Frontiers in Molecular Neuroscience最新文献

{"title":"Nutrition as a systems regulator of brain aging trajectories.","authors":"Ludmila Müller, Svetlana Di Benedetto, Viktor Müller","doi":"10.3389/fnmol.2026.1825800","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1825800","url":null,"abstract":"<p><p>Nutrition is increasingly recognized as a central determinant of brain health across the lifespan. Beyond their classical roles as energetic substrates, dietary components and their bioactive metabolites may act as signaling molecules capable of reshaping neuronal and glial phenotypes through integrated metabolic, epigenetic, and immunological mechanisms. Emerging evidence positions nutritional inputs as dynamic regulators of synaptic integrity, cellular bioenergetics, neurotransmission, neuroimmune interactions, and blood-brain barrier function. These effects occur across multiple temporal and spatial scales, from acute modulation of neuronal excitability to long-term reprogramming of gene expression and chromatin landscapes. This mini-review integrates current molecular neuroscience perspectives to propose a systems-level framework in which nutritional signals act across interconnected regulatory layers linking peripheral metabolism with central nervous system homeostasis. We examine nutrient-sensing pathways that preserve proteostasis and synaptic resilience, as well as metabolic and membrane-associated processes that govern neuronal excitability, network stability, and mitochondrial quality control. Furthermore, we discuss how dietary modulation may influence glial activation states, neuroinflammatory cascades, and epigenetic remodeling, and how gut-derived metabolites contribute to these processes. Understanding nutrition as an active signaling network rather than a passive support system may offer novel opportunities for preventive and therapeutic intervention in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as in age-associated cognitive decline. We propose that targeted nutritional modulation represents a tractable strategy to reprogram brain aging trajectories toward enhanced resilience, functional plasticity, and long-term cognitive health.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1825800"},"PeriodicalIF":3.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837012","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":"LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal integrity via phosphorylation within its lipid-sensing ALPS2 motif.","authors":"Md Shariful Islam, Valentin Cóppola-Segovia, Alessandra Musso, Darren J Moore","doi":"10.3389/fnmol.2026.1786336","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1786336","url":null,"abstract":"<p><strong>Introduction: </strong>Mutations in the <i>leucine-rich repeat kinase 2</i> (<i>LRRK2</i>) gene cause late-onset, autosomal dominant Parkinson's disease (PD). <i>LRRK2</i> encodes a multi-domain protein containing a Roc GTPase domain and a serine/threonine-directed protein kinase domain, with PD-linked mutations known to enhance LRRK2 kinase activity and neuronal toxicity. Our previous studies identified the Golgi protein, ADP-Ribosylation Factor GTPase-Activating Protein 1 (ArfGAP1), as a novel modifier of LRRK2-induced cellular toxicity, where it can serve as a GAP-like protein and a robust kinase substrate of LRRK2.</p><p><strong>Methods: </strong>Here, we further explore the phosphorylation of ArfGAP1 by LRRK2 and its functional consequences.</p><p><strong>Results: </strong>LRRK2 mediates the robust phosphorylation of ArfGAP1 <i>in vitro</i> within its lipid-sensing ALPS2 motif at residues Ser284, Thr291, and Thr292. We mutated these three candidate phosphorylation sites, either alone or combined, to create hydrophobic phospho-null or charged phospho-mimicking versions of ArfGAP1. We find that modulating ArfGAP1 phosphorylation at these sites impairs its normal capacity to induce Golgi fragmentation upon overexpression in neural cells. Blocking phosphorylation impairs ArfGAP1-induced neurite outgrowth inhibition in primary neurons and protects against the pathogenic effects of PD-linked G2019S LRRK2. ArfGAP1 interactome analysis in neural cells identifies 114 putative interacting proteins with a proportion of these localized to mitochondria, including the outer membrane proteins Voltage-Dependent Anion Channel (VDAC) 1-3. An ArfGAP1 triple phospho-mimic mutant displays an increased interaction with mitochondrial VDACs owing to the redistribution of ArfGAP1 from the <i>cis</i>-Golgi to the cytoplasm. Mimicking ArfGAP1 phosphorylation also blocks the formation of Golgi-derived vesicles following mild ER stress.