Pub Date : 2025-11-28DOI: 10.1016/j.neures.2025.104993
Keita Matsumoto, Sumihiro Maeda
The advent of directly induced neurons (iNs) from human somatic cells has revolutionized disease modeling in neurodegeneration. This approach bypasses pluripotent stage during the neuronal cell inducing steps and preserves donor age-related signatures. This review explores the trajectory of iNs, including multiple induction methods, their applications in modeling neurodegenerative diseases, recent innovations such as three-dimensional (3D) culture platforms, and their potential to advance personalized medicine.
{"title":"The application of directly induced neurons into neurodegenerative disease modeling","authors":"Keita Matsumoto, Sumihiro Maeda","doi":"10.1016/j.neures.2025.104993","DOIUrl":"10.1016/j.neures.2025.104993","url":null,"abstract":"<div><div>The advent of directly induced neurons (iNs) from human somatic cells has revolutionized disease modeling in neurodegeneration. This approach bypasses pluripotent stage during the neuronal cell inducing steps and preserves donor age-related signatures. This review explores the trajectory of iNs, including multiple induction methods, their applications in modeling neurodegenerative diseases, recent innovations such as three-dimensional (3D) culture platforms, and their potential to advance personalized medicine.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104993"},"PeriodicalIF":2.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648999","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}
Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-based models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.
{"title":"Neurodegenerative disease and autophagy in iPSC-based models","authors":"Sodbileg Odonchimed , Keiko Imamura , Haruhisa Inoue","doi":"10.1016/j.neures.2025.104991","DOIUrl":"10.1016/j.neures.2025.104991","url":null,"abstract":"<div><div>Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-based models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104991"},"PeriodicalIF":2.3,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636820","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}
Pub Date : 2025-11-22DOI: 10.1016/j.neures.2025.104988
Tengfei Zhang , Chunhui Wang , Ying Li , Xiaowei Fei , Yanan Dou , Junbin Liu , Junyu Wang , Danfeng Zhang , Lei Jiang , Liang Zhao , Jialiang Wei , Lijun Hou
Microglia and macrophages (M/M) play significant roles in intracerebral hemorrhage (ICH) injury, but the underlying mechanism is complicated and remains largely unknown. Lipocalin-2 (LCN2) expression elevates in M/M after ICH, yet its role in M/M-induced inflammation after ICH has not been fully elucidated. In the current study, a mouse ICH model was established in LCN2fl/fl,CX3CR1-Cre male (LCN2 cKO) mice and LCN2fl/fl male mice. We then aimed to inject LCN2 protein or the Nrf2 inhibitor brusatol groups for mechanism study, and the BV2 and Raw264.7 cell lines were used for in vitro study. LCN2 induces pro-inflammatory phenotype and promotes pro-inflammatory secretion in M/M after blood injury, and M/M LCN2 knockout reduced the pro-inflammatory phenotype after ICH. The Nrf2 protein is activated and nuclear-translocated by LCN2 knockout/downregulation, and the Nrf2 inhibition abrogates the anti-inflammatory effect induced by LCN2 knockout/downregulation. LCN2 knockout/downregulation boosts M/M phagocytosis after ICH, which is partially reversed by Nrf2 inhibition. The LCN2 expression also increases in aged mouse brains and participates in pro-inflammation induction and phagocytosis inhibition after ICH. Our study demonstrates that post-ICH LCN2 expression in M/M induces pro-inflammatory phenotype via inhibiting Nrf2 signaling pathway.
