Frontiers in Cellular Neuroscience最新文献

{"title":"Role of glial cells in motor neuron degeneration in hereditary spastic paraplegias.","authors":"Manaswini Vijayaraghavan, Sarvika Periyapalayam Murali, Gitika Thakur, Xue-Jun Li","doi":"10.3389/fncel.2025.1553658","DOIUrl":"https://doi.org/10.3389/fncel.2025.1553658","url":null,"abstract":"<p><p>This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1553658"},"PeriodicalIF":4.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996272","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 learning primacy hypothesis of dopamine: reconsidering dopamine's dual functions.","authors":"Charltien Long, Sotiris C Masmanidis","doi":"10.3389/fncel.2025.1538500","DOIUrl":"https://doi.org/10.3389/fncel.2025.1538500","url":null,"abstract":"<p><p>The dopaminergic modulation of striatal circuit function remains intensely studied and debated. Nevertheless, a prevalent view is that striatal dopamine serves important roles in both reinforcement learning and the performance of movements, two highly distinct processes. But this dichotomy has led to a longstanding problem of how to interpret the functional consequences of a particular dopaminergic signal-is it to learn or to move? In order to explore this ambiguity and approach a possible resolution, this review examines the key evidence for dopamine's role in learning and movement. As part of that discussion, we consider a recent body of evidence that views the common dichotomous perspective through a more nuanced lens, by suggesting a comparatively limited dopaminergic contribution to movement. This concept, which we refer to as the learning primacy hypothesis, offers a unified conceptual framework for understanding dopaminergic function.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1538500"},"PeriodicalIF":4.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967250","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":"Cases of Creutzfeldt-Jakob disease in young individuals: open questions regarding aetiology.","authors":"Ilia V Baskakov","doi":"10.3389/fncel.2025.1571662","DOIUrl":"https://doi.org/10.3389/fncel.2025.1571662","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1571662"},"PeriodicalIF":4.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970210","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":"Genetic mechanisms of dynamic functional connectivity density in diabetic retinopathy brains: a combined transcriptomic and resting-state functional magnetic resonance imaging study.","authors":"Yu-Lin Zhong, Hao Liu, Xin Huang","doi":"10.3389/fncel.2025.1476038","DOIUrl":"https://doi.org/10.3389/fncel.2025.1476038","url":null,"abstract":"<p><strong>Background: </strong>Diabetic retinopathy (DR) is a condition characterized by fundus lesions resulting from retinal microvascular leakage and obstruction linked to chronic progressive diabetes mellitus. Previous neuroimaging research has revealed both structural and functional changes in the brains of DR patients. Nevertheless, the variations in dynamic functional connectivity density (dFCD) within the brains of DR patients, along with the underlying molecular mechanisms connected to these changes, have yet to be fully understood.</p><p><strong>Methods: </strong>Forty-seven diabetic retinopathy (DR) patients and 46 healthy controls (HCs) matched for sex, age, and education were recruited for this study from the Department of Ophthalmology at the Jiangxi Provincial People's Hospital. All subjects underwent resting-state functional magnetic resonance imaging scans to analyze the differences in dFCD between the two groups. Utilizing the Allen Human Brain Atlas, we conducted spatial correlation analyses integrating transcriptomic and neuroimaging data to pinpoint genes showing correlated expression levels with dFCD alterations in DR patients. Subsequently, we carried out gene enrichment, specific expression, and protein-protein interaction analyses.</p><p><strong>Results: </strong>In comparison to the HC group, the DR group exhibited significantly reduced dFCD variability in the left anterior cingulum, left superior occipital gyrus, and right postcentral gyrus. The abnormal dFCD variability is linked to 1,318 positively and 1,318 negatively associated genes, primarily enriched for biological functions such as ion channels, synapses, and cellular junctions. Specific expression analysis revealed that these genes were distinctly expressed in Purkinje neurons, cortex, and striatum brain regions. Furthermore, protein-protein interaction (PPI) analyses indicated that these positive and negative genes could organize PPI networks with the support of respective hub genes.</p><p><strong>Conclusion: </strong>our study identified altered dFCD variability in brain regions linked to visual and cognitive functions in DR patients. Moreover, transcriptome-neuroimaging correlation analyses revealed a spatial association between these dFCD changes and the genes with unique functional profiles. These genes were enriched in biologically significant functions and pathways, specific to certain cells and brain areas. Our research offers novel understandings of the genetic mechanisms influencing dFCD alterations in DR.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1476038"},"PeriodicalIF":4.