Pub Date : 2026-01-27DOI: 10.1016/j.brainres.2026.150186
Shuma Tsurumi , So Kanazawa , Masami K. Yamaguchi , Jun-ichiro Kawahara
Visual attention enhances perception by facilitating detection, localization, and identification of stimuli. Classic accounts propose that such modulation depends on feedback from higher cortical areas, whereas recent evidence suggests contributions from feedforward processes within early visual regions. Infants provide a unique opportunity to test these mechanisms because their feedback pathways remain immature during the first half of the first year. Here, we examined whether covert attention influences perception in 3- to 4-month-old infants using a spatial cueing task. In Experiment 1, infants discriminated orientation, and in Experiment 2, they discriminated motion direction of cued peripheral gratings, despite not making eye movements. These findings demonstrate that covert attention modulates perception in early infancy, indicating that attentional effects can emerge via feedforward processes before the maturation of top–down feedback.
{"title":"Covert attention modulates visual perception in early infancy","authors":"Shuma Tsurumi , So Kanazawa , Masami K. Yamaguchi , Jun-ichiro Kawahara","doi":"10.1016/j.brainres.2026.150186","DOIUrl":"10.1016/j.brainres.2026.150186","url":null,"abstract":"<div><div>Visual attention enhances perception by facilitating detection, localization, and identification of stimuli. Classic accounts propose that such modulation depends on feedback from higher cortical areas, whereas recent evidence suggests contributions from feedforward processes within early visual regions. Infants provide a unique opportunity to test these mechanisms because their feedback pathways remain immature during the first half of the first year. Here, we examined whether covert attention influences perception in 3- to 4-month-old infants using a spatial cueing task. In Experiment 1, infants discriminated orientation, and in Experiment 2, they discriminated motion direction of cued peripheral gratings, despite not making eye movements. These findings demonstrate that covert attention modulates perception in early infancy, indicating that attentional effects can emerge via feedforward processes before the maturation of top–down feedback.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150186"},"PeriodicalIF":2.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075108","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 : 2026-01-27DOI: 10.1016/j.brainres.2026.150185
Beyza Yilmaz , Altay Savalan , Ayyub Ebrahimi
Exosomes play a vital role in intercellular communication, significantly influencing cell behavior and fate. Their influence is particularly evident in diseases like glioblastoma, one of the most challenging cancers to treat. Due to glioblastoma’s high resistance to conventional therapies, novel treatment strategies are urgently needed. Exosomes, being nano-sized vesicles capable of crossing the blood–brain barrier, can deliver bioactive molecules, including nucleic acids, proteins, and metabolites, to suppress tumor-promoting activities in cancer cells. Induced pluripotent stem cells (iPSCs), known for their unlimited proliferation potential and lack of ethical concerns compared to embryonic sources, present a valuable source of exosomes for therapeutic purposes. Although embryonic stem cell-derived exosomes have shown anti-tumor effects against glioblastoma, the therapeutic potential of iPSC-derived exosomes remains largely unexplored. In this study, we demonstrate that exosomes derived from iPSCs exert anti-tumorigenic effects on glioblastoma cells. We also focused on microRNAs (miRNAs), key regulators of cellular proliferation and apoptosis, which are considered promising therapeutic targets in glioblastoma. Specifically, we observed that microRNA-7 (miR-7) significantly inhibits glioblastoma cell proliferation, migration, and invasion. Our findings show that treatment with a miR-7-5p mimic reduces glioblastoma cell proliferation, and its combination with iPSC-derived exosomes leads to either additive or synergistic anti-cancer effects. These results highlight iPSC-derived exosomes and miR-7 as promising therapeutic candidates for glioblastoma and potentially other malignancies.