{"title":"Lipocalin-2 induces macrophage/microglia pro-inflammatory phenotype after intracerebral hemorrhage via Nrf2 signaling inhibition in young and aged mice","authors":"Tengfei Zhang , Chunhui Wang , Ying Li , Xiaowei Fei , Yanan Dou , Junbin Liu , Junyu Wang , Danfeng Zhang , Lei Jiang , Liang Zhao , Jialiang Wei , Lijun Hou","doi":"10.1016/j.neures.2025.104988","DOIUrl":"10.1016/j.neures.2025.104988","url":null,"abstract":"<div><div>Microglia and macrophages (M/M) play significant roles in intracerebral hemorrhage (ICH) injury, but the underlying mechanism is complicated and remains largely unknown. Lipocalin-2 (LCN2) expression elevates in M/M after ICH, yet its role in M/M-induced inflammation after ICH has not been fully elucidated. In the current study, a mouse ICH model was established in LCN2<sup>fl/fl,CX3CR1-Cre</sup> male (LCN2 cKO) mice and LCN2<sup>fl/fl</sup> male mice. We then aimed to inject LCN2 protein or the Nrf2 inhibitor brusatol groups for mechanism study, and the BV2 and Raw264.7 cell lines were used for <em>in vitro</em> study. LCN2 induces pro-inflammatory phenotype and promotes pro-inflammatory secretion in M/M after blood injury, and M/M LCN2 knockout reduced the pro-inflammatory phenotype after ICH. The Nrf2 protein is activated and nuclear-translocated by LCN2 knockout/downregulation, and the Nrf2 inhibition abrogates the anti-inflammatory effect induced by LCN2 knockout/downregulation. LCN2 knockout/downregulation boosts M/M phagocytosis after ICH, which is partially reversed by Nrf2 inhibition. The LCN2 expression also increases in aged mouse brains and participates in pro-inflammation induction and phagocytosis inhibition after ICH. Our study demonstrates that post-ICH LCN2 expression in M/M induces pro-inflammatory phenotype via inhibiting Nrf2 signaling pathway.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104988"},"PeriodicalIF":2.3,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588144","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}
Schizophrenia is characterized by profound semantic impairments that manifest as disrupted language and thought. We provide empirical support for the hypothesis that predictive coding forms a unifying framework for understanding these deficits by reinforcing theoretical ideas with quantitative neuroimaging evidence. According to predictive coding theory, the brain continuously generates predictions about incoming information, and prediction errors drive model updates when expectations diverge from sensory input. This review synthesizes evidence from cognitive neuroscience, computational psychiatry, and neurolinguistics to demonstrate how aberrant prediction error signaling disrupts hierarchical semantic processing in schizophrenia. Behavioral studies have revealed atypical semantic processing in priming and fluency tasks. Electrophysiological studies have shown altered neural responses to semantic incongruence, particularly reduced N400 effects. Furthermore, we have used voxel-wise modeling, graph theory, and topological analysis to demonstrate fundamentally disorganized semantic networks in schizophrenia, characterized by reduced small-worldness, excessive homogenization, and diminished representational variability. These converging findings are consistent with a neurocomputational account wherein semantic deficits reflect disrupted predictive mechanisms. This theoretical framework suggests that miscalibrated precision weighting of prediction errors leads to either over-activation of irrelevant semantic associations or impoverished semantic processing. This perspective offers insights into schizophrenia pathophysiology and guidance for targeted interventions to restore predictive coding function.