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001890","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 roles of immune factors in neurodevelopment.","authors":"Chong Wang, Tingting He, Jie Qin, Jianwei Jiao, Fen Ji","doi":"10.3389/fncel.2025.1451889","DOIUrl":"https://doi.org/10.3389/fncel.2025.1451889","url":null,"abstract":"<p><p>The development of the nervous system is a highly complex process orchestrated by a multitude of factors, including various immune elements. These immune components play a dual role, not only regulating the immune response but also actively influencing brain development under both physiological and pathological conditions. The brain's immune barrier includes microglia in the brain parenchyma, which act as resident macrophages, astrocytes that support neuronal function and contribute to the inflammatory response, as well as circulating immune cells that reside at the brain's borders, including the choroid plexus, meninges, and perivascular spaces. Cytokines-soluble signaling molecules released by immune cells-play a crucial role in mediating communication between immune cells and the developing nervous system. Cytokines regulate processes such as neurogenesis, synaptic pruning, and inflammation, helping to shape the neural environment. Dysregulation of these immune cells, astrocytes, or cytokine signaling can lead to alterations in neurodevelopment, potentially contributing to neurodevelopmental abnormalities. This article reviews the central role of microglia, astrocytes, cytokines, and other immune factors in neurodevelopment, and explores how neuroinflammation can lead to the onset of neurodevelopmental disorders, shedding new light on their pathogenesis.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1451889"},"PeriodicalIF":4.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961052","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":"A humanized Gs-coupled DREADD for circuit and behavior modulation.","authors":"Qi Zhang, Ruiqi Wang, Liang Zhang, Mengqi Li, Jianbang Lin, Xiaoyang Lu, Yixuan Tian, Yunping Lin, Taian Liu, Yefei Chen, Yuantao Li, Jun Cao, Qiang Wu, Jinhui Wang, Zhonghua Lu, Zexuan Hong","doi":"10.3389/fncel.2025.1577117","DOIUrl":"https://doi.org/10.3389/fncel.2025.1577117","url":null,"abstract":"<p><p>Designer receptors exclusively activated by designer drugs (DREADDs) play important roles in neuroscience research and show great promise for future clinical interventions in neurological diseases. The Gs-coupled DREADD, rM3Ds, modulates excitability in neuron subsets that are sensitive to downstream effectors of Gs protein. However, given the non-human nature of the rM3Ds backbone, risks about potential immunogenicity and tolerability exist when considering clinical translation. Here, we report the development of a whole sequence-humanized Gs-coupled DREADD, hM3Ds. We found that hM3Ds has a comparable DREADD ligand response profile to rM3Ds. We then selectively expressed hM3Ds in D1 medium spiny neurons (D1-MSNs) and found that hM3Ds was able to activate the D1-MSNs-mediated basal ganglia direct pathway and alleviate Parkinsonian phenotypes in a Parkinson's disease mouse model. In conclusion, this engineered humanized Gs-coupled DREADD is suitable as an effective, and likely safer, DREADD tool for both research and future clinical applications.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1577117"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975979","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":"Activity-dependent refinement of axonal projections forms one-to-one connection pattern in the developing chick ciliary ganglion.","authors":"Ryo Egawa, Hiromu Yawo, Hiroshi Kuba","doi":"10.3389/fncel.2025.1560402","DOIUrl":"https://doi.org/10.3389/fncel.2025.1560402","url":null,"abstract":"<p><p>Although it is well established that initially overproduced synaptic connections are extensively remodeled through activity-dependent competition for postsynaptic innervation, the mechanisms determining the final number of postsynaptic targets per axon remain unclear. Here, we investigated the morphology of individual axonal projections during development and the influence of neural activity in the chick ciliary ganglion (CG), a traditional model system for synapse maturation. By single-axon tracing combining Brainbow labeling and tissue clearing, we revealed that by embryonic day 14 (E14), hundreds of preganglionic axons each establish a one-to-one synaptic connection with single CG neurons via a calyx-type presynaptic terminal enveloping the soma of its postsynaptic target. This homogeneous connection pattern emerged through presynaptic terminal maturation from bouton-like to calyx-like morphology and concurrent axonal branch pruning starting around E10. The calyx maturation was retarded by the presynaptic expression of genetically encoded tools for silencing neuronal activity, enhanced tetanus neurotoxin light chain (eTeNT) or Kir2.1, demonstrating the activity-dependence of this morphological refinement. These findings suggest that some presynaptic mechanisms as well as synaptic competition would operate to restrict the number of postsynaptic targets innervated by each axon in the CG. Together with the easy accessibility to single-axon tracing, our results highlight the potential of the chick CG as a model for investigating the presynaptic factors underlying circuit remodeling.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1560402"},"PeriodicalIF":4.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12014593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975647","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":"Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation.","authors":"Ludmila Müller, Svetlana Di Benedetto","doi":"10.3389/fncel.2025.1575022","DOIUrl":"https://doi.org/10.3389/fncel.2025.1575022","url":null,"abstract":"<p><p>Neuroinflammation is a fundamental feature of many chronic neurodegenerative diseases, where it contributes to disease onset, progression, and severity. This persistent inflammatory state arises from the activation of innate and adaptive immune responses within the central nervous system (CNS), orchestrated by a complex interplay of resident immune cells, infiltrating peripheral immune cells, and an array of molecular mediators such as cytokines, chemokines, and extracellular vesicles. Among CNS-resident cells, microglia play a central role, exhibiting a dynamic spectrum of phenotypes ranging from neuroprotective to neurotoxic. In chronic neurodegenerative