</p><p><strong>Discussion: </strong>Our data provides evidence for a complex functional interaction between LRRK2 and ArfGAP1 that serves to regulate ArfGAP1 subcellular localization, protein interactions, activity and neuronal integrity via LRRK2-mediated phosphorylation of its membrane-binding ALPS2 motif. Our findings support additional validation of ArfGAP1 as a putative therapeutic target for modulating <i>LRRK2</i>-linked PD.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1786336"},"PeriodicalIF":3.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836983","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":"Sphingomyelin synthase 1 as a potential upstream amplifier of microglial CSF1R signaling in neuropathic pain.","authors":"Minghui Tan, Meiping Wu, Meikui Wu","doi":"10.3389/fnmol.2026.1798921","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1798921","url":null,"abstract":"<p><p>Neuropathic pain is a debilitating chronic condition sustained by maladaptive neuroimmune interactions within the central nervous system, with microglial activation in the spinal dorsal horn serving as a critical driver of pain initiation and chronification. Within this framework, microglial activation mediated by colony-stimulating factor 1 receptor (CSF1R) signaling has emerged as a pathway that is both necessary and sufficient for the development and maintenance of neuropathic pain; however, the upstream mechanisms that determine CSF1R membrane availability and signaling intensity in microglia remain poorly defined. Here, we propose the hypothesis that sphingomyelin synthase 1 (SMS1) functions as a metabolic gatekeeper that amplifies microglial CSF1R signaling by regulating diacylglycerol (DAG)/protein kinase D (PKD)-dependent receptor trafficking. Following peripheral nerve injury, SMS1 expression is upregulated in spinal microglia, leading to increased Golgi-associated DAG production and subsequent PKD activation. Activated PKD promotes vesicular transport of CSF1R from the Golgi apparatus to the plasma membrane, thereby increasing CSF1R surface density and prolonging receptor signaling. Enhanced CSF1R membrane availability amplifies CSF1-driven microglial proliferation and neuroinflammatory signaling, ultimately facilitating synaptic dysregulation and persistent pain hypersensitivity. This hypothesis establishes a direct mechanistic link between sphingolipid metabolism and microglial neuroimmune signaling and identifies SMS1 as a previously unrecognized upstream regulator of neuropathic pain. Targeting SMS1 may therefore represent a novel therapeutic strategy that modulates microglial activation while avoiding the systemic immune suppression associated with direct CSF1R blockade. If validated, this lipid-regulated trafficking mechanism may have broader implications for other microglia-dependent disorders of the central nervous system.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1798921"},"PeriodicalIF":3.8,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837062","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":"Integrated multi-omics profiling reveals novel molecular biomarkers and pathways associated with Fragile X-associated tremor/ataxia syndrome.","authors":"Marwa Zafarullah, Matthew Ponzini, Kyoungmi Kim, Paul J Hagerman, Randi J Hagerman, Flora Tassone","doi":"10.3389/fnmol.2026.1752903","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1752903","url":null,"abstract":"<p><strong>Introduction: </strong>Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation expansions (55-200 CGG repeats) in the fragile X messenger ribonucleoprotein 1 (<i>FMR1</i>) gene. Despite its clinical significance, FXTAS currently lacks reliable molecular markers for disease monitoring and evaluation of therapeutic efficacy.</p><p><strong>Methods: </strong>To address this critical gap, we performed an integrated multi-omics study combining plasma metabolomics (lipidomics, amine, and primary metabolites) with proteomics analyses in plasma and peripheral blood mononuclear cells (PBMCs) from FXTAS participants (<i>n</i> = 5, FXTAS stages 3-5) and age-matched non-carrier healthy controls (HC, <i>n</i> = 15).</p><p><strong>Results: </strong>Integrated analyses revealed molecular differences distinguishing FXTAS from HC, including alterations in metabolites related to energy metabolism (e.g., UDP-glucuronic acid, succinic acid, mannose), lipids (e.g., cholesterol, triglycerides, glycerophospholipids, ceramide), and selected amines (e.g., cystine, glycerophosphocholine, histidine). Proteomic analyses identified proteins associated with FXTAS clinical stage and CGG repeat size, implicating pathways related to mitochondrial function, immune-inflammatory signaling, and lipid metabolism. Comparative analysis of plasma and PBMC proteomes identified Basigin (CD147) and phospholipid transfer protein C2CD2 as overlapping candidate markers across biological matrices.