{"title":"Therapeutic potential of iPSC-exosomes and miR-7 in Targeting Glioblastoma","authors":"Beyza Yilmaz , Altay Savalan , Ayyub Ebrahimi","doi":"10.1016/j.brainres.2026.150185","DOIUrl":"10.1016/j.brainres.2026.150185","url":null,"abstract":"<div><div>Exosomes play a vital role in intercellular communication, significantly influencing cell behavior and fate. Their influence is particularly evident in diseases like glioblastoma, one of the most challenging cancers to treat. Due to glioblastoma’s high resistance to conventional therapies, novel treatment strategies are urgently needed. Exosomes, being nano-sized vesicles capable of crossing the blood–brain barrier, can deliver bioactive molecules, including nucleic acids, proteins, and metabolites, to suppress tumor-promoting activities in cancer cells. Induced pluripotent stem cells (iPSCs), known for their unlimited proliferation potential and lack of ethical concerns compared to embryonic sources, present a valuable source of exosomes for therapeutic purposes. Although embryonic stem cell-derived exosomes have shown anti-tumor effects against glioblastoma, the therapeutic potential of iPSC-derived exosomes remains largely unexplored. In this study, we demonstrate that exosomes derived from iPSCs exert anti-tumorigenic effects on glioblastoma cells. We also focused on microRNAs (miRNAs), key regulators of cellular proliferation and apoptosis, which are considered promising therapeutic targets in glioblastoma. Specifically, we observed that microRNA-7 (miR-7) significantly inhibits glioblastoma cell proliferation, migration, and invasion. Our findings show that treatment with a miR-7-5p mimic reduces glioblastoma cell proliferation, and its combination with iPSC-derived exosomes leads to either additive or synergistic anti-cancer effects. These results highlight iPSC-derived exosomes and miR-7 as promising therapeutic candidates for glioblastoma and potentially other malignancies.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150185"},"PeriodicalIF":2.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075107","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 : 2026-01-21DOI: 10.1016/j.brainres.2026.150181
Ming-Lian Luo , Yi-Heng Li , Xue-Mei Gao , Yuan-Jian Yang , Shu-Zhen Jiang
Background
The lifetime prevalence of depression is significantly higher in women. But the lack of ideal antidepressant severely limits therapies for female specific depressive disorders like perinatal depression. Herein, we evaluated whether vitamin C (ascorbic acid), a widely used nutritional supplement and perinatal therapeutic agent, could serve as a potential treatment for female-related depressive disorders using a chronic restraint stress (CRS) mouse model.
Methods
C57BL/6 adult female mice were submitted to a 14-day CRS paradigm to induce depression-like behaviors. The antidepressant potential of vitamin C (200 mg/kg, i.p., a single dose) were assessed in CRS-exposed female mice that exhibited depression-like phenotype. Furthermore, we explored the underlying mechanisms through RNA sequencing, western blotting, and pharmacological interventions.
Results
Vitamin C rapidly ameliorated depression-like phenotypes in CRS-exposed female mice within 24 h. The sucrose preference test indicated that the antidepressant effect of vitamin C lasted for more than 72 h. Transcriptome sequencing analysis revealed that vitamin C reversed CRS-induced transcriptional alterations in 104 genes in the medial prefrontal cortex (mPFC) of female mice, including the dopamine receptor D2 (D2R). Western blotting confirmed that CRS suppressed the D2R-ERK1/2-CREB-BDNF pathway in the mPFC, which was effectively rescued by vitamin C. The antidepressant effect of vitamin C was antagonized by the D2R antagonist sulpiride. Additionally, protein–protein interaction network analysis revealed functional linkages between D2R and other vitamin C-regulated stress-sensitive genes.
Conclusions
Our findings suggest that vitamin C may serve as an ideal candidate for the treatment of depression in females, potentially through the restoration of the D2R-BDNF pathway.
{"title":"Single administration of vitamin C produces rapid antidepressant-like effects in female mice: A possible role of dopamine D2 receptor signalling","authors":"Ming-Lian Luo , Yi-Heng Li , Xue-Mei Gao , Yuan-Jian Yang , Shu-Zhen Jiang","doi":"10.1016/j.brainres.2026.150181","DOIUrl":"10.1016/j.brainres.2026.150181","url":null,"abstract":"<div><h3>Background</h3><div>The lifetime prevalence of depression is significantly higher in women. But the lack of ideal antidepressant severely limits therapies for female specific depressive disorders like perinatal depression. Herein, we evaluated whether vitamin C (ascorbic acid), a widely used nutritional supplement and perinatal therapeutic agent, could serve as a potential treatment for female-related depressive disorders using a chronic restraint stress (CRS) mouse model.</div></div><div><h3>Methods</h3><div>C57BL/6 adult female mice were submitted to a 14-day CRS paradigm to induce depression-like behaviors. The antidepressant potential of vitamin C (200 mg/kg, i.p., a single dose) were assessed in CRS-exposed female mice that exhibited depression-like phenotype. Furthermore, we explored the underlying mechanisms through RNA sequencing, western blotting, and pharmacological interventions.</div></div><div><h3>Results</h3><div>Vitamin C rapidly ameliorated depression-like phenotypes in CRS-exposed female mice within 24 h. The sucrose preference test indicated that the antidepressant effect of vitamin C lasted for more than 72 h. Transcriptome sequencing analysis revealed that vitamin C reversed CRS-induced transcriptional alterations in 104 genes in the medial prefrontal cortex (mPFC) of female mice, including the dopamine receptor D2 (D2R). Western blotting confirmed that CRS suppressed the D2R-ERK1/2-CREB-BDNF pathway in the mPFC, which was effectively rescued by vitamin C. The antidepressant effect of vitamin C was antagonized by the D2R antagonist sulpiride. Additionally, protein–protein interaction network analysis revealed functional linkages between D2R and other vitamin C-regulated stress-sensitive genes.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that vitamin C may serve as an ideal candidate for the treatment of depression in females, potentially through the restoration of the D2R-BDNF pathway.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150181"},"PeriodicalIF":2.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036610","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 : 2026-01-21DOI: 10.1016/j.brainres.2026.150180
Luciana Ramalho Pimentel-Silva , Renata Barbosa , Alexandre Hilario Berenguer de Matos , Raphael Fernandes Casseb , Brunno Machado de Campos , Mônica Mingone Cordeiro , Juliana Francischinelli Casseb , Elayne Vieira Dias , Andre Schwambach Vieira , Luis Concha , Iscia Lopes-Cendes , Fernando Cendes
Purpose
We aimed to evaluate longitudinal structural and metabolic changes after induced status epilepticus (SE) in the pilocarpine model of TLE, over the three phases of epileptogenesis.
