Pub Date : 2025-12-31DOI: 10.1016/j.expneurol.2025.115632
E. Hegnet, S. Häkli, H. Koivisto, P.O. Miettinen, N. Jin, I. Gureviciene, H. Tanila
Both seizures and epileptiform discharges have been reported in various amyloid plaque- forming mouse models of Alzheimer's disease (AD). These mice also show premature mortality possibly related to epileptic seizures. Yet, the relationship between epileptic manifestations and amyloid pathology remains elusive. We utilized deltaFosB as a marker for sustained neuronal hyperactivity to localize the epileptic focus and compared it with age and sex differences in premature mortality between APP/PS1, 5xFAD and wildtype littermate mice and epileptiform discharges (EDs) during sleep in cortex and hippocampus. APP/PS1 mice showed elevated FosB/deltaFosB (shortly FosB) staining in the dentate granule (DG) cells and CA1-CA3 pyramidal cells. These were also the origins of identified epileptiform discharges (EDs) in LFP recordings. APP/PS1 mice showed much higher premature mortality than 5xFAD mice, females more than males. FosB staining intensity in APP/PS1 mice was robustly elevated compared to wildtype mice and peaked at 3 months of age. In contrast, FosB intensity in 5xFAD was lower than in wildtype mice at 1 and 3 months of age, showing a modest elevation at 10 months. In APP/PS1 mice between 1.5 and 3 months of age, the DG amyloid load correlated positively with FosB intensity. Furthermore, the DG FosB intensity showed a positive correlation with the frequency of EDs during sleep. These findings suggest that FosB staining intensity can be used as a proxy for local epileptiform activity in AD model mice and help unveil cellular and molecular basis of AD related neuronal hyperactivity and epilepsy.
{"title":"Age and sex dependent hippocampal neuronal hyperactivity in Alzheimer model mice","authors":"E. Hegnet, S. Häkli, H. Koivisto, P.O. Miettinen, N. Jin, I. Gureviciene, H. Tanila","doi":"10.1016/j.expneurol.2025.115632","DOIUrl":"10.1016/j.expneurol.2025.115632","url":null,"abstract":"<div><div>Both seizures and epileptiform discharges have been reported in various amyloid plaque- forming mouse models of Alzheimer's disease (AD). These mice also show premature mortality possibly related to epileptic seizures. Yet, the relationship between epileptic manifestations and amyloid pathology remains elusive. We utilized deltaFosB as a marker for sustained neuronal hyperactivity to localize the epileptic focus and compared it with age and sex differences in premature mortality between APP/PS1, 5xFAD and wildtype littermate mice and epileptiform discharges (EDs) during sleep in cortex and hippocampus. APP/PS1 mice showed elevated FosB/deltaFosB (shortly FosB) staining in the dentate granule (DG) cells and CA1-CA3 pyramidal cells. These were also the origins of identified epileptiform discharges (EDs) in LFP recordings. APP/PS1 mice showed much higher premature mortality than 5xFAD mice, females more than males. FosB staining intensity in APP/PS1 mice was robustly elevated compared to wildtype mice and peaked at 3 months of age. In contrast, FosB intensity in 5xFAD was lower than in wildtype mice at 1 and 3 months of age, showing a modest elevation at 10 months. In APP/PS1 mice between 1.5 and 3 months of age, the DG amyloid load correlated positively with FosB intensity. Furthermore, the DG FosB intensity showed a positive correlation with the frequency of EDs during sleep. These findings suggest that FosB staining intensity can be used as a proxy for local epileptiform activity in AD model mice and help unveil cellular and molecular basis of AD related neuronal hyperactivity and epilepsy.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115632"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892378","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 : 2025-12-31DOI: 10.1016/j.expneurol.2025.115626
Viviam Sanabria , Matheus B. Braga , Simone Romariz , Christiane Gimenes , Michele Longoni Calió , Maira Licia Foresti , Luiz Eugênio Mello , Beatriz M. Longo
Traumatic brain injury (TBI) disrupts brain function and may lead to post-traumatic epilepsy (PTE), a long-term complication. Anticholinergic drugs, such as biperiden, have shown potential in modulating neural plasticity. This study evaluated whether biperiden treatment influences motor and cognitive recovery, seizure susceptibility, and neurovascular and inflammatory responses in rats subjected to the lateral fluid percussion injury (LFPI) model. Adult male Wistar rats underwent LFPI or sham surgery and were treated with saline or biperiden (8 mg/kg) administered intraperitoneally every 8 h for 10 days, starting 6 h after trauma. Neuromotor battery tests were assessed over 28 days, spatial memory at 30 days using the Barnes Maze, and seizure susceptibility was tested with pentylenetetrazol (PTZ) at 90 days after trauma as a