</p><p><strong>Discussion: </strong>Although limited by sample size and the cross-sectional design, this exploratory study demonstrates the value of integrated, cross-matrix multi-omics profiling for identifying molecular patterns associated with advanced FXTAS. These findings reinforce prior mechanistic models and provide a foundation for future validation in larger, longitudinal cohorts.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1752903"},"PeriodicalIF":3.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13132834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813825","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":"Priming neuronal regeneration: early adaptive mechanisms in zebrafish CNS injury.","authors":"Ignacio Babiloni Chust, Lucia Poggi, Michela Alessandra Denti, Andrea Pedroni","doi":"10.3389/fnmol.2026.1807396","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1807396","url":null,"abstract":"<p><p>The zebrafish (<i>Danio rerio</i>) exhibits a remarkable capacity to regenerate the central nervous system following injury, restoring both tissue architecture and neural function. This review focuses on the earliest phases of the injury response, when conserved damage signals are first sensed, integrated, and translated into trajectories that bias tissue outcomes toward regeneration or persistent degeneration. We examine how early molecular cues, including damage-associated molecular patterns, inflammatory signals, calcium, and redox dynamics are differentially interpreted in zebrafish compared to mammals, leading to distinct cellular and tissue-level responses. Within this early signaling landscape, emerging evidence indicates that neuronal activity and neurotransmitter plasticity constitute a neuron-specific regulatory layer fundamental to the regulation of early injury responses and the initiation of regenerative programs. Rather than cataloging downstream regenerative mechanisms, we emphasize the importance of early temporal coordination of these injury-derived signals, which establishes permissive or non-permissive regulatory states. Overall, this review positions the zebrafish as a powerful vertebrate model for identifying general principles of early signal integration and temporal control that govern regenerative competence, providing a conceptual framework that may inform strategies to enhance repair in the injured mammalian CNS.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1807396"},"PeriodicalIF":3.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813987","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":"CaMPARI2 enables stimulus-locked whole-brain activity mapping at cellular resolution in unrestrained larval zebrafish.","authors":"Kate R Robbins, Amelia Bredbenner, Rebecca A Osbaldeston, Kevin S Villafañe, Eva E Shin, Elizaveta Merkulova, Ava Clevenger, Payton B Delean, Cristina Campos, Graham C Peet, Roshan A Jain","doi":"10.3389/fnmol.2026.1772915","DOIUrl":"10.3389/fnmol.2026.1772915","url":null,"abstract":"<p><p>Visualizing active neurons and circuits <i>in vivo</i> is critical for investigating the neural activity that underlies behavior. While several established methodologies are available to achieve this end in larval zebrafish, they are limited by the scale of tissue visualization, temporal resolution, need to restrain larvae, and/or accessibility of necessary instruments. Here, we establish a pipeline for the visualization and quantification of spatiotemporally precise whole-brain neural activity in larval zebrafish using CaMPARI2, a genetically-encoded calcium indicator. Using temporally specific photoconverting UV light exposures, we capture whole-brain \"snapshots\" of neural activity time-locked to stimuli during unrestrained larval behavior. We optimize experimental conditions for recording sub-second neuronal activity changes across acoustically-evoked behavioral paradigms spanning minutes to hours. We then leverage this system to pinpoint brain-wide neural activity changes during non-associative habituation learning, observing distinct activity signatures in the subpallium, preoptic area, and habenulae that are altered through pharmacological disruption of habituation learning. This approach effectively complements the temporal precision achievable through <i>post-hoc</i> activity detection methods and expands the accessibility of large-scale behavioral circuit dissection beyond highly specialized real-time volumetric imaging equipment.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1772915"},"PeriodicalIF":3.