Methods
We analyzed 48 male eight-week-old Wistar rats assigned to sham-control and SE-induced groups. T2-weighted images and 1H-MR spectra were acquired using a 3 T MRI clinical scanner (Philips Achieva) equipped with an animal coil. We measured hippocampal volumes (dorsal-HVol) and total N-acetylaspartate ratios to total creatine (tNAA/tCr) in four points in time (MRI-scan): baseline (before pilocarpine or sham treatments), 48 h (acute phase), 15 days (silent period), and 30 days (beginning of the chronic phase) after experimental treatment. To test differences in dorsal-HVol and hippocampal tNAA/tCr we built generalized linear mixed effects models including groups (pilo-SE and control) and MRI-scan as main effects and a group*MRI-scan interaction.
Results
Pilo-SE and control animals showed similar baseline dorsal-HVol and hippocampal tNAA/tCr (both p > 0.1). Pilo-SE showed reduced dorsal-HVol and tNAA/tCr at all MRI-scans (all p < 0.001) when compared to controls. Intragroup analysis revealed that dorsal-HVol and tNAA/tCr significantly increased at 15- and 30-days (all p < 0.001) when compared to 48 h, although remaining lower than the baseline scan. There were no changes over time in sham-controls (all p > 0.4).
Conclusions
The novelty of our study was to analyze non-invasively structural and metabolic markers of hippocampal dysfunction across the three main phases of pilocarpine-induced epileptogenesis in comparison to the typical brain development over the same period. Acute dorsal hippocampal volume loss and hippocampal neuronal dysfunction are present as early as 48 h post-pilocarpine-induced SE, dynamically changing over time. This acute damage is followed by a pattern of gradual recovery throughout the silent and chronic phases of epileptogenesis, though with an offset for the pilo-SE group. A better understanding of the course of noninvasive markers of epileptogenesis and HS may contribute to stablish surrogate endpoints in interventions to treat or prevent focal epilepsy.
{"title":"Dynamic structural and metabolic changes during the epileptogenesis in the pilocarpine model of temporal lobe epilepsy: A longitudinal MRI study","authors":"Luciana Ramalho Pimentel-Silva , Renata Barbosa , Alexandre Hilario Berenguer de Matos , Raphael Fernandes Casseb , Brunno Machado de Campos , Mônica Mingone Cordeiro , Juliana Francischinelli Casseb , Elayne Vieira Dias , Andre Schwambach Vieira , Luis Concha , Iscia Lopes-Cendes , Fernando Cendes","doi":"10.1016/j.brainres.2026.150180","DOIUrl":"10.1016/j.brainres.2026.150180","url":null,"abstract":"<div><h3>Purpose</h3><div>We aimed to evaluate longitudinal structural and metabolic changes after induced <em>status epilepticus</em> (SE) in the pilocarpine model of TLE, over the three phases of epileptogenesis.</div></div><div><h3>Methods</h3><div>We analyzed 48 male eight-week-old Wistar rats assigned to sham-control and SE-induced groups. T2-weighted images and 1H-MR spectra were acquired using a 3 T MRI clinical scanner (Philips Achieva) equipped with an animal coil. We measured hippocampal volumes (dorsal-HVol) and total N-acetylaspartate ratios to total creatine (tNAA/tCr) in four points in time (MRI-scan): baseline (before pilocarpine or sham treatments), 48 h (acute phase), 15 days (silent period), and 30 days (beginning of the chronic phase) after experimental treatment. To test differences in dorsal-HVol and hippocampal tNAA/tCr we built generalized linear mixed effects models including groups (pilo-SE and control) and MRI-scan as main effects and a group*MRI-scan interaction.</div></div><div><h3>Results</h3><div>Pilo-SE and control animals showed similar baseline dorsal-HVol and hippocampal tNAA/tCr (both p > 0.1). Pilo-SE showed reduced dorsal-HVol and tNAA/tCr at all MRI-scans (all p < 0.001) when compared to controls. Intragroup analysis revealed that dorsal-HVol and tNAA/tCr significantly increased at 15- and 30-days (all p < 0.001) when compared to 48 h, although remaining lower than the baseline scan. There were no changes over time in sham-controls (all p > 0.4).