Frontiers in Cellular Neuroscience最新文献

{"title":"Rotenone-induced oxidative stress triggers peroxisomal alterations in BV-2 microglial cells.","authors":"Alessio Valenza, Maurizio Muzzi, Francesca Rendina, Irene Montali, Daniele Pensabene, Anna Fracassi, Marco Segatto, Sandra Moreno","doi":"10.3389/fncel.2026.1941513","DOIUrl":"10.3389/fncel.2026.1941513","url":null,"abstract":"<p><strong>Introduction: </strong>Peroxisomes are highly dynamic organelles that contribute to cellular homeostasis by coordinating lipid metabolism, reactive oxygen species handling, and adaptive responses to metabolic stress. Their plasticity is particularly relevant in the nervous system, where peroxisomes cooperate with mitochondria to maintain redox and metabolic balance in neuronal and glial cells. Peroxisome proliferator-activated receptor alpha (PPARα), together with its coactivator PGC-1α, represents a major transcriptional regulator of peroxisomal and mitochondrial metabolic programs.</p><p><strong>Methods: </strong>BV2 microglial cells were exposed to rotenone to investigate how mitochondrial oxidative stress influences the peroxisomal compartment. Mitochondrial and peroxisomal morphology, intracellular distribution, oxidative damage, and the expression of proteins involved in peroxisomal metabolism and PPARα signaling were evaluated.</p><p><strong>Results: </strong>Rotenone induced a stress-associated microglial phenotype characterized by cytoskeletal remodeling, mitochondrial network disruption, and oxidative damage. These alterations were accompanied by a coordinated reorganization of the peroxisomal compartment, including increased abundance of peroxisomal membrane markers, redistribution of peroxisomes toward the perinuclear region, and enhanced expression of enzymes associated with peroxisomal fatty acid oxidation. An increased spatial association between peroxisomes and mitochondria was also observed, suggesting that peroxisomal remodeling forms part of a broader inter-organelle adaptation to mitochondrial dysfunction. These changes occurred together with increased nuclear phosphorylated PPARα and enhanced PGC-1α immunoreactivity, supporting the engagement of a PPARα-PGC-1α-related transcriptional response.</p><p><strong>Discussion: </strong>Overall, our findings suggest that mitochondrial dysfunction in microglial cells activates a PPARα-associated adaptive program that promotes peroxisomal remodeling and strengthens mitochondria-peroxisome coordination. This response may represent an attempt to preserve lipid and redox homeostasis during cellular stress and identifies PPARα-regulated peroxisomal pathways as potentially relevant components of microglial metabolic adaptation in neurodegenerative conditions.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1941513"},"PeriodicalIF":4.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reward contingency reorganizes lateral orbitofrontal cortex pyramidal neuron activity from reward-aligned to action-aligned during associative learning.","authors":"Zicheng Yang, Xiaolan Chen, Xiaohong Sun, Huimeng Lei","doi":"10.3389/fncel.2026.1850197","DOIUrl":"10.3389/fncel.2026.1850197","url":null,"abstract":"<p><strong>Background: </strong>Animals must learn not only which cues predict reward, but also when to act to obtain it. Although the orbitofrontal cortex (OFC) encodes reward-related information, whether reward contingency is sufficient to reorganize the temporal alignment of OFC activity remains unclear.</p><p><strong>Methods: </strong>We recorded calcium signals from lateral OFC pyramidal neurons (lOFC-PNs) in wild-type (WT) and <i>Sapap3</i> knockout (KO) mice using fiber photometry, during sequential learning of Pavlovian and instrumental contingencies in a single-odor reward association task. We further used a cue-free lick test and linear mixed-effects modeling to dissociate the contribution of reward contingency from that of licking behavior.</p><p><strong>Results: </strong>Licking behavior and lOFC-PN activity were comparable between WT and KO mice, supporting pooled analysis. Under Pavlovian contingencies, licking and lOFC-PN activity were concentrated around reward delivery. Under instrumental contingencies, both shifted to the pre-reward delay period, and the timing of lOFC-PN activity became progressively coupled to anticipatory licking as learning advanced. A cue-free lick test and linear mixed-effects modeling confirmed that these contingency-related differences reflected reward contingency rather than licking <i>per se</i>.</p><p><strong>Conclusion: </strong>These findings indicate that reward contingency dynamically reorganizes the temporal alignment of lOFC-PN activity and its coupling with behavior, shifting from reward-aligned under Pavlovian learning to action-aligned under instrumental learning. This contingency-dependent temporal reorganization may support flexible adaptation of neural processing to changing reward contingencies during associative learning.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1850197"},"PeriodicalIF":4.