loss and cognition, underscoring the potentially limited impact of these dietary interventions in AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115647"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-27DOI: 10.1016/j.expneurol.2025.115608
Eri Iwasawa , Farrah N. Brown , Crystal Shula , A. Scott Emmert , Elizabeth M. Fugate , Diana Lindquist , Francesco T. Mangano , June Goto
Neonatal hydrocephalus is a prevalent neurological condition typically managed through cerebrospinal fluid (CSF) diversion procedures, such as ventriculoperitoneal shunting. Despite surgical intervention, many patients exhibit persistent hypomyelination and long-term neurocognitive deficits, and no permanent pharmacological treatments currently exist. In this study, we investigated the therapeutic potential of combining shunting with bindarit, an anti-inflammatory agent, using a shunt-treated neonatal progressive hydrocephalus (prh) rat model. Ventriculo-subcutaneous shunting was performed between postnatal days (P) 6–8 in both wild-type and prh mutant rats. In the treatment group, bindarit was administered subcutaneously from P4 to P10. MRI and histological analyses were conducted at P10/11. Shunting alone significantly reduced ventricular volume and partially suppressed activated, amoeboid microglia expressing monocyte chemoattractant protein-1 in the corpus callosum. However, activated microglia with CD68 expression persisted in both grey and white matter. Notably, bindarit treatment further attenuated microglial activation, as evidenced by reduced morphological changes and CD68 expression. This was accompanied by improved myelination, indicated by increased myelin basic protein expression in the corpus callosum—an effect not achieved by shunting alone during our follow-up. Furthermore, the population of premyelinating and myelinating oligodendrocytes, which is diminished in prh mutants, was restored only with the combined treatment. These findings suggest that adjunctive anti-inflammatory therapy with bindarit enhances the neuroprotective effects of CSF diversion surgery by mitigating microglial activation and promoting oligodendrocyte maturation and myelination. This combined approach may offer a promising strategy for supporting brain development and improving neurocognitive outcomes in neonatal hydrocephalus.
{"title":"Suppression of microglial activation with anti-inflammatory drug bindarit enhances neural development in the shunt-treated neonatal hydrocephalus model rat","authors":"Eri Iwasawa , Farrah N. Brown , Crystal Shula , A. Scott Emmert , Elizabeth M. Fugate , Diana Lindquist , Francesco T. Mangano , June Goto","doi":"10.1016/j.expneurol.2025.115608","DOIUrl":"10.1016/j.expneurol.2025.115608","url":null,"abstract":"<div><div>Neonatal hydrocephalus is a prevalent neurological condition typically managed through cerebrospinal fluid (CSF) diversion procedures, such as ventriculoperitoneal shunting. Despite surgical intervention, many patients exhibit persistent hypomyelination and long-term neurocognitive deficits, and no permanent pharmacological treatments currently exist. In this study, we investigated the therapeutic potential of combining shunting with bindarit, an anti-inflammatory agent, using a shunt-treated neonatal <em>progressive hydrocephalus</em> (<em>prh</em>) rat model. Ventriculo-subcutaneous shunting was performed between postnatal days (P) 6–8 in both wild-type and <em>prh</em> mutant rats. In the treatment group, bindarit was administered subcutaneously from P4 to P10. MRI and histological analyses were conducted at P10/11. Shunting alone significantly reduced ventricular volume and partially suppressed activated, amoeboid microglia expressing monocyte chemoattractant protein-1 in the corpus callosum. However, activated microglia with CD68 expression persisted in both grey and white matter. Notably, bindarit treatment further attenuated microglial activation, as evidenced by reduced morphological changes and CD68 expression. This was accompanied by improved myelination, indicated by increased myelin basic protein expression in the corpus callosum—an effect not achieved by shunting alone during our follow-up. Furthermore, the population of premyelinating and myelinating oligodendrocytes, which is diminished in <em>prh</em> mutants, was restored only with the combined treatment. These findings suggest that adjunctive anti-inflammatory therapy with bindarit enhances the neuroprotective effects of CSF diversion surgery by mitigating microglial activation and promoting oligodendrocyte maturation and myelination. This combined approach may offer a promising strategy for supporting brain development and improving neurocognitive outcomes in neonatal hydrocephalus.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115608"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145855246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-31DOI: 10.1016/j.expneurol.2025.115627
Yubo Xiao , Zichen Li , Haojun Yao , Yimeng Wang , Ruyue Bai , Zhili Yu , Gaomuyi Wang , Zhixuan He , Jingbo Yang , Jiale Chu , Yixuan Pang , Qiuyin Li , Jiahao Cui , Longen Yang , Adam Michael Stewart , Valentina N. Perfilova , Clement Napo , Murilo S. de Abreu , Allan V. Kalueff
Second among global disability causes, migraine is a severely debilitating neurological disorder that affects over 1 billion people. Recognized clinically for millennia, migraine exhibits complex multifactorial pathogenesis, whose mechanisms, risk factors, and therapy remain poorly understood. This also necessitates robust animal models that recapitulate this disorder. Complementing rodent models, the zebrafish (Danio rerio) is a commonly used organism in neuroscience research. Can these fish be used to study pathophysiology of migraine? Here, we discuss the developing utility of these fish for modeling migraine-like conditions and the potential for high-throughput pharmacological testing of its therapies. Critically evaluating the existing challenges of modeling migraine in zebrafish, we also outline potential future lines of research in this field.
