Frontiers in Molecular Neuroscience最新文献

{"title":"Editorial: Mechanisms of auditory development, maintenance, damage, and protection.","authors":"Ruosha Lai, Lihua Li, Su-Hua Sha","doi":"10.3389/fnmol.2025.1580793","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1580793","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1580793"},"PeriodicalIF":3.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709545","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":"Editorial: Editors' showcase: neuroplasticity and development.","authors":"Giovanni Cirillo, Michele Papa","doi":"10.3389/fnmol.2025.1558715","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1558715","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1558715"},"PeriodicalIF":3.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11922866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669631","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":"Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament.","authors":"Elaine K Hebda-Bauer, Megan H Hagenauer, Daniel B Munro, Peter Blandino, Fan Meng, Keiko Arakawa, John D H Stead, Apurva S Chitre, A Bilge Ozel, Pejman Mohammadi, Stanley J Watson, Shelly B Flagel, Jun Li, Abraham A Palmer, Huda Akil","doi":"10.3389/fnmol.2025.1469467","DOIUrl":"10.3389/fnmol.2025.1469467","url":null,"abstract":"<p><p>Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F₀-F₁-F₂) to produce a heterogeneous F₂ sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F₀s (<i>n</i> = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F₂s (<i>n</i> = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F₂ behavior. In F₀ and F₂ samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F₂ RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation (<i>cis</i>-expression quantitative trait loci or <i>cis</i>-eQTLs). These <i>cis</i>-eQTLs successfully predict bHR/bLR differential gene expression based on F₀ genotype. Sixteen of these genes are associated with <i>cis</i>-eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1469467"},"PeriodicalIF":3.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656794","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":"Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.","authors":"Melissa J Alldred, Kyrillos W Ibrahim, Harshitha Pidikiti, Sang Han Lee, Adriana Heguy, Gabriela Chiosis, Elliott J Mufson, Grace E Stutzmann, Stephen D Ginsberg","doi":"10.3389/fnmol.2025.1546375","DOIUrl":"10.3389/fnmol.2025.1546375","url":null,"abstract":"<p><strong>Introduction: </strong>Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry.</p><p><strong>Methods: </strong>We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity.</p><p><strong>Results: </strong>The hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD.</p><p><strong>Conclusions: </strong>These cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1546375"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614569","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":"Erratum: Uncovering novel KCC2 regulatory motifs through a comprehensive transposon-based mutant library.","authors":"","doi":"10.3389/fnmol.2025.1576660","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1576660","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnmol.2024.1505722.].</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1576660"},"PeriodicalIF":3.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604400","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":"Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.","authors":"Menekse Oeztuerk, Diran Herebian, Kale Dipali, Andreas Hentschel, Nina Rademacher, Florian Kraft, Rita Horvath, Felix Distelmaier, Sven G Meuth, Tobias Ruck, Ulrike Schara-Schmidt, Andreas Roos","doi":"10.3389/fnmol.2025.1548255","DOIUrl":"10.3389/fnmol.2025.1548255","url":null,"abstract":"<p><p>Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions. This study employs a multi-omics approach to investigate the biochemical impact of AFG3L2 mutations in immortalized lymphoblastoid cell lines derived from a patient with biallelic variants leading to spastic ataxia (SPAX5). Our proteomic analysis revealed AFG3L2 impairment, with significant dysregulation of proteins critical for mitochondrial function, cytoskeletal integrity, and cellular metabolism. Specifically, disruptions were observed in mitochondrial dynamics and calcium homeostasis, alongside downregulation of key proteins like COX11, a copper chaperone for complex IV assembly, and NFU1, an iron-sulfur cluster protein linked to spastic paraparesis and infection-related worsening. Lipidomic analysis highlighted substantial alterations in lipid composition, with significant decreases in sphingomyelins, phosphatidylethanolamine, and phosphatidylcholine, reflecting disruptions in lipid metabolism and membrane integrity. Metabolomic profiling did not reveal any significant findings. Our comprehensive investigation into loss of functional AFG3L2 elucidates a pathophysiology extending beyond mitochondrial proteostasis, implicating a wide array of cellular processes. The findings reveal substantial cellular disturbances at multiple levels, contributing to neurodegeneration through disrupted mitochondrial respiratory chain, calcium homeostasis, cytoskeletal integrity, and altered lipid homeostasis. This study underscores the complexity of SPAX5 pathophysiology and the importance of multi-omics approaches in developing effective strategies to address the impact of loss of functional AFG3L2. Our data also highlight the value of immortalized lymphoblastoid cells as a tool for pre-clinical testing and research, offering a detailed biochemical fingerprint that enhances our understanding of SPAX5 and identifies potential areas for further investigation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1548255"},"PeriodicalIF":3.