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and emerging therapeutic targets.","authors":"Lianjing Xu, Ying Zhang, Li Jiang, Jin Feng Xing, Jing Hu, Tianye Lan, Guang Ta","doi":"10.3389/fncel.2026.1902577","DOIUrl":"10.3389/fncel.2026.1902577","url":null,"abstract":"<p><p>Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a \"cellular state-pathological network-therapeutic window\" framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA-cGAS-STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia-tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7-NLRP3 and cGAS-STING, CSF1R/complement, and TNF-TNFR1-RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1902577"},"PeriodicalIF":4.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olfactory models as a platform for neuroscience research.","authors":"María Figueres-Oñate","doi":"10.3389/fncel.2026.1897347","DOIUrl":"10.3389/fncel.2026.1897347","url":null,"abstract":"<p><p>The capacity of the olfactory epithelium (OE) to sustain adult neurogenesis offers an unprecedented opportunity to investigate the mechanisms of neural lineage specification, cellular turnover, and tissue regeneration in a human context. Unlike conventional brain organoids, which predominantly model embryonic or fetal neurodevelopment, olfactory organoid systems uniquely provide experimental access to active adult human neurogenic and regenerative dynamics. As the only accessible adult neural stem cell niche that can be repeatedly sampled from living patients, this neuroepithelium opens new paths for generating patient-specific, non-reprogrammed neural models. This review provides an overview of OE-derived <i>in vitro</i> systems, detailing their evolution from early neurospheres to advanced three-dimensional (3D) organoids, highlighting their capacity to preserve donor genetic, epigenetic, transcriptomic and proteomic signatures, establishing them as a powerful platform for personalized medicine, disease modeling, and \"nose-to-brain\" therapeutic discovery.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1897347"},"PeriodicalIF":4.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Boldine treatment prevents chronic cognitive impairment and exaggerated fear learning in rats exposed to repetitive low-level blast injury.","authors":"Georgina Perez Garcia, Gissel M Perez, Rita De Gasperi, Miguel A Gama Sosa, Serena Yeung, Carolyn W Zhu, Patrick R Hof, Jiangping Pan, Shahrukh Khalique, Alexey Kozlenkov, Wei Zhao, Carlos A Toro, Gregory A Elder, Christopher P Cardozo","doi":"10.3389/fncel.2026.1894226","DOIUrl":"10.3389/fncel.2026.1894226","url":null,"abstract":"<p><p>Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (<i>Peumus boldus</i>), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms \"Cognition\" and \"Neurotransmitter Transport,\" consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1894226"},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hippocampal subgranular zone neurogenic niche: a modular perspective on neural stem cell regulation.","authors":"Tengyu Zhao, Yuhan Zhou, Pengyu Pan, Ying Jia, Xinyue Zhang, Zeyuan An, Jingdong Yan, Quan Li, Yanyan Zhou","doi":"10.3389/fncel.2026.1887577","DOIUrl":"10.3389/fncel.2026.1887577","url":null,"abstract":"<p><p>The subgranular zone (SGZ) of the hippocampus represents a principal site of adult neurogenesis and exhibits distinct structural and organizational features. Increasing evidence indicates that neural stem cell (NSC) behavior in the SGZ is not solely determined by intrinsic cellular properties, but is critically shaped by its surrounding neurogenic niche. However, current studies largely describe niche-derived regulatory factors in isolation, and a systematic framework integrating these diverse signals remains lacking. In this review, we propose a structured perspective that links the unique anatomical and organizational characteristics of the SGZ to its regulatory mechanisms. We conceptualize SGZ niche regulation as a multi-dimensional and non-hierarchical system, in which multiple interacting components-including spatial organization, metabolic-vascular support, neural circuit activity, immune modulation, and extracellular matrix-mediated signaling-collectively govern NSC state transitions. Within this framework, neurogenesis is understood as an emergent outcome of coordinated changes across these regulatory dimensions rather than the result of single-factor control. We further discuss how shifts in the neurogenic niche under pathological conditions-such as aging, Alzheimer's disease, and chronic cerebral hypoperfusion (CCH) -reshape NSC behavior, driving maladaptive responses that may ultimately lead to dysregulated neurogenesis. By providing a modular and system-level perspective, this review offers a conceptual basis for understanding SGZ regulation and may help identify potential targets for restoring neurogenic capacity.