{"title":"Understanding semantic impairments in schizophrenia from a predictive coding perspective","authors":"Yukiko Matsumoto , Ryusuke Hayashi , Hidehiko Takahashi","doi":"10.1016/j.neures.2025.104990","DOIUrl":"10.1016/j.neures.2025.104990","url":null,"abstract":"<div><div>Schizophrenia is characterized by profound semantic impairments that manifest as disrupted language and thought. We provide empirical support for the hypothesis that predictive coding forms a unifying framework for understanding these deficits by reinforcing theoretical ideas with quantitative neuroimaging evidence. According to predictive coding theory, the brain continuously generates predictions about incoming information, and prediction errors drive model updates when expectations diverge from sensory input. This review synthesizes evidence from cognitive neuroscience, computational psychiatry, and neurolinguistics to demonstrate how aberrant prediction error signaling disrupts hierarchical semantic processing in schizophrenia. Behavioral studies have revealed atypical semantic processing in priming and fluency tasks. Electrophysiological studies have shown altered neural responses to semantic incongruence, particularly reduced N400 effects. Furthermore, we have used voxel-wise modeling, graph theory, and topological analysis to demonstrate fundamentally disorganized semantic networks in schizophrenia, characterized by reduced small-worldness, excessive homogenization, and diminished representational variability. These converging findings are consistent with a neurocomputational account wherein semantic deficits reflect disrupted predictive mechanisms. This theoretical framework suggests that miscalibrated precision weighting of prediction errors leads to either over-activation of irrelevant semantic associations or impoverished semantic processing. This perspective offers insights into schizophrenia pathophysiology and guidance for targeted interventions to restore predictive coding function.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104990"},"PeriodicalIF":2.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570974","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}
Tau protein is a microtubule-associated protein that plays a crucial role in maintaining neuronal morphology and axonal transport. While phosphorylation is known to regulate Tau-microtubule interactions, the contribution of specific phosphorylation patterns in situ remains poorly understood due to the complexity of the intracellular environment. In this study, we combined fluorescence recovery after photobleaching (FRAP) in primary cultured rat hippocampal neurons with dephosphorylation-mimetic mutations and computational modeling to analyze the effects of phosphorylation on Tau-microtubule interaction. We particularly focused on the proline-rich region, of which phosphorylation has been studied in physiological and pathological perspectives, and generated a dephosphorylation-mimetic Tau mutant by substituting key phosphorylation sites with alanine residues and compared its microtubule-binding dynamics to those of WT-Tau in FRAP experiments. Experimental data, together with simulation-based parameter exploration, revealed that the overall number of non-phosphorylated sites plays a more dominant role than their specific locations in modulating Tau-microtubule affinity. These findings provide new insights into the post-translational regulation of Tau and establish a computational-experimental framework for interrogating intracellular protein dynamics.
{"title":"Graded regulation of microtubule-binding of Tau by the phosphorylation state of the proline-rich region in living neurons","authors":"Rinaho Nakata , Tomohiro Torii , Tomohiro Miyasaka , Hiroaki Misonou","doi":"10.1016/j.neures.2025.104987","DOIUrl":"10.1016/j.neures.2025.104987","url":null,"abstract":"<div><div>Tau protein is a microtubule-associated protein that plays a crucial role in maintaining neuronal morphology and axonal transport. While phosphorylation is known to regulate Tau-microtubule interactions, the contribution of specific phosphorylation patterns <em>in situ</em> remains poorly understood due to the complexity of the intracellular environment. In this study, we combined fluorescence recovery after photobleaching (FRAP) in primary cultured rat hippocampal neurons with dephosphorylation-mimetic mutations and computational modeling to analyze the effects of phosphorylation on Tau-microtubule interaction. We particularly focused on the proline-rich region, of which phosphorylation has been studied in physiological and pathological perspectives, and generated a dephosphorylation-mimetic Tau mutant by substituting key phosphorylation sites with alanine residues and compared its microtubule-binding dynamics to those of WT-Tau in FRAP experiments. Experimental data, together with simulation-based parameter exploration, revealed that the overall number of non-phosphorylated sites plays a more dominant role than their specific locations in modulating Tau-microtubule affinity. These findings provide new insights into the post-translational regulation of Tau and establish a computational-experimental framework for interrogating intracellular protein dynamics.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104987"},"PeriodicalIF":2.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564633","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}
Feeding behavior is influenced by both metabolic drive and emotional context, yet how acute stress interferes with hunger-driven motivation remains poorly understood. Using a conflict-based open-field feeding paradigm, we examined how 30-min restraint stress alters food-seeking behavior in fasted mice and how pharmacological or physiological interventions modulate this effect. Acute restraint abolished fasting-induced increases in food seeking and intake, an effect that was reversed by intraperitoneal diazepam, an anxiolytic, and by MK-677, a ghrelin receptor agonist that enhances appetite. To identify neural correlates, we quantified c-Fos (neuronal activation) and phosphorylated pyruvate dehydrogenase (pPDH; neuronal inhibition) in the paraventricular hypothalamic nucleus (PVN). Diazepam suppressed restraint-induced c-Fos expression, whereas MK-677 increased pPDH, revealing distinct PVN signatures for anxiolysis and enhanced feeding drive. Notably, refeeding after fasting induced a similar pPDH-dominant pattern and attenuated stress-induced anxiety-related behaviors, indicating that restoration of energy balance exerts intrinsic anti-stress effects through PVN inhibition. Together, these findings reveal that acute stress suppresses hunger-driven food seeking via PVN activation, pharmacological inhibition reverses this suppression, and physiological refeeding promotes stress resilience via PVN-medicated inhibition, highlighting PVN modulation as a shared mechanism linking emotional and metabolic homeostasis.