diseases, sustained microglial activation often leads to the amplification of inflammatory cascades, reinforcing a pathogenic cycle of immune-mediated damage. Intercellular communication within the inflamed CNS is central to the persistence and progression of neuroinflammation. Microglia engage in extensive crosstalk with astrocytes, neurons, oligodendrocytes, and infiltrating immune cells, shaping both local and systemic inflammatory responses. These interactions influence key processes such as synaptic pruning, phagocytosis, blood-brain barrier integrity, and cytokine-mediated signaling. Understanding the mechanisms of cell-cell signaling in this context is critical for identifying therapeutic strategies to modulate the immune response and restore homeostasis. This review explores the key players in CNS neuroinflammation, with a focus on the role of microglia, the molecular pathways underlying intercellular communication, and potential therapeutic approaches to mitigate neuroinflammatory damage in chronic neurodegenerative diseases.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1575022"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976120","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":"Physiological roles of embryonic microglia and their perturbation by maternal inflammation.","authors":"Tsukasa Shimamura, Masashi Kitashiba, Kazutaka Nishizawa, Yuki Hattori","doi":"10.3389/fncel.2025.1552241","DOIUrl":"https://doi.org/10.3389/fncel.2025.1552241","url":null,"abstract":"<p><p>The interplay between the nervous and immune systems is well documented in the context of adult physiology and disease. Recent advances in understanding immune cell development have highlighted a significant interaction between neural lineage cells and microglia, the resident brain macrophages, during developmental stages. Throughout development, particularly from the embryonic to postnatal stages, diverse neural lineage cells are sequentially generated, undergo fate determination, migrate dynamically to their appropriate locations while maturing, and establish connections with their surroundings to form neural circuits. Previous studies have demonstrated that microglia contribute to this highly orchestrated process, ensuring the proper organization of brain structure. These findings underscore the need to further investigate how microglia behave and function within a broader framework of neurodevelopment. Importantly, recent epidemiological studies have suggested that maternal immune activation (MIA), triggered by various factors, such as viral or bacterial infections, environmental stressors, or other external influences, can affect neurogenesis and neural circuit formation, increasing the risk of neurodevelopmental disorders (NDDs) in offspring. Notably, many studies have revealed that fetal microglia undergo significant changes in response to MIA. Given their essential roles in neurogenesis and vascular development, inappropriate activation or disruption of microglial function may impair these critical processes, potentially leading to abnormal neurodevelopment. This review highlights recent advances in rodent models and human studies that have shed light on the behaviors and multifaceted roles of microglia during brain development, with a particular focus on the embryonic stage. Furthermore, drawing on insights from rodent MIA models, this review explores how MIA disrupts microglial function and how such disturbances may impair brain development, ultimately contributing to the onset of NDDs.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1552241"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009144","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":"Mitochonic acid 5 mitigates age-related hearing loss progression by targeting defective 2-methylthiolation in mitochondrial transfer RNAs.","authors":"Teppei Kouga, Toru Miwa, Fan-Yan Wei, Kishiko Sunami, Kazuhito Tomizawa","doi":"10.3389/fncel.2025.1541347","DOIUrl":"https://doi.org/10.3389/fncel.2025.1541347","url":null,"abstract":"<p><strong>Introduction: </strong>Age-related hearing loss (ARHL) is linked to dementia, with mitochondrial dysfunction playing a key role in its progression. Deficient mitochondrial tRNA modifications impair protein synthesis and energy metabolism, accelerating ARHL. Mitochonic acid 5 (MA-5) has shown promise as a therapeutic candidate by improving mitochondrial function, reducing oxidative stress, and stabilizing membrane potential.</p><p><strong>Methods: </strong>In this study, we investigated the effects of MA-5 on ARHL in cyclin-dependent kinase 5 regulatory subunit-associated protein 1 (<i>Cdk5rap1</i>) knockout (KO) mice, which exhibit early-onset ARHL due to abnormalities in mitochondrial transfer RNA (mt-tRNA) modifications.</p><p><strong>Results: </strong>MA-5 treatment effectively attenuated ARHL progression in <i>Cdk5rap1</i>-KO mice by improving auditory brainstem response thresholds and distortion product otoacoustic emissions. It also reduced spiral ganglion and outer hair cell loss, while preserving the cochlear structural integrity by preventing mitochondrial degeneration in spiral ligament fibrocytes. Mechanistically, MA-5 upregulated the expression of silent information regulator sirtuin 1 and promoted the nuclear translocation of yes-associated protein, both of which are involved in regulating mitochondrial function and cellular senescence. Metabolomics analysis further demonstrated that MA-5 restored mitochondrial metabolism, reduced lactate accumulation, and maintained mitochondrial integrity.</p><p><strong>Conclusion: </strong>These findings suggest that MA-5 is a viable treatment option for ARHL and other age-related disorders associated with mitochondrial dysfunction.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1541347"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983732","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}