second hit. Plasma samples were collected 10 days after trauma for Single Molecular Array (SIMOA) analysis of trauma biomarkers, neurofilament light chain (NfL), and total tau. Histological and immunofluorescence analyses were conducted at 91 days. TBI significantly increased plasma NfL levels compared to the Naive group, indicating neuronal damage. Animals that underwent LFPI and were treated with saline solution were called TBI-SAL group, while animals that underwent LFPI and were treated with biperiden solution were called TBI-BIP group. TBI-SAL group exhibited memory impairments and random search strategies in the Barnes Maze. Both TBI groups (those treated with saline and with biperiden) exhibited higher seizure susceptibility to PTZ at 30 mg/kg, but biperiden slightly reduced seizure intensity. Histological analyses revealed larger lesion volumes, reduced NeuN expression in hippocampal regions (CA1, CA3), and altered astrocytic and microglial morphology in the TBI-SAL group. Notably, biperiden treatment promoted vascular remodeling, characterized by an increase in vessel density, in the motor cortex and hippocampal regions, suggesting potential modulation of post-traumatic neuroinflammation. Biperiden enhanced vascular remodeling and partially mitigated long-term histopathological changes after TBI, though its protective effects on cognitive and seizure-susceptibility responses were limited. These findings highlight biperiden's potential to influence vascular and inflammatory responses in the injured brain.
{"title":"Chronic effects of traumatic brain injury and the impact of biperiden treatment in a male rat model","authors":"Viviam Sanabria , Matheus B. Braga , Simone Romariz , Christiane Gimenes , Michele Longoni Calió , Maira Licia Foresti , Luiz Eugênio Mello , Beatriz M. Longo","doi":"10.1016/j.expneurol.2025.115626","DOIUrl":"10.1016/j.expneurol.2025.115626","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) disrupts brain function and may lead to post-traumatic epilepsy (PTE), a long-term complication. Anticholinergic drugs, such as biperiden, have shown potential in modulating neural plasticity. This study evaluated whether biperiden treatment influences motor and cognitive recovery, seizure susceptibility, and neurovascular and inflammatory responses in rats subjected to the lateral fluid percussion injury (LFPI) model. Adult male Wistar rats underwent LFPI or sham surgery and were treated with saline or biperiden (8 mg/kg) administered intraperitoneally every 8 h for 10 days, starting 6 h after trauma. Neuromotor battery tests were assessed over 28 days, spatial memory at 30 days using the Barnes Maze, and seizure susceptibility was tested with pentylenetetrazol (PTZ) at 90 days after trauma as a second hit. Plasma samples were collected 10 days after trauma for Single Molecular Array (SIMOA) analysis of trauma biomarkers, neurofilament light chain (NfL), and total tau. Histological and immunofluorescence analyses were conducted at 91 days. TBI significantly increased plasma NfL levels compared to the Naive group, indicating neuronal damage. Animals that underwent LFPI and were treated with saline solution were called TBI-SAL group, while animals that underwent LFPI and were treated with biperiden solution were called TBI-BIP group. TBI-SAL group exhibited memory impairments and random search strategies in the Barnes Maze. Both TBI groups (those treated with saline and with biperiden) exhibited higher seizure susceptibility to PTZ at 30 mg/kg, but biperiden slightly reduced seizure intensity. Histological analyses revealed larger lesion volumes, reduced NeuN expression in hippocampal regions (CA1, CA3), and altered astrocytic and microglial morphology in the TBI-SAL group. Notably, biperiden treatment promoted vascular remodeling, characterized by an increase in vessel density, in the motor cortex and hippocampal regions, suggesting potential modulation of post-traumatic neuroinflammation. Biperiden enhanced vascular remodeling and partially mitigated long-term histopathological changes after TBI, though its protective effects on cognitive and seizure-susceptibility responses were limited. These findings highlight biperiden's potential to influence vascular and inflammatory responses in the injured brain.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115626"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882227","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 : 2025-12-31DOI: 10.1016/j.expneurol.2025.115630
Xiaoxiao Chen , Hanbing Yao , Shuqing Ma , Hong Zhu , Yujia Xu , Yun Zhu , Yaozhe Ying , Luhui Wang , Qiongying Zhang , Chenfei Zheng , Ying Zhou , Zhiqian Tong , Kate Huang , Yangping Shentu
Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1–42) (Aβ1–42) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ1–42-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.