{"title":"Towards zebrafish models of migraine","authors":"Yubo Xiao , Zichen Li , Haojun Yao , Yimeng Wang , Ruyue Bai , Zhili Yu , Gaomuyi Wang , Zhixuan He , Jingbo Yang , Jiale Chu , Yixuan Pang , Qiuyin Li , Jiahao Cui , Longen Yang , Adam Michael Stewart , Valentina N. Perfilova , Clement Napo , Murilo S. de Abreu , Allan V. Kalueff","doi":"10.1016/j.expneurol.2025.115627","DOIUrl":"10.1016/j.expneurol.2025.115627","url":null,"abstract":"<div><div>Second among global disability causes, migraine is a severely debilitating neurological disorder that affects over 1 billion people. Recognized clinically for millennia, migraine exhibits complex multifactorial pathogenesis, whose mechanisms, risk factors, and therapy remain poorly understood. This also necessitates robust animal models that recapitulate this disorder. Complementing rodent models, the zebrafish (<em>Danio rerio</em>) is a commonly used organism in neuroscience research. Can these fish be used to study pathophysiology of migraine? Here, we discuss the developing utility of these fish for modeling migraine-like conditions and the potential for high-throughput pharmacological testing of its therapies. Critically evaluating the existing challenges of modeling migraine in zebrafish, we also outline potential future lines of research in this field.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115627"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-23DOI: 10.1016/j.expneurol.2025.115606
Jiemei Chen , Fei Zhao , Jiena Hong , Jiantao Zhang , Qiuping Ye , Jiahui Hu , Yong Dai , Yilong Shan , Chao Li , Hongmei Wen
Background
High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) can improve swallowing function in poststroke dysphagia (PSD) patients. The nucleus tractus solitarius (NTS) is the core of swallowing initiation and patterned swallowing actions. However, the effects of HF-rTMS on NTS excitability and the underlying molecular mechanisms are still unknown.
Objective
This study aimed to examine the effects of HF-rTMS on NTS excitability and the underlying molecular mechanisms in rats with PSD.
Methods
A PSD rat model was established using transient middle cerebral artery occlusion. The videofluoroscopy swallowing study (VFSS) was conducted to evaluate swallowing function of rats. The rats in the rTMS group were stimulated with 10 Hz HF-rTMS. The expression of vesicular glutamate transporter 2 (VGLUT2), Vesicular γ-amino butyric acid amino acid transporter (VGAT), Calcium/calcium-dependent protein kinase II α (CAMKIIα), miniature excitatory postsynaptic currents (mEPSCs), N-methyl-d-aspartate receptor 1 (NMDAR1), Neuronal Per Arnt Sim domain protein 4 (Npas4) and Voltage-Gated Sodium Channel Alpha Subunit Type 1 (Nav1.1) were detected. The virus taCasp3 and chemical genetic inhibition were used to inhibit NTS excitability, and then the swallowing function of the rats was observed. The Npas4 inhibitor ITSA-1 and Npas4 shRNA virus were further used to inhibit Npas4 expression, and then the swallowing function and Nav1.1 current were observed.
Results
HF-rTMS significantly improved swallowing function of PSD rats and increased the expression of CaMKIIα and VGLUT2; increased the amplitude of mEPSCs; increased the expression of NMDAR1, Npas4, and Nav1.1; and decreased the expression of VGAT. After inhibiting the excitability of the NTS or inhibiting the expression of Npas4, HF-rTMS stimulation could not promote the swallowing function in PSD rats.