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572619","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":"Astrocyte-secreted factors modulate synaptic protein synthesis as revealed by puromycin labeling of isolated synaptosomes.","authors":"Aida de la Cruz-Gambra, Jimena Baleriola","doi":"10.3389/fnmol.2025.1427036","DOIUrl":"10.3389/fnmol.2025.1427036","url":null,"abstract":"<p><p>The synaptic proteome can be shaped by proteins transported from the neuronal soma and/or by mRNAs that are delivered to synapses where proteins are locally synthesized. This last mechanism is known as local translation. Local translation has been extensively studied in neurons in physiological conditions and, more recently, in neurological disorders, in which local transcriptomes and translatomes become dysregulated. It is widely believed that in neurons, the main source of localized transcripts is the neuronal soma and that localized translation is primarily regulated by the neuron itself. However, we wondered whether glial cells, especially astrocytes, could contribute to the modulation of synaptic local protein synthesis. To address this question, we compared levels of proteins produced in synaptic compartments in neuronal and neuron-astrocyte co-cultures using modified Boyden chambers or astrocyte-conditioned medium. We developed a methodology to measure local protein synthesis by puromycin labeling of isolated synaptosomes devoid of somatic input. Our results show that synaptic local translation is enhanced or retained when neurons are cultured in the presence of astrocytes and in response to astrocyte-conditioned medium. Puromycin labeling coupled with proximity ligation identified Rpl26 as one of the proteins whose local synthesis is regulated by astrocyte-secreted factors. Our results thus unravel the contribution of glia to synaptic protein synthesis and point to a previously unexplored extra layer of complexity in the regulation of local translation in neurons.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1427036"},"PeriodicalIF":3.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572394","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":"Impaired cerebrospinal fluid circulation and cerebral lymphatic drainage in a rat model of chronic hydrocephalus.","authors":"Dong Bin Back, Bo-Ryoung Choi, Kyoung Ja Kwon, Dong-Hee Choi, Chan Young Shin, Jongmin Lee, Hahn Young Kim","doi":"10.3389/fnmol.2025.1516265","DOIUrl":"10.3389/fnmol.2025.1516265","url":null,"abstract":"<p><p>The cerebrospinal fluid (CSF) not only protects the brain but also maintains homeostasis by removing metabolic waste produced by brain activity. This study hypothesizes that chronic CSF circulatory dysfunction, such as chronic hydrocephalus or normal pressure hydrocephalus (NPH), may be a critical condition in neurodegenerative diseases associated with metabolic waste accumulation. To investigate the CSF circulation and cerebral lymphatic drainage in a rat model of chronic hydrocephalus induced by kaolin injection, we performed time-dependent evaluations of intraparenchymal injection of tracers as well as intraventricular injection of Evans blue. The study systemically evaluated the dysfunction of CSF circulation and lymphatic drainage in the brain from various perspectives, including the glymphatic system, transependymal CSF flow, subarachnoid CSF flow, meningeal lymphatic drainage, and peripheral lymphatic drainage to deep cervical lymph nodes. The results indicated delayed CSF circulation, including glymphatic system, and cerebral lymphatic drainage in the kaolin-induced chronic hydrocephalus model. Based on these findings, our research indicated that dysfunction of CSF circulation, as observed in conditions such as chronic hydrocephalus or NPH, may act as an initiating or exacerbating factor in neurodegenerative diseases. This can lead to the accumulation of metabolic waste, as seen in Alzheimer's disease. Our research can help identify risk factors and provide insight into the underlying pathophysiology of neurodegenerative diseases, which may lead to the development of novel therapeutic strategies.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1516265"},"PeriodicalIF":3.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566483","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":"Histone monoaminylation is a novel epigenetic mechanism in psychiatric disorders.","authors":"Jacob Peedicayil, Samuel Santhosh","doi":"10.3389/fnmol.2025.1534569","DOIUrl":"10.3389/fnmol.2025.1534569","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1534569"},"PeriodicalIF":3.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556533","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":"Extrinsic and intrinsic control of striatal cholinergic interneuron activity.","authors":"Desh Deepak Ratna, Tanner Chase Francis","doi":"10.3389/fnmol.2025.1528419","DOIUrl":"10.3389/fnmol.2025.1528419","url":null,"abstract":"<p><p>The striatum is an integrated component of the basal ganglia responsible for associative learning and response. Besides the presence of the most abundant <i>γ</i>-aminobutyric acid (GABA-ergic) medium spiny neurons (MSNs), the striatum also contains distributed populations of cholinergic interneurons (ChIs), which bidirectionally communicate with many of these neuronal subtypes. Despite their sparse distribution, ChIs provide the largest source of acetylcholine (ACh) to striatal cells, have a prominent level of arborization and activity, and are potent modulators of striatal output and play prominent roles in plasticity underlying associative learning and reinforcement. Deviations from this tonic activity, including phasic bursts or pauses caused by region-selective excitatory input, neuromodulator, or neuropeptide release can exert strong influences on intrinsic activity and synaptic plasticity via diverse receptor signaling. Recent studies and new tools have allowed improved identification of factors driving or suppressing cholinergic activity, including peptides. This review aims to outline our current understanding of factors that control tonic and phasic ChI activity, specifically focusing on how neuromodulators and neuropeptides interact to facilitate or suppress phasic ChI responses underlying learning and plasticity.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1528419"},"PeriodicalIF":3.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523247","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}