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13121368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769505","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 metabolic substrate to epigenetic regulation: roles and mechanisms of lactylation in brain health and disease.","authors":"Wei Chen, Ruobing Li, Jinlong Zhang, Jun Lei, Xicheng Jiang, Xiaowei Sun","doi":"10.3389/fnmol.2026.1779468","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1779468","url":null,"abstract":"<p><p>Lactate, traditionally regarded as a metabolic byproduct of glycolysis, is now recognized as a critical signaling molecule in the central nervous system. Emerging evidence indicates that lactate participates in a dynamic metabolic-epigenetic regulatory network through protein lactylation, a post-translational modification capable of modulating chromatin structure and gene transcription. We summarize the physiological roles of lactate in neuronal-glial metabolic coupling and highlight cell-type-specific functions of the lactate-lactylation axis under both normal and pathological conditions. Particular emphasis is placed on its involvement in ischemic stroke, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Available findings indicate that this axis is integral to synaptic plasticity, neuroinflammatory balance, and metabolic homeostasis. Under pathological conditions, excessive lactate accumulation promotes aberrant lactylation patterns that may drive persistent inflammation, metabolic reprogramming, and neuronal dysfunction by reshaping chromatin accessibility and transcriptional landscapes. Collectively, the lactate-lactylation axis represents a unifying mechanistic framework linking metabolic flux to epigenetic regulation in neurological disorders and may serve as a promising source of diagnostic biomarkers and precision therapeutic targets.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1779468"},"PeriodicalIF":3.8,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769538","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":"Exploring the molecular mechanism of dexmedetomidine in alleviating blood-brain barrier disruption in rats with cerebral ischemia reperfusion injury based on network pharmacology.","authors":"Xue Lv, Wei Gao, Zhi-Guo Zhang, Jian-Xin Jia","doi":"10.3389/fnmol.2026.1750882","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1750882","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to clarify the neuroprotective effect of dexmedetomidine (DEX) against cerebral ischemia reperfusion injury (CIRI) and its underlying mechanism using network pharmacology and <i>in vivo</i> validation.</p><p><strong>Methods: </strong>Network pharmacology was employed to explore the mechanism underlying DEX-mediated alleviation of CIRI. A rat CIRI model was established using the suture-occlusion method. Neurological scoring and behavioral assessments were conducted to evaluate neurological and motor functions; histological examination was performed to observe brain tissue and blood-brain barrier (BBB) injury. Western blotting and immunofluorescence analysis were utilized to assess the protein levels of factors associated with BBB integrity.</p><p><strong>Results: </strong>Network pharmacology analysis revealed that DEX may exert a protective effect against CIRI through the AMPK/mTOR signaling pathway. DEX treatment significantly attenuated CIRI-induced impairments in neurological function and motor performance. Specifically, DEX upregulated the protein expression levels of P-AMPK/AMPK ratio, beclin 1, LC3 II/I, and ZO-1, whereas the P-mTOR/mTOR ratio and P62 were significantly downregulated, and cerebral tissue injury was alleviated.</p><p><strong>Conclusion: </strong>DEX exerts a significant protective effect against BBB injury in rats with CIRI. This neuroprotective effect is mediated by multiple synergistic mechanisms, including the upregulation of tight junction proteins and the regulation of the AMPK/mTOR signaling pathway. Collectively, the findings of the present study suggest that DEX represents a promising potential agent for the clinical treatment of CIRI-associated BBB impairment.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1750882"},"PeriodicalIF":3.8,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769472","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":"Abnormal lymphatic system function in patients with chronic neck and shoulder pain: neuroimaging evidence from DTI-ALPS.","authors":"Jiayu Yang, Tianci Liu, Ruhui Xiao, Yu Fu, Xiaowei Kong, Zhiqiang Qiu, Xiaoxue Xu","doi":"10.3389/fnmol.2026.1707858","DOIUrl":"10.3389/fnmol.2026.1707858","url":null,"abstract":"<p><strong>Objective: </strong>Chronic neck and shoulder pain (CNSP) is frequently associated with structural and functional brain damage that progressively worsens over time. The glymphatic system (GS), a gel-like extracellular fluid in the brain, plays a crucial role in clearing waste products and maintaining interstitial fluid homeostasis. However, its relationship with CNSP remains unclear. This study employed diffusion tensor imaging along perivascular spaces (DTI-ALPS) to investigate functional changes in the lymphatic system among patients with chronic neck and shoulder pain, while exploring potential correlations with clinical outcomes.