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1887577"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomics identifies a putative perivascular macrophage-endothelial MIF-ACKR3 axis associated with endothelial activation in acute traumatic brain injury.","authors":"Yanya Lin, Chengda Lin, Jianhui Chen, Shijun Chen, Jianhuang Huang, Jianxiong Hu","doi":"10.3389/fncel.2026.1863509","DOIUrl":"10.3389/fncel.2026.1863509","url":null,"abstract":"<p><strong>Background: </strong>Blood-brain barrier (BBB) disruption is a hallmark of acute traumatic brain injury (TBI), yet the immune-vascular mechanisms underlying endothelial dysfunction remain incompletely understood. Perivascular macrophages (PVMs) are strategically positioned to modulate cerebrovascular homeostasis, but their role in acute post-traumatic endothelial activation has not been systematically characterized.</p><p><strong>Methods: </strong>We re-analyzed a publicly available mouse single-cell RNA sequencing (scRNA-seq) dataset (GSE290150, 24 h post-TBI) to characterize the landscape of immune and vascular cell populations and to infer intercellular communication. Bone marrow-derived macrophages (BMDMs) served as a PVM surrogate model, and bEnd.3 cerebral endothelial cells were used for <i>in vitro</i> validation of key signaling pathways.</p><p><strong>Results: </strong>Single-cell analysis revealed concurrent expansion of PVM-like cells and activated endothelial cells (Activated ECs) in the TBI brain, with CellChat-predicted enhancement of MIF-ACKR3 signaling from PVM-like cells toward Activated ECs. Inflammatory stimulation of BMDMs significantly increased MIF expression and secretion in a STAT3-dependent manner. Macrophage-conditioned medium induced endothelial activation-associated molecular changes, including upregulation of Angpt2 and Adm and downregulation of tight junction genes Claudin5 and Tjp1; these effects were attenuated by MIF inhibitor ISO-1 or ACKR3 antagonist CCX771. Recombinant MIF dose-dependently reproduced these changes, which were substantially abrogated by ACKR3 pharmacological blockade or siRNA knockdown. STAT3 inhibition further suppressed rMIF-induced endothelial transcriptional responses.</p><p><strong>Conclusion: </strong>These findings provide transcriptomic and <i>in vitro</i> evidence supporting a PVM-derived MIF-ACKR3-STAT3 signaling axis associated with endothelial activation-related molecular changes in acute TBI. Direct functional effects on BBB integrity and <i>in vivo</i> relevance require further validation. This candidate axis highlights perivascular immune-vascular crosstalk as a potential avenue for therapeutic investigation.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1863509"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aquaporin dysfunction and impaired brain interstitial fluid clearance in Alzheimer's disease - an integrative review.","authors":"Marina Daniela Manescu, Teodora Minca, Ionica Pirici, Cristina Jana Busuioc, Valentin Octavian Mateescu, Daniel Pirici","doi":"10.3389/fncel.2026.1903812","DOIUrl":"10.3389/fncel.2026.1903812","url":null,"abstract":"<p><p>Accumulation of amyloid-beta (Aβ) deposits is one of the neuropathological hallmarks of Alzheimer's disease (AD), the most frequent neurodegenerative disease in all age groups. While decades of research have focused on the production and aggregation of Aβ peptides, mounting evidence implicate impaired brain fluid dynamics and protein waste clearance as critical contributors to AD pathogenesis. The aquaporin family of water channels, particularly aquaporin-4 (AQP4) and AQP1, has emerged as central regulators of brain interstitial fluid (ISF) homeostasis and Aβ clearance. AQP4, expressed at the perivascular endfeet of astrocytes, is the principal water channel driving fluid convection exchange, acting as a brain-wide network in which ISF and solutes are cleared via venous, paravenous and periarterial routes, as well as through dural lymphatic vessels and along perineural spaces. AQP1, expressed predominantly in the choroid plexus epithelium, governs cerebrospinal fluid (CSF) secretion and thereby modulates the pressure gradients that sustain this convective flow. This review provides an integrated overview of the molecular pathology of AD, the physiological roles of AQP4 and AQP1, together with the major anatomical pathways of ISF and CSF drainage from the brain. We next address to the genetic and pharmacological modulation of AQP4 and AQP1 in transgenic AD mouse models and describe the resulting pathological changes. AQP4 knockout consistently exacerbates Aβ pathology and cognitive deficits, with the abnormal distribution of AQP4 within the astrocyte being sufficient to impair clearance, and these data highlight the critical importance of polarized expression versus bulk expression levels. AQP1 modulation, though less studied, alters CSF dynamics and may influence Aβ clearance indirectly through changes in CSF turnover. Pharmacological agents targeting AQP4 and AQP1 offer promising avenues for therapeutic intervention. Understanding the distinct and intersecting roles of aquaporins in brain fluid homeostasis may yield novel strategies for restoring protein clearance in AD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1903812"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From cellular regeneration toward functional integration: a 15-year bibliometric analysis of inner ear hair cell regeneration (2011-2025).","authors":"Xiaoyi Zhang, Lintao Tang, Dongmei Guan, Xinghong Liu, Hui Xie","doi":"10.3389/fncel.2026.1888383","DOIUrl":"10.3389/fncel.2026.1888383","url":null,"abstract":"<p><p>Sensorineural hearing loss, affecting over 1.5 billion people worldwide, results largely from irreversible damage to inner ear hair cells-specialized mechanosensory receptor cells that mammals cannot spontaneously regenerate. While recent advances in gene therapy and stem cell biology have raised hopes for biological repair, the rapid expansion of research has made it difficult to identify overarching trends, knowledge gaps, and translational bottlenecks. This study provides the first bibliometric analysis focusing on inner ear hair cell regeneration, covering 1,035 publications identified from the Web of Science Core Collection after systematic screening. To ensure the robustness of the findings and assess the sensitivity of the findings to database choice, we performed cross-database validation using Scopus and PubMed, which revealed high overlap rates (82.65% for PubMed and 75.76% for Scopus) and consistent patterns in the non-overlapping subset, suggesting that the primary WoSCC-based findings are not qualitatively altered by the inclusion of literature from other major databases. Using VOSviewer and CiteSpace, we analyzed publication trajectories, country/institution contributions, collaboration networks, and keyword dynamics. The results reveal a sustained increase in annual output, with the United States and China emerging as the two most productive and collaboratively central countries in the global research network. Keyword burst analysis shows a temporal shift from structural characterization (early 2010s) to signaling pathways (mid-late 2010s), and more recently to pathological mechanisms and protective strategies (late 2010s-present), including synaptopathy, transplantation, protection, ototoxicity, replacement, autophagy, and disease. VOSviewer co-occurrence analysis further reveals thematic clusters centered on hair cell regeneration and signaling, ototoxic injury and protection, and gene therapy and delivery, suggesting a field expanding from basic mechanisms toward translational research. These findings demonstrate that the field has diversified from a predominant emphasis on cellular regeneration toward broader attention to functional reconstruction of the hair cell-spiral ganglion neuron synapse. This transition underscores a growing emphasis on multi-target synaptic integration and highlights an unmet need for immune-compatible, subtype-specific gene delivery systems. Overall, this analysis, supplemented by cross-database consistency checks, provides a quantitative roadmap.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1888383"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The prefrontal cortex as a target of HIV-1 neurotoxicity: molecular mechanisms of viral protein-mediated neurodegeneration and executive dysfunction.","authors":"Erin S Honsa","doi":"10.3389/fncel.2026.1899622","DOIUrl":"10.3389/fncel.2026.1899622","url":null,"abstract":"<p><p>Despite the success of combined antiretroviral therapy (cART) in achieving peripheral viral suppression, HIV-associated neurocognitive disorder (HAND) remains a persistent challenge, affecting approximately 50% of people living with HIV. This review identifies the prefrontal cortex (PFC) as a primary target of HIV-1 neurotoxicity, as HIV-1 can directly infect the brain, and cART fails to eliminate the production of viral proteins from latent HIV-microglial reservoirs. The blood-brain barrier receives several hits from HIV-1 proteins, leading to a leaky and highly permeable barrier. Several proteins drive chronic neuroinflammation through inflammasome activation and pyroptosis, and ferroptosis in microglia. Glutamatergic dysregulation in the CNS results in increased neuron excitability and neurotoxicity. Also, overactive complement-mediated synaptic pruning and microglial senescence disrupt the intricate neural networks required for higher-order signaling. Neuroimaging and PFC dysfunction can be linked to specific HIV-1 proteins and their effects on the brain. Clinical symptoms of HAND directly reflect specialized PFC dysfunction. Deficits include impaired executive processes, which can present as lacking foresight for goal-directed actions, poor planning, and difficulty switching between tasks. Significant behavioral changes, including disinhibition, impaired moral reasoning, and increased risk-taking, can also be seen. Patients experience apathy, emotional blunting, and rapid mood shifts. Cognitive impairments include working memory loss, distractibility, and inappropriate memory linking. PFC disruptions can escalate into neuropsychiatric sequelae, driven by damaged dopamine and serotonin pathways. Defining these viral-mediated mechanisms will facilitate the development of pharmacological strategies that target several HIV-mediated neurotoxic pathways to prevent the debilitating characteristics of HAND.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1899622"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}