</div></div><div><h3>Conclusions</h3><div>The novelty of our study was to analyze non-invasively structural and metabolic markers of hippocampal dysfunction across the three main phases of pilocarpine-induced epileptogenesis in comparison to the typical brain development over the same period. Acute dorsal hippocampal volume loss and hippocampal neuronal dysfunction are present as early as 48 h post-pilocarpine-induced SE, dynamically changing over time. This acute damage is followed by a pattern of gradual recovery throughout the silent and chronic phases of epileptogenesis, though with an offset for the pilo-SE group. A better understanding of the course of noninvasive markers of epileptogenesis and HS may contribute to stablish surrogate endpoints in interventions to treat or prevent focal epilepsy.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150180"},"PeriodicalIF":2.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036611","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 : 2026-01-18DOI: 10.1016/j.brainres.2026.150169
Shad Ahmad , Adil Husain , Parul Jain , Firoz Ahmad
Background
Central nervous system tuberculosis (CNS-TB), most frequently manifesting as tuberculous meningitis, is associated with high mortality and significant long-term neurological morbidity. Increasing evidence suggests that disease severity and neurological damage are driven largely by dysregulated host neuroinflammatory responses rather than direct Mycobacterium tuberculosis–mediated cytotoxicity. However, the mechanistic links between glial activation, inflammatory signaling, and neuronal injury remain incompletely defined.
Materials and Methods
A comprehensive literature review was conducted using PubMed, Scopus, and Web of Science databases to identify experimental, clinical, and translational studies investigating neuroimmune mechanisms in CNS-TB. Studies focusing on glial activation, cytokine signaling, oxidative stress, excitotoxicity, mitochondrial dysfunction, and neuronal death were included. Recent advances in single-cell transcriptomics, immunometabolism, and host-directed therapeutic strategies were also analyzed and integrated.
Results
The reviewed evidence indicates that CNS invasion by M. tuberculosis leads to sustained activation of microglia and astrocytes, resulting in excessive production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. This inflammatory milieu disrupts blood–brain barrier (BBB) integrity, promotes leukocyte infiltration, and induces oxidative and nitrosative stress. Astrocyte dysfunction further contributes to excitotoxicity through impaired glutamate clearance. These converging inflammatory, oxidative, and excitotoxic pathways drive mitochondrial dysfunction, synaptic impairment, and activation of regulated neuronal cell death pathways, culminating in neurodegeneration.
Conclusion
CNS-TB–associated neuronal injury arises primarily from maladaptive host neuroimmune responses rather than direct mycobacterial effects. A unifying framework centered on glial-driven inflammation and mitochondrial dysfunction provides critical insight into disease pathogenesis. Targeting these convergent pathways through host-directed therapies, alongside antimicrobial treatment, represents a promising strategy to mitigate neuroinflammation and improve long-term neurological outcomes in CNS tuberculosis.
背景：中枢神经系统结核（CNS-TB），最常表现为结核性脑膜炎，与高死亡率和显著的长期神经系统发病率相关。越来越多的证据表明，疾病的严重程度和神经损伤主要是由失调的宿主神经炎症反应驱动的，而不是结核分枝杆菌介导的直接细胞毒性。然而，神经胶质活化、炎症信号和神经元损伤之间的机制联系仍不完全明确。材料和方法：使用PubMed、Scopus和Web of Science数据库进行了全面的文献综述，以确定研究CNS-TB神经免疫机制的实验、临床和转化研究。研究重点包括神经胶质活化、细胞因子信号、氧化应激、兴奋毒性、线粒体功能障碍和神经元死亡。在单细胞转录组学、免疫代谢和宿主导向治疗策略方面的最新进展也进行了分析和整合。结果：已有证据表明，结核分枝杆菌侵袭中枢神经系统导致小胶质细胞和星形胶质细胞持续活化，导致促炎细胞因子如TNF-α、IL-1β和IL-6的过量产生。这种炎症环境破坏血脑屏障的完整性，促进白细胞浸润，并诱导氧化和亚硝化应激。星形胶质细胞功能障碍通过谷氨酸清除受损进一步促进兴奋毒性。这些趋同的炎症、氧化和兴奋毒性通路驱动线粒体功能障碍、突触损伤和受调节的神经元细胞死亡通路的激活，最终导致神经退行性变。结论：cns - tb相关的神经元损伤主要是由宿主神经免疫反应不良引起的，而不是直接的分枝杆菌作用。以神经胶质驱动的炎症和线粒体功能障碍为中心的统一框架为疾病发病机制提供了关键的见解。通过宿主定向治疗和抗菌治疗靶向这些趋同通路，是缓解中枢神经系统结核病的神经炎症和改善长期神经预后的一种有希望的策略。