Conclusion
HF-rTMS enhances the excitability of the NTS through the NMDAR1–Npas4–Nav1.1 pathway, thus improving the swallowing function of PSD rats.
{"title":"HF-rTMS improves swallowing function in rats with poststroke dysphagia by increasing nucleus tractus solitarius excitability through the NMDAR1–Npas4–Nav1.1 pathway","authors":"Jiemei Chen , Fei Zhao , Jiena Hong , Jiantao Zhang , Qiuping Ye , Jiahui Hu , Yong Dai , Yilong Shan , Chao Li , Hongmei Wen","doi":"10.1016/j.expneurol.2025.115606","DOIUrl":"10.1016/j.expneurol.2025.115606","url":null,"abstract":"<div><h3>Background</h3><div>High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) can improve swallowing function in poststroke dysphagia (PSD) patients. The nucleus tractus solitarius (NTS) is the core of swallowing initiation and patterned swallowing actions. However, the effects of HF-rTMS on NTS excitability and the underlying molecular mechanisms are still unknown.</div></div><div><h3>Objective</h3><div>This study aimed to examine the effects of HF-rTMS on NTS excitability and the underlying molecular mechanisms in rats with PSD.</div></div><div><h3>Methods</h3><div>A PSD rat model was established using transient middle cerebral artery occlusion. The videofluoroscopy swallowing study (VFSS) was conducted to evaluate swallowing function of rats. The rats in the rTMS group were stimulated with 10 Hz HF-rTMS. The expression of vesicular glutamate transporter 2 (VGLUT2), Vesicular γ-amino butyric acid amino acid transporter (VGAT), Calcium/calcium-dependent protein kinase II α (CAMKIIα), miniature excitatory postsynaptic currents (mEPSCs), <em>N</em>-methyl-<span>d</span>-aspartate receptor 1 (NMDAR1), Neuronal Per Arnt Sim domain protein 4 (Npas4) and Voltage-Gated Sodium Channel Alpha Subunit Type 1 (Nav1.1) were detected. The virus taCasp3 and chemical genetic inhibition were used to inhibit NTS excitability, and then the swallowing function of the rats was observed. The Npas4 inhibitor ITSA-1 and Npas4 shRNA virus were further used to inhibit Npas4 expression, and then the swallowing function and Nav1.1 current were observed.</div></div><div><h3>Results</h3><div>HF-rTMS significantly improved swallowing function of PSD rats and increased the expression of CaMKIIα and VGLUT2; increased the amplitude of mEPSCs; increased the expression of NMDAR1, Npas4, and Nav1.1; and decreased the expression of VGAT. After inhibiting the excitability of the NTS or inhibiting the expression of Npas4, HF-rTMS stimulation could not promote the swallowing function in PSD rats.</div></div><div><h3>Conclusion</h3><div>HF-rTMS enhances the excitability of the NTS through the NMDAR1–Npas4–Nav1.1 pathway, thus improving the swallowing function of PSD rats.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115606"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-01-13DOI: 10.1016/j.expneurol.2026.115644
Huajiang Deng , Shuang Zhang , Haoxiang Wang , Xiaoyin Liu , Kunhong Zhong , Keru Huang , Yuanyou Li , Ziang Deng , Aiping Tong , Liangxue Zhou
Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH), yet its underlying mechanisms remain unclear. The glymphatic system (GS), a key pathway involved in cerebrospinal fluid (CSF) circulation and metabolic waste clearance, has recently been implicated in the pathogenesis of PHH. In this study, we employed a mouse model of IVH (n = 6 per group, assessed from 6 h to 28 days post-IVH) to investigate the role of the CCL2/CCR2 signaling axis in GS dysfunction and PHH progression. Behavioral tests, CSF tracer imaging, immunofluorescence, and Western blot analyses were used to assess CSF dynamics, AQP4 polarization, and relevant protein levels. The results showed that IVH induced upregulation of CCL2/CCR2, endoplasmic reticulum stress, and NF-κB activation, accompanied by the loss of AQP4 polarization and impairment of GS function. Notably, CCR2 inhibition was significantly associated with restored AQP4 polarization, improved CSF clearance, reduced ventricular enlargement, and ameliorated neurological deficits. These findings suggest that the CCL2/CCR2 signaling pathway may contribute to GS dysfunction in PHH and provide a foundation for exploring its therapeutic potential.