{"title":"Acute stress suppresses hunger-driven food seeking through PVN activation: Reversal by anxiolytic drug and ghrelin receptor agonist, with anxiolytic-like effects of refeeding","authors":"Ryusei Tojo , Mayuka Tashiro , Haruka Takahashi , Hideki Tamura","doi":"10.1016/j.neures.2025.104989","DOIUrl":"10.1016/j.neures.2025.104989","url":null,"abstract":"<div><div>Feeding behavior is influenced by both metabolic drive and emotional context, yet how acute stress interferes with hunger-driven motivation remains poorly understood. Using a conflict-based open-field feeding paradigm, we examined how 30-min restraint stress alters food-seeking behavior in fasted mice and how pharmacological or physiological interventions modulate this effect. Acute restraint abolished fasting-induced increases in food seeking and intake, an effect that was reversed by intraperitoneal diazepam, an anxiolytic, and by MK-677, a ghrelin receptor agonist that enhances appetite. To identify neural correlates, we quantified c-Fos (neuronal activation) and phosphorylated pyruvate dehydrogenase (pPDH; neuronal inhibition) in the paraventricular hypothalamic nucleus (PVN). Diazepam suppressed restraint-induced c-Fos expression, whereas MK-677 increased pPDH, revealing distinct PVN signatures for anxiolysis and enhanced feeding drive. Notably, refeeding after fasting induced a similar pPDH-dominant pattern and attenuated stress-induced anxiety-related behaviors, indicating that restoration of energy balance exerts intrinsic anti-stress effects through PVN inhibition. Together, these findings reveal that acute stress suppresses hunger-driven food seeking via PVN activation, pharmacological inhibition reverses this suppression, and physiological refeeding promotes stress resilience via PVN-medicated inhibition, highlighting PVN modulation as a shared mechanism linking emotional and metabolic homeostasis.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104989"},"PeriodicalIF":2.3,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557556","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}
Pub Date : 2025-11-11DOI: 10.1016/j.neures.2025.104986
Takahiro Morito , Naoto Watamura
Tauopathies are a group of neurodegenerative diseases characterized by the aberrant accumulation of tau protein in the brain. While numerous mouse models have been developed to study tauopathies, the majority depend on tau overexpression, which may encompass non-physiological artifacts and limit the translational relevance of findings. In this review, we highlight the development and application of an isogenic panel of MAPT knock-in (KI) mouse lines that carry single or multiple pathogenic mutations within the human MAPT gene. In these models, the endogenous murine Mapt gene was replaced with the humanized MAPT sequence, and tau is expressed under the control of the native murine Mapt promoter. This approach preserves spatiotemporal regulation of tau, providing a more physiological representation of human tauopathies. As such, these mutant MAPT KI models serve as powerful tools for elucidating the pathomechanisms of tauopathies and discovering drugs that aid tau-mediated neurodegeneration.