</p><p><strong>Methods: </strong>This study enrolled 20 patients with CNSP and 20 healthy controls (HCs). All participants underwent standardized scans using a 3.0T MRI scanner. By calculating the bilateral DTI-ALPS indices of the two groups, we compared the functional status of GS between the groups and further established its correlation with clinical indicators.</p><p><strong>Results: </strong>Following a permutation test (10,000), the DTI-ALPS index in the left cerebral hemisphere of the CNSP group was significantly lower than that in the HCs group (<i>P</i> = 0.0413). Within the CNSP group itself, the left hemisphere showed a more pronounced reduction compared to the right side (<i>P</i> = 0.0012). Partial correlation analysis revealed that after excluding disease duration as a variable, VAS scores demonstrated a significant correlation with left hemisphere DTI-ALPS index (<i>r</i> = -0.651, <i>P</i> = 0.003). When VAS was excluded from the analysis, disease duration showed a statistically significant association with left hemisphere DTI-ALPS index (<i>r</i> = -0.727, <i>P</i> < 0.001).</p><p><strong>Conclusion: </strong>Our findings indicate that CNSP may lead to abnormal GS function in the left hemisphere as the disease duration prolongs and pain intensity increases.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1707858"},"PeriodicalIF":3.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13083129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722534","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":"Exploring the mechanism of Yin Huo decoction in PCPA-induced depression mice: a metabolomics and network pharmacology approach.","authors":"Yu Zhou, Lu Jia Liu, Yue Zhang, Wen Wen Wang, Dan Hong Xu","doi":"10.3389/fnmol.2025.1725806","DOIUrl":"10.3389/fnmol.2025.1725806","url":null,"abstract":"<p><strong>Introduction: </strong>Depression is a prevalent neuropsychiatric disorder, and traditional Chinese medicine formulations such as Yin Huo Decoction (YHD) have shown potential antidepressant effects, yet their underlying mechanisms remain incompletely elucidated. This study aimed to investigate the therapeutic effects and molecular mechanisms of YHD in a PCPA-induced depression model in mice.</p><p><strong>Methods: </strong>PCPA-induced depressive-like mice were treated with YHD, and changes in body weight, sucrose preference, and behavioral performance in the forced swim and tail suspension tests were assessed. Hippocampal neuron structure and Nissl body integrity were examined, and brain serotonin (5-HT) levels were quantified. Liquid Chromatograph Mass Spectrometer (LC-MS)-based metabolomic profiling was performed on serum, urine, and brain tissue to identify metabolic disturbances, while network pharmacology analysis was used to explore the intersection of YHD targets and depression-related pathways. Pathway enrichment analysis was conducted to clarify key regulatory pathways.</p><p><strong>Results: </strong>YHD treatment significantly improved body weight, sucrose preference, and depressive-like behaviors in PCPA-induced mice, and preserved hippocampal neuron structure and Nissl body integrity-effects comparable to fluoxetine. YHD also restored reduced brain 5-HT levels in PCPA model mice. Metabolomic analysis revealed distinct metabolic perturbations in the PCPA model (e.g., in tryptophan and riboflavin metabolism), which were largely reversed by YHD. Network pharmacology identified 156 intersecting targets between YHD and depression-related pathways, primarily involved in neuroactive ligand-receptor interactions, dopaminergic synapses, and inflammatory processes (e.g., TNF signaling and cytokine production). Key targets including AKT1, TNF, IL-6, and EGFR were identified as central to YHD's action.</p><p><strong>Discussion: </strong>YHD alleviates PCPA-induced depression-like behaviors in mice by modulating 5-HT levels, correcting metabolic imbalances in tryptophan and riboflavin pathways, and regulating neuroinflammation, neurotransmitter systems, and cellular signaling via targets such as AKT1 and TNF. These findings provide a comprehensive mechanistic understanding of YHD's antidepressant effects, supporting its potential as a therapeutic agent for depression.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1725806"},"PeriodicalIF":3.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13083098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722508","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}