{"title":"Inflammation-induced Neuronal Damage in CNS Tuberculosis: Molecular Mechanism and Therapeutic Targets","authors":"Shad Ahmad , Adil Husain , Parul Jain , Firoz Ahmad","doi":"10.1016/j.brainres.2026.150169","DOIUrl":"10.1016/j.brainres.2026.150169","url":null,"abstract":"<div><h3>Background</h3><div>Central nervous system tuberculosis (CNS-TB), most frequently manifesting as tuberculous meningitis, is associated with high mortality and significant long-term neurological morbidity. Increasing evidence suggests that disease severity and neurological damage are driven largely by dysregulated host neuroinflammatory responses rather than direct Mycobacterium tuberculosis–mediated cytotoxicity. However, the mechanistic links between glial activation, inflammatory signaling, and neuronal injury remain incompletely defined.</div></div><div><h3>Materials and Methods</h3><div>A comprehensive literature review was conducted using PubMed, Scopus, and Web of Science databases to identify experimental, clinical, and translational studies investigating neuroimmune mechanisms in CNS-TB. Studies focusing on glial activation, cytokine signaling, oxidative stress, excitotoxicity, mitochondrial dysfunction, and neuronal death were included. Recent advances in single-cell transcriptomics, immunometabolism, and host-directed therapeutic strategies were also analyzed and integrated.</div></div><div><h3>Results</h3><div>The reviewed evidence indicates that CNS invasion by M. tuberculosis leads to sustained activation of microglia and astrocytes, resulting in excessive production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. This inflammatory milieu disrupts blood–brain barrier (BBB) integrity, promotes leukocyte infiltration, and induces oxidative and nitrosative stress. Astrocyte dysfunction further contributes to excitotoxicity through impaired glutamate clearance. These converging inflammatory, oxidative, and excitotoxic pathways drive mitochondrial dysfunction, synaptic impairment, and activation of regulated neuronal cell death pathways, culminating in neurodegeneration.</div></div><div><h3>Conclusion</h3><div>CNS-TB–associated neuronal injury arises primarily from maladaptive host neuroimmune responses rather than direct mycobacterial effects. A unifying framework centered on glial-driven inflammation and mitochondrial dysfunction provides critical insight into disease pathogenesis. Targeting these convergent pathways through host-directed therapies, alongside antimicrobial treatment, represents a promising strategy to mitigate neuroinflammation and improve long-term neurological outcomes in CNS tuberculosis.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150169"},"PeriodicalIF":2.6,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008955","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 : 2026-01-13DOI: 10.1016/j.brainres.2026.150164
Sarani Dey, Abhijit Das
Autism Spectrum Disorder (ASD) represents a diverse set of neurodevelopmental disorders diagnosed in children exhibiting common behavioral impairments in social communication and excessive repetitive behaviors. Genetic approaches and large-scale genomic studies have uncovered hundreds of ASD-associated genes with diverse molecular functions contributing to various biochemical and physiological pathways. Despite the underlying genetic diversity, the convergence of phenotypic features suggests the disruption in shared neurobiological mechanisms contributing to ASD. Spontaneous neuronal activity (SNA), the stimulus-independent firing of neurons, which is observed even during neuronal development, has been known to be crucial for neural circuit maturation. Functional neuroimaging studies have demonstrated that SNA is a central process disrupted in ASD patients and mutation-based animal and cellular models. SNA orchestrates critical developmental programs during neuronal maturation such as dendritic arborization, synaptic pruning, excitatory-inhibitory balance, and activity-dependent transcriptional regulation. Perturbations in these dynamics may provide a unifying mechanistic framework linking genetic mutations to abnormal circuit formation and behavioral anomalies. In this review, we collate the genetic and genomic studies to evaluate the contribution of ASD genes in regulating the spontaneous firing of neurons. We classify ASD genes into generators, sensors, transducers, and responders of activity-induced signals and discuss their roles in regulating membrane excitability, transducing the signal to cytoplasmic or nuclear targets to transform the neuronal gene expression program, eventually impacting neuronal and synaptic development. We attempt to substantiate the contribution of altered SNA as the single major common neurological mediator connecting genetic mutations with the common behavioral irregularities manifested in ASD.