{"title":"FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease","authors":"Xiaoxiao Chen , Hanbing Yao , Shuqing Ma , Hong Zhu , Yujia Xu , Yun Zhu , Yaozhe Ying , Luhui Wang , Qiongying Zhang , Chenfei Zheng , Ying Zhou , Zhiqian Tong , Kate Huang , Yangping Shentu","doi":"10.1016/j.expneurol.2025.115630","DOIUrl":"10.1016/j.expneurol.2025.115630","url":null,"abstract":"<div><div>Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1–42) (Aβ<sub>1</sub><sub>–</sub><sub>42</sub>) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ<sub>1</sub><sub>–</sub><sub>42</sub>-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115630"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892333","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 : 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":"2025-12-30","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 : 2025-12-30DOI: 10.1016/j.expneurol.2025.115631
Yue Zhang , Liuyi Chen , Jiaqin Jin , Ying Xin , Junyu Wang , Anren Zhang
Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.
{"title":"Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives","authors":"Yue Zhang , Liuyi Chen , Jiaqin Jin , Ying Xin , Junyu Wang , Anren Zhang","doi":"10.1016/j.expneurol.2025.115631","DOIUrl":"10.1016/j.expneurol.2025.115631","url":null,"abstract":"<div><div>Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115631"},"PeriodicalIF":4.2,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888581","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 : 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":"2025-12-27","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 : 2025-12-24DOI: 10.1016/j.expneurol.2025.115602
W. Brad Hubbard , Rania Abutarboush , Stephen T. Ahlers , Pamela J. VandeVord
{"title":"Letter to the editor: “Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures” by Kakulavarapu V. Rama Rao, et al.","authors":"W. Brad Hubbard , Rania Abutarboush , Stephen T. Ahlers , Pamela J. VandeVord","doi":"10.1016/j.expneurol.2025.115602","DOIUrl":"10.1016/j.expneurol.2025.115602","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115602"},"PeriodicalIF":4.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843581","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 : 2025-12-24DOI: 10.1016/j.expneurol.2025.115625
Jun Wang, Rama Maganti
Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, often occurring during sleep and lacking reliable predictive biomarkers. Here we used the Kv1.1−/− mouse model of SUDEP to examine sleep-related biomarkers. Kv1.1−/− and wild-type mice were implanted with electroencephalography (EEG) and electromyography (EMG) electrodes for continuous video-EEG recording. Vigilance states were scored in 4-s epochs, and spectral power was analyzed across frequency bands. Sleep homeostasis (SH) was assessed by: a) the decay of slow-wave activity (SWA; 0.5–4 Hz) during NREM sleep, b) SWA increase with prior wakefulness, and c) NREM and SWA rebound following sleep deprivation (SD). Kv1.1−/− mice exhibited spontaneous seizures of varying frequency. Compared to wildtypes, Kv1.1−/− mice had reduced time in NREM and REM sleep, that were worse on days with seizures (p < 0.001). The diurnal oscillation of NREM and REM was impaired in Kv1.1−/− mice regardless of seizures. SH was abnormal in Kv1.1−/− mice with absence of SWA decay during lights-on when mice sleep (p = 0.002) and no increase in SWA with wakefulness after sleep onset (p = 0.005). In Kv1.1−/− mice SWA remained unchanged in 10-day recordings with no SD (p = 0.22) or as mortality approached in the SD group (p = 0.15). Furthermore, sleep deprivation (SD) resulted in rebound increase NREM sleep (p < 0.0001) and SWA (p = 0.01) in wild-types but not in Kv1.1−/− mice. These findings suggest that abnormalities in SH may serve as candidate biomarkers of SUDEP. The data also support translational studies to develop sleep-targeted interventions to reduce SUDEP risk.