出血性脑积水（PHH）是脑室内出血（IVH）的严重并发症，但其潜在机制尚不清楚。glymphatic system （GS）是参与脑脊液（CSF）循环和代谢废物清除的关键途径，最近被认为与PHH的发病机制有关。在这项研究中，我们采用IVH小鼠模型（每组n = 6，IVH后6 h至28 天评估）来研究CCL2/CCR2信号轴在GS功能障碍和PHH进展中的作用。行为测试、脑脊液示踪成像、免疫荧光和Western blot分析用于评估脑脊液动力学、AQP4极化和相关蛋白水平。结果表明，IVH诱导CCL2/CCR2上调、内质网应激、NF-κB活化，同时伴有AQP4极化缺失和GS功能损伤。值得注意的是，CCR2抑制与恢复AQP4极化、改善CSF清除率、减少心室增大和改善神经功能缺陷显著相关。这些发现提示CCL2/CCR2信号通路可能参与PHH中GS功能障碍，并为探索其治疗潜力提供了基础。
{"title":"CCR2 knockdown attenuates post-hemorrhagic hydrocephalus and improves glymphatic function after intraventricular hemorrhage","authors":"Huajiang Deng , Shuang Zhang , Haoxiang Wang , Xiaoyin Liu , Kunhong Zhong , Keru Huang , Yuanyou Li , Ziang Deng , Aiping Tong , Liangxue Zhou","doi":"10.1016/j.expneurol.2026.115644","DOIUrl":"10.1016/j.expneurol.2026.115644","url":null,"abstract":"<div><div>Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH), yet its underlying mechanisms remain unclear. The glymphatic system (GS), a key pathway involved in cerebrospinal fluid (CSF) circulation and metabolic waste clearance, has recently been implicated in the pathogenesis of PHH. In this study, we employed a mouse model of IVH (<em>n</em> = 6 per group, assessed from 6 h to 28 days post-IVH) to investigate the role of the CCL2/CCR2 signaling axis in GS dysfunction and PHH progression. Behavioral tests, CSF tracer imaging, immunofluorescence, and Western blot analyses were used to assess CSF dynamics, AQP4 polarization, and relevant protein levels. The results showed that IVH induced upregulation of CCL2/CCR2, endoplasmic reticulum stress, and NF-κB activation, accompanied by the loss of AQP4 polarization and impairment of GS function. Notably, CCR2 inhibition was significantly associated with restored AQP4 polarization, improved CSF clearance, reduced ventricular enlargement, and ameliorated neurological deficits. These findings suggest that the CCL2/CCR2 signaling pathway may contribute to GS dysfunction in PHH and provide a foundation for exploring its therapeutic potential.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115644"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-30DOI: 10.1016/j.expneurol.2025.115629
Elika Z. Moallem , Hemendra J. Vekaria , Teresa Macheda , Margaret R. Hawkins , Kelly N. Roberts , Samir P. Patel , Patrick G. Sullivan , Adam D. Bachstetter
Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood–brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4–5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4–8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.
{"title":"Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways","authors":"Elika Z. Moallem , Hemendra J. Vekaria , Teresa Macheda , Margaret R. Hawkins , Kelly N. Roberts , Samir P. Patel , Patrick G. Sullivan , Adam D. Bachstetter","doi":"10.1016/j.expneurol.2025.115629","DOIUrl":"10.1016/j.expneurol.2025.115629","url":null,"abstract":"<div><div>Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood–brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4–5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4–8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115629"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2025-12-31DOI: 10.1016/j.expneurol.2025.115637
Ruixue Zheng , Xueyun Liu , Zhenge Liao , Runjie Wan , Gengbin Qiu , Min Li , Chunzhi Tang , Runjin Zhou , Juxian Song
Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers—including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns—persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.
{"title":"Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice","authors":"Ruixue Zheng , Xueyun Liu , Zhenge Liao , Runjie Wan , Gengbin Qiu , Min Li , Chunzhi Tang , Runjin Zhou , Juxian Song","doi":"10.1016/j.expneurol.2025.115637","DOIUrl":"10.1016/j.expneurol.2025.115637","url":null,"abstract":"<div><div>Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers—including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns—persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115637"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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