{"title":"Genetics of Autism Spectrum Disorder underscores the role of altered spontaneous neuronal activity as a catalyst for the neurodevelopmental anomalies","authors":"Sarani Dey, Abhijit Das","doi":"10.1016/j.brainres.2026.150164","DOIUrl":"10.1016/j.brainres.2026.150164","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) represents a diverse set of neurodevelopmental disorders diagnosed in children exhibiting common behavioral impairments in social communication and excessive repetitive behaviors. Genetic approaches and large-scale genomic studies have uncovered hundreds of ASD-associated genes with diverse molecular functions contributing to various biochemical and physiological pathways. Despite the underlying genetic diversity, the convergence of phenotypic features suggests the disruption in shared neurobiological mechanisms contributing to ASD. Spontaneous neuronal activity (SNA), the stimulus-independent firing of neurons, which is observed even during neuronal development, has been known to be crucial for neural circuit maturation. Functional neuroimaging studies have demonstrated that SNA is a central process disrupted in ASD patients and mutation-based animal and cellular models. SNA orchestrates critical developmental programs during neuronal maturation such as dendritic arborization, synaptic pruning, excitatory-inhibitory balance, and activity-dependent transcriptional regulation. Perturbations in these dynamics may provide a unifying mechanistic framework linking genetic mutations to abnormal circuit formation and behavioral anomalies. In this review, we collate the genetic and genomic studies to evaluate the contribution of ASD genes in regulating the spontaneous firing of neurons. We classify ASD genes into generators, sensors, transducers, and responders of activity-induced signals and discuss their roles in regulating membrane excitability, transducing the signal to cytoplasmic or nuclear targets to transform the neuronal gene expression program, eventually impacting neuronal and synaptic development. We attempt to substantiate the contribution of altered SNA as the single major common neurological mediator connecting genetic mutations with the common behavioral irregularities manifested in ASD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150164"},"PeriodicalIF":2.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988252","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 : 2026-01-13DOI: 10.1016/j.brainres.2026.150168
V. Pravin, Chitra Vellapandian, V. Naveen Kumar
Periodontitis, a chronic inflammatory disease of the oral cavity, has been identified as a modifiable risk factor of the development of systemic and neurological disorders via a complicated interplay of microbiological, immunological, and neural interactions. Periodontal pathogens breach local immune homeostasis, are translocated to the gut and brain, and trigger a cascade of immune deregulation, leaky gut, and blood–brain barrier, thereby forming a tri-directional communication network that links local oral inflammation to systemic and neurovascular conditions. This review synthesizes existing evidence on how oral dysbiosis, can spread to the gut and trigger systemic inflammation, leading to neuroinflammation and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Mechanistically, the OGB axis acts through various processes, such as hematogenous spread, retrograde axonal transport, immune cell trafficking (Trojan horse mechanism), and extracellular vesicle-based signaling corresponding to the causes of neuroinflammation, microglial activation, and the pathology of tau and amyloid. The diagnostic and therapeutic implications of the OGB axis provide new pathways toward early intervention with precision medicine, microbiome remodeling, immune-based therapy, and neuroprotective approaches. Emerging technologies, including AI-based diagnostics and biosensing technologies, offers noninvasive tools to track host-microbial interactions and inflammatory biomarkers. This integrative view underscores the central importance of oral health in systemic homeostasis and the development of neurodegenerative conditions, necessitating collaborative approaches between dentistry, neurology, and immunology to cooperate to deliver efficacy in disease elimination and mitigation.
{"title":"The oral-gut-brain axis in periodontitis: microbial signaling in systemic and neuroinflammatory disease","authors":"V. Pravin, Chitra Vellapandian, V. Naveen Kumar","doi":"10.1016/j.brainres.2026.150168","DOIUrl":"10.1016/j.brainres.2026.150168","url":null,"abstract":"<div><div>Periodontitis, a chronic inflammatory disease of the oral cavity, has been identified as a modifiable risk factor of the development of systemic and neurological disorders via a complicated interplay of microbiological, immunological, and neural interactions. Periodontal pathogens breach local immune homeostasis, are translocated to the gut and brain, and trigger a cascade of immune deregulation, leaky gut, and blood–brain barrier, thereby forming a tri-directional communication network that links local oral inflammation to systemic and neurovascular conditions. This review synthesizes existing evidence on how oral dysbiosis, can spread to the gut and trigger systemic inflammation, leading to neuroinflammation and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Mechanistically, the OGB axis acts through various processes, such as hematogenous spread, retrograde axonal transport, immune cell trafficking (Trojan horse mechanism), and extracellular vesicle-based signaling corresponding to the causes of neuroinflammation, microglial activation, and the pathology of tau and amyloid. The diagnostic and therapeutic implications of the OGB axis provide new pathways toward early intervention with precision medicine, microbiome remodeling, immune-based therapy, and neuroprotective approaches. Emerging technologies, including AI-based diagnostics and biosensing technologies, offers noninvasive tools to track host-microbial interactions and inflammatory biomarkers. This integrative view underscores the central importance of oral health in systemic homeostasis and the development of neurodegenerative conditions, necessitating collaborative approaches between dentistry, neurology, and immunology to cooperate to deliver efficacy in disease elimination and mitigation.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150168"},"PeriodicalIF":2.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988307","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 : 2026-01-12DOI: 10.1016/j.brainres.2026.150167