{"title":"Sleep biomarkers of sudden unexpected death in epilepsy: Data from the Kv1.1 mouse model","authors":"Jun Wang, Rama Maganti","doi":"10.1016/j.expneurol.2025.115625","DOIUrl":"10.1016/j.expneurol.2025.115625","url":null,"abstract":"<div><div>Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, often occurring during sleep and lacking reliable predictive biomarkers. Here we used the Kv1.1<sup>−/−</sup> mouse model of SUDEP to examine sleep-related biomarkers. Kv1.1<sup>−/−</sup> and wild-type mice were implanted with electroencephalography (EEG) and electromyography (EMG) electrodes for continuous video-EEG recording. Vigilance states were scored in 4-s epochs, and spectral power was analyzed across frequency bands. Sleep homeostasis (SH) was assessed by: a) the decay of slow-wave activity (SWA; 0.5–4 Hz) during NREM sleep, b) SWA increase with prior wakefulness, and c) NREM and SWA rebound following sleep deprivation (SD). Kv1.1<sup>−/−</sup> mice exhibited spontaneous seizures of varying frequency. Compared to wildtypes, Kv1.1<sup>−/−</sup> mice had reduced time in NREM and REM sleep, that were worse on days with seizures (<em>p</em> < 0.001). The diurnal oscillation of NREM and REM was impaired in Kv1.1<sup>−/−</sup> mice regardless of seizures. SH was abnormal in Kv1.1<sup>−/−</sup> mice with absence of SWA decay during lights-on when mice sleep (<em>p</em> = 0.002) and no increase in SWA with wakefulness after sleep onset (<em>p</em> = 0.005). In Kv1.1<sup>−/−</sup> mice SWA remained unchanged in 10-day recordings with no SD (<em>p</em> = 0.22) or as mortality approached in the SD group (<em>p</em> = 0.15). Furthermore, sleep deprivation (SD) resulted in rebound increase NREM sleep (<em>p</em> < 0.0001) and SWA (<em>p</em> = 0.01) in wild-types but not in Kv1.1<sup>−/−</sup> mice. These findings suggest that abnormalities in SH may serve as candidate biomarkers of SUDEP. The data also support translational studies to develop sleep-targeted interventions to reduce SUDEP risk.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115625"},"PeriodicalIF":4.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843531","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 : 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":"2025-12-23","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 : 2025-12-23DOI: 10.1016/j.expneurol.2025.115603
Venkatasivasai Sujith Sajja , Joseph Long , Venkata Rama Rao Kakulavarapu , Shataakshi Dahal
{"title":"Authors Response to Hubbard et al., Letter to Editor, YEXNR_115375 - (EXNR-25-183) on the manuscript “Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret and nonhuman primate) and lissencephalic (rat) models following blast overpressure exposures”","authors":"Venkatasivasai Sujith Sajja , Joseph Long , Venkata Rama Rao Kakulavarapu , Shataakshi Dahal","doi":"10.1016/j.expneurol.2025.115603","DOIUrl":"10.1016/j.expneurol.2025.115603","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115603"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814285","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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