{"title":"Experimental modeling for tauopathies: An isogenic panel of humanized MAPT knock-in mice","authors":"Takahiro Morito , Naoto Watamura","doi":"10.1016/j.neures.2025.104986","DOIUrl":"10.1016/j.neures.2025.104986","url":null,"abstract":"<div><div>Tauopathies are a group of neurodegenerative diseases characterized by the aberrant accumulation of tau protein in the brain. While numerous mouse models have been developed to study tauopathies, the majority depend on tau overexpression, which may encompass non-physiological artifacts and limit the translational relevance of findings. In this review, we highlight the development and application of an isogenic panel of <em>MAPT</em> knock-in (KI) mouse lines that carry single or multiple pathogenic mutations within the human <em>MAPT</em> gene. In these models, the endogenous murine <em>Mapt</em> gene was replaced with the humanized <em>MAPT</em> sequence, and tau is expressed under the control of the native murine <em>Mapt</em> promoter. This approach preserves spatiotemporal regulation of tau, providing a more physiological representation of human tauopathies. As such, these mutant <em>MAPT</em> KI models serve as powerful tools for elucidating the pathomechanisms of tauopathies and discovering drugs that aid tau-mediated neurodegeneration.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"221 ","pages":"Article 104986"},"PeriodicalIF":2.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513472","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}
Pub Date : 2025-11-08DOI: 10.1016/j.neures.2025.104985
Masahiro Adachi , Haruhiko Banno , Haruhisa Inoue
Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. iPSC-based screening is recognized as a valuable approach in drug discovery research. Additionally, efforts are underway to develop high-quality models for drug discovery and to better integrate translational research with clinical studies. This review focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), and provides a broad overview of research using iPSCs, ranging from studies of disease mechanisms to applications in drug discovery. Furthermore, several clinical trials based on iPSC research have been initiated, including those of bosutinib, ropinirole, and ezogabine for ALS, and WVE-004 and BII078 for ALS/FTD. Finally, we also wish to highlight screening studies that incorporate artificial intelligence (AI).
{"title":"Drug discovery research with iPSC models of neurodegenerative diseases","authors":"Masahiro Adachi , Haruhiko Banno , Haruhisa Inoue","doi":"10.1016/j.neures.2025.104985","DOIUrl":"10.1016/j.neures.2025.104985","url":null,"abstract":"<div><div>Induced pluripotent stem cells (iPSCs) are widely used in research because they can be used to create models of diseases with the same genomic background as in patients. iPSC-based screening is recognized as a valuable approach in drug discovery research. Additionally, efforts are underway to develop high-quality models for drug discovery and to better integrate translational research with clinical studies. This review focuses on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), and provides a broad overview of research using iPSCs, ranging from studies of disease mechanisms to applications in drug discovery. Furthermore, several clinical trials based on iPSC research have been initiated, including those of bosutinib, ropinirole, and ezogabine for ALS, and WVE-004 and BII078 for ALS/FTD. Finally, we also wish to highlight screening studies that incorporate artificial intelligence (AI).</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"222 ","pages":"Article 104985"},"PeriodicalIF":2.3,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489301","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}
Pub Date : 2025-11-08DOI: 10.1016/j.neures.2025.104982
Jingyi Xie , Xiaotong Zhang , Shengli Li , Zichen Chen , Xujia Zhang , Jinyi Tian , Yulu Yan , Yongqi Pan , Ke Shi , Jianbin Sun , Teru Kamogashira , Ying Gao
Bilateral vestibular dysfunction disrupts balance and spatial orientation, yet mechanisms of injury and compensation remain incompletely defined. We established a mouse model of bilateral acute inner-ear (labyrinthine) injury with vestibular involvement by sequentially incising the round and oval windows, and evaluate auditory brainstem responses (ABR), vestibular sensory-evoked potentials (VsEP), behavior, and histology across postoperative days 1–28. Threshold elevations and behavioral impairment peaked on day 3, with hair-cell degeneration most prominent early and partial morphological recovery by day 28. These findings delineate the acute injury phase and early stabilization, providing a platform to study vestibular repair and functional recovery.