André Simões Cadaxo , Juliana Cordovil Cotrin , Ana Paula Valente , Flávia Gomes Lopes , Renato Peixoto Veras , Daniel Simplício Torres , Raquel Quimas Molina da Costa , Gilson Costa dos Santos Junior , Cíntia Barros Santos-Rebouças
Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder worldwide. A prodromal stage, often manifested as Mild Cognitive Impairment (MCI), can precede dementia onset. Metabolomics provides a powerful approach to detect metabolic alterations capturing combined genetic, epigenetic, dietary, gut microbiota, and environmental influences on AD pathogenesis and progression from MCI to AD. In this study, we analysed plasma, urine, and saliva metabolomes of 94 ethnically diverse Brazilian individuals (30 AD, 16 MCI and 48 healthy controls), all comorbidity-free, using Nuclear Magnetic Resonance (NMR)-based metabolomics. Cross-sectional analysis employed multivariate modelling (PLS-DA) and univariate Mann-Whitney U tests. We identified distinct group-specific metabolic signatures involving amino acids (phenylalanine, glutamine, asparagine, valine, alanine), energy-related metabolites (pyruvate, citrate, glucose), compounds linked to lipid/redox pathways (acetate, glutamate, aspartate), epigenetic regulation (betaine), neuroinflammation, immune fitness, and gut microbiome-influenced metabolites (scyllo-inositol). Valine increased progressively (controls < MCI < AD), while alanine showed a biphasic pattern (reduced in MCI, elevated in AD). These consistent, biofluid-spanning alterations highlight their potential as minimally invasive biomarkers for diagnosis and monitoring. Integration of metabolite data with AD-associated genes from genome-wide association studies (GWAS) revealed six genes (CYCS, NFAT5, GRIN2B, SLC43A2, MAPT, and SLC38A1) common to all biofluids, reinforcing convergent systemic pathways. Collectively, these findings underscore the importance of integrating metabolomics with genetic networks to enhance understanding of AD pathophysiology, identify potential therapeutic targets, and guide future clinical validation and precision medicine strategies for dementia in ethnically mixed populations.
{"title":"Multi-biofluid metabolomics coupled with gene network reveals stage-specific alterations in mild cognitive impairment and Alzheimer’s disease in an ethnically mixed cohort","authors":"André Simões Cadaxo , Juliana Cordovil Cotrin , Ana Paula Valente , Flávia Gomes Lopes , Renato Peixoto Veras , Daniel Simplício Torres , Raquel Quimas Molina da Costa , Gilson Costa dos Santos Junior , Cíntia Barros Santos-Rebouças","doi":"10.1016/j.brainres.2026.150167","DOIUrl":"10.1016/j.brainres.2026.150167","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder worldwide. A prodromal stage, often manifested as Mild Cognitive Impairment (MCI), can precede dementia onset. Metabolomics provides a powerful approach to detect metabolic alterations capturing combined genetic, epigenetic, dietary, gut microbiota, and environmental influences on AD pathogenesis and progression from MCI to AD. In this study, we analysed plasma, urine, and saliva metabolomes of 94 ethnically diverse Brazilian individuals (30 AD, 16 MCI and 48 healthy controls), all comorbidity-free, using Nuclear Magnetic Resonance (NMR)-based metabolomics. Cross-sectional analysis employed multivariate modelling (PLS-DA) and univariate Mann-Whitney U tests. We identified distinct group-specific metabolic signatures involving amino acids (phenylalanine, glutamine, asparagine, valine, alanine), energy-related metabolites (pyruvate, citrate, glucose), compounds linked to lipid/redox pathways (acetate, glutamate, aspartate), epigenetic regulation (betaine), neuroinflammation, immune fitness, and gut microbiome-influenced metabolites (scyllo-inositol). Valine increased progressively (controls < MCI < AD), while alanine showed a biphasic pattern (reduced in MCI, elevated in AD). These consistent, biofluid-spanning alterations highlight their potential as minimally invasive biomarkers for diagnosis and monitoring. Integration of metabolite data with AD-associated genes from genome-wide association studies (GWAS) revealed six genes (<em>CYCS</em>, <em>NFAT5</em>, <em>GRIN2B</em>, <em>SLC43A2</em>, <em>MAPT</em>, and <em>SLC38A1</em>) common to all biofluids, reinforcing convergent systemic pathways. Collectively, these findings underscore the importance of integrating metabolomics with genetic networks to enhance understanding of AD pathophysiology, identify potential therapeutic targets, and guide future clinical validation and precision medicine strategies for dementia in ethnically mixed populations.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150167"},"PeriodicalIF":2.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974055","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 : 2026-01-12DOI: 10.1016/j.brainres.2026.150166
Laila Zahran, Reham H. Elnabawy
This narrative review examines optogenetic strategies for retinal prostheses, which represent an advanced step in vision restoration, particularly for patients with retinitis pigmentosa and age-related macular degeneration. This review highlights the use of optogenetic stimulation to target high-density retinal ganglion cells (RGCs), focusing on developments like the FlexLED device. Opsins such as ChR2, ReaChR, and ChrimsonR, engineered for light sensitivity and faster responses, are critical for enhancing vision restoration. Combining optogenetic and electrical stimulation improves the reproducibility and specificity of RGC responses. Neuroimaging techniques like adaptive optics scanning laser ophthalmoscopy (AOSLO) help monitor cell activity, aiding in the development of visual repair methods. However, challenges remain in improving opsin sensitivity, gene delivery techniques, and ensuring long-term efficacy of retinal responses in patients. This review emphasizes the potential of optogenetic retinal prostheses to offer lasting, effective vision rehabilitation, significantly improving the quality of life for patients. This narrative review emphasizes that further research is needed to overcome current obstacles, such as improving opsin sensitivity and gene delivery techniques, to ensure long-term, effective vision restoration in patients.
{"title":"Key optogenetic advances in retinal prostheses: A comparative narrative review","authors":"Laila Zahran, Reham H. Elnabawy","doi":"10.1016/j.brainres.2026.150166","DOIUrl":"10.1016/j.brainres.2026.150166","url":null,"abstract":"<div><div>This narrative review examines optogenetic strategies for retinal prostheses, which represent an advanced step in vision restoration, particularly for patients with retinitis pigmentosa and age-related macular degeneration. This review highlights the use of optogenetic stimulation to target high-density retinal ganglion cells (RGCs), focusing on developments like the FlexLED device. Opsins such as ChR2, ReaChR, and ChrimsonR, engineered for light sensitivity and faster responses, are critical for enhancing vision restoration. Combining optogenetic and electrical stimulation improves the reproducibility and specificity of RGC responses. Neuroimaging techniques like adaptive optics scanning laser ophthalmoscopy (AOSLO) help monitor cell activity, aiding in the development of visual repair methods. However, challenges remain in improving opsin sensitivity, gene delivery techniques, and ensuring long-term efficacy of retinal responses in patients. This review emphasizes the potential of optogenetic retinal prostheses to offer lasting, effective vision rehabilitation, significantly improving the quality of life for patients. This narrative review emphasizes that further research is needed to overcome current obstacles, such as improving opsin sensitivity and gene delivery techniques, to ensure long-term, effective vision restoration in patients.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150166"},"PeriodicalIF":2.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974421","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}
Parkinson’s disease (PD) characterized by the selective loss of dopaminergic neurons in the brain resulting in motor and cognitive deficits. While apoptosis has long been considered a primary mechanism of neuronal death in PD, emerging evidence highlights the significant roles of non-apoptotic programmed cell death pathways, particularly ferroptosis and pyroptosis-in driving PD progression. Ferroptosis is form of cell death that is dependent on iron and driven by lipid peroxidation, appears to be associated with PD. On the other hand, Pyroptosis, a caspase-1-dependent inflammatory cell death pathway mediated by activation of inflammasome and release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18. Both pathways contribute to the neurodegeneration in PD through distinct yet interconnected pathways. Therefore, this review highlights molecular mechanisms underlying ferroptosis and pyroptosis in PD and recent advances in pharmacological strategies targeting these pathways.
{"title":"Programmed cell death pathways in Parkinson’s disease: Spotlight on ferroptosis and pyroptosis","authors":"Veerta Sharma, Reet Verma, Prateek Sharma, Thakur Gurjeet Singh","doi":"10.1016/j.brainres.2026.150165","DOIUrl":"10.1016/j.brainres.2026.150165","url":null,"abstract":"<div><div>Parkinson’s disease (PD) characterized by the selective loss of dopaminergic neurons in the brain resulting in motor and cognitive deficits. While apoptosis has long been considered a primary mechanism of neuronal death in PD, emerging evidence highlights the significant roles of non-apoptotic programmed cell death pathways, particularly ferroptosis and pyroptosis-in driving PD progression. Ferroptosis is form of cell death that is dependent on iron and driven by lipid peroxidation, appears to be associated with PD. On the other hand, Pyroptosis, a caspase-1-dependent inflammatory cell death pathway mediated by activation of inflammasome and release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18. Both pathways contribute to the neurodegeneration in PD through distinct yet interconnected pathways. Therefore, this review highlights molecular mechanisms underlying ferroptosis and pyroptosis in PD and recent advances in pharmacological strategies targeting these pathways.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1875 ","pages":"Article 150165"},"PeriodicalIF":2.6,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965149","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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