{"title":"A mouse model of bilateral acute inner-ear (labyrinthine) injury with vestibular involvement reveals functional, behavioral, and histological correlates of vestibular compensation","authors":"Jingyi Xie , Xiaotong Zhang , Shengli Li , Zichen Chen , Xujia Zhang , Jinyi Tian , Yulu Yan , Yongqi Pan , Ke Shi , Jianbin Sun , Teru Kamogashira , Ying Gao","doi":"10.1016/j.neures.2025.104982","DOIUrl":"10.1016/j.neures.2025.104982","url":null,"abstract":"<div><div>Bilateral vestibular dysfunction disrupts balance and spatial orientation, yet mechanisms of injury and compensation remain incompletely defined. We established a mouse model of bilateral acute inner-ear (labyrinthine) injury with vestibular involvement by sequentially incising the round and oval windows, and evaluate auditory brainstem responses (ABR), vestibular sensory-evoked potentials (VsEP), behavior, and histology across postoperative days 1–28. Threshold elevations and behavioral impairment peaked on day 3, with hair-cell degeneration most prominent early and partial morphological recovery by day 28. These findings delineate the acute injury phase and early stabilization, providing a platform to study vestibular repair and functional recovery.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"221 ","pages":"Article 104982"},"PeriodicalIF":2.3,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489232","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}
Pub Date : 2025-11-08DOI: 10.1016/j.neures.2025.104983
Chun Wang , Shiqin Yao , Bowen Tian , Zhifeng Zhao , Yanrong Wang , Xiaoliang Li , Xuzhao Li , Qinxian Huang
This study was intended to verify the potential role of Fluoxetine (Flx) in treating depression associated with opioid-induced constipation (OIC). We established a mouse model of chronic unpredictable mild stress (CUMS) and used loperamide to induce constipation based on the CUMS mice, generating a mouse model of depression associated with OIC (CUMS+OIC). The depressive behavior was evaluated via the open field and sucrose preference tests, while constipation was evaluated using defecation frequency and fecal water content. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and bioinformatics analyses were performed. Treatment with Flx alleviated the depressive behavior of mice and inhibited OIC. We identified 153 differential metabolites between the control and the CUMS+OIC groups, among which 51 were downregulated while the other 102 were upregulated. These metabolites were involved in metabolic pathways such as pyrimidine metabolism, purine metabolism, and beta-alanine metabolism. Moreover, 64 differential metabolites between the Flx and the CUMS+OIC groups were involved in nicotinate and nicotinamide metabolism, and prion disease metabolism metabolic pathways. Through cluster analysis, we identified metabolites deregulated by CUMS+OIC and restored by Flx. Conclusively, Flx can improve the behavior and metabolic profile changes of CUMS associated with OIC, providing a basis for treating depression-related constipation.
{"title":"Fluoxetine enhances the treatment of depression linked to opioid-induced constipation in mice by influencing the metabolomic profile","authors":"Chun Wang , Shiqin Yao , Bowen Tian , Zhifeng Zhao , Yanrong Wang , Xiaoliang Li , Xuzhao Li , Qinxian Huang","doi":"10.1016/j.neures.2025.104983","DOIUrl":"10.1016/j.neures.2025.104983","url":null,"abstract":"<div><div>This study was intended to verify the potential role of Fluoxetine (Flx) in treating depression associated with opioid-induced constipation (OIC). We established a mouse model of chronic unpredictable mild stress (CUMS) and used loperamide to induce constipation based on the CUMS mice, generating a mouse model of depression associated with OIC (CUMS+OIC). The depressive behavior was evaluated via the open field and sucrose preference tests, while constipation was evaluated using defecation frequency and fecal water content. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and bioinformatics analyses were performed. Treatment with Flx alleviated the depressive behavior of mice and inhibited OIC. We identified 153 differential metabolites between the control and the CUMS+OIC groups, among which 51 were downregulated while the other 102 were upregulated. These metabolites were involved in metabolic pathways such as pyrimidine metabolism, purine metabolism, and beta-alanine metabolism. Moreover, 64 differential metabolites between the Flx and the CUMS+OIC groups were involved in nicotinate and nicotinamide metabolism, and prion disease metabolism metabolic pathways. Through cluster analysis, we identified metabolites deregulated by CUMS+OIC and restored by Flx. Conclusively, Flx can improve the behavior and metabolic profile changes of CUMS associated with OIC, providing a basis for treating depression-related constipation.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"221 ","pages":"Article 104983"},"PeriodicalIF":2.3,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489284","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}
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