{"title":"PUS7-dependent Ψ reshapes specific synaptic gene exons to facilitate fear extinction memory formation.","authors":"Runming Liu, Yuhan Dong, Zhipeng Gao, Jichun Shi, Ziyue Xu, Junhui Liu, Gaomeng Luo, Shengda Ye, Feiyang Zhang, Hongyu Xu, Xiang Li, Sha Liu, Wei Wei","doi":"10.1186/s13041-025-01250-6","DOIUrl":"10.1186/s13041-025-01250-6","url":null,"abstract":"<p><p>RNA modifications serve as dynamic regulators of neural plasticity through their ability to fine-tune transcript stability and splicing. Pseudouridine (Ψ), an evolutionarily conserved RNA modification catalyzed by pseudouridine synthases, plays established roles in neurodevelopment, yet its functional significance in activity-dependent behavioral adaptation remains poorly defined. Here, we investigate Ψ-mediated epitranscriptomic regulation within the infralimbic prefrontal cortex (ILPFC), a brain region requiring precise synaptic remodeling for the clinically relevant form of fear extinction memory. Combining transcriptome-wide pseudouridylation profiling with behavioral analysis in mice, we identified selective Ψ enrichment at exons of synaptic regulatory genes within ILPFC during fear extinction learning. Fear extinction in the ILPFC drives concomitant exonic Ψ deposition and upregulation of synaptogenic transcripts, processes that involve pseudouridine synthase PUS7. Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction memory formation without altering baseline fear expression, establishing a causal link between Ψ-dependent RNA processing and activity-dependent synaptic structural remodeling in this microcircuit. Our findings demonstrate that PUS7-mediated Ψ modification spatiotemporally regulates activity-dependent RNA dynamics in the ILPFC, providing the evidence that epitranscriptomic mechanisms precisely coordinate synaptic gene expression within behaviorally defined brain sub-region. This work bridges molecular RNA biology with systems neuroscience, revealing a novel mechanism for activity-dependent regulation of fear extinction in ILPFC.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"80"},"PeriodicalIF":2.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301975","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}
Molecular BrainPub Date : 2025-10-14DOI: 10.1186/s13041-025-01239-1
Lei Shi, Yizhen Pan, Jie Yuan, Jue Zhang, Zhiqi Lee, Xuan Li, Haonan Zhang, Xiang Zhang, Tingting Wu, Jierui Ding, Tao Liu, Nengrui Guo, Zhuonan Wang, Lijun Bai
{"title":"BDNF genotype associated with changes in cortical thickness, severity of symptoms, and cognitive impairments in mild traumatic brain injury.","authors":"Lei Shi, Yizhen Pan, Jie Yuan, Jue Zhang, Zhiqi Lee, Xuan Li, Haonan Zhang, Xiang Zhang, Tingting Wu, Jierui Ding, Tao Liu, Nengrui Guo, Zhuonan Wang, Lijun Bai","doi":"10.1186/s13041-025-01239-1","DOIUrl":"10.1186/s13041-025-01239-1","url":null,"abstract":"<p><strong>Objective: </strong>Brain-derived neurotrophic factor (BDNF) is a critical blood protein for brain function; however, its genotypic influence on clinical outcomes and brain structure following mild traumatic brain injury (mTBI) remains unclear. This study investigated the relationship between BDNF polymorphisms and cognitive impairment, symptom severity, and cortical structural injury in mTBI patients.</p><p><strong>Materials and methods: </strong>Sixty-one mTBI patients underwent neuropsychological assessments and MRI scans within one week post-injury, with 46 patients followed up at one month. Fifty-two healthy controls were included for comparison. Patients with mTBI exhibited clinical symptoms, cognitive impairment, and alterations in cortical thickness during in the acute phase.</p><p><strong>Results: </strong>BDNF Met gene carriers (n = 41) and Val gene carriers (n = 20) demonstrated different cognitive performance in the acute phase and exhibited distinct recovery trajectories. Val carriers showed significantly better cognitive flexibility compared to Met carriers (p = 0.028) during the acute phase and greater improvement in clinical symptoms at one month (p = 0.035). Follow-up MRI scans revealed more extensive and statistically significant alterations in cortical thickness in Met carriers than in Val carriers (p < 0.01), particularly in regions associated with cognitive and emotional regulation.</p><p><strong>Conclusion: </strong>These findings suggest that BDNF polymorphisms in mTBI patients are associated with brain structural changes and may serve as valuable biomarkers for identifying individuals at risk for long-term clinical symptoms and cognitive impairment.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"79"},"PeriodicalIF":2.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292998","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}
Molecular BrainPub Date : 2025-10-09DOI: 10.1186/s13041-025-01238-2
Abdul Aziz Khan, Shuai Wang, Ziying Wang, Zainab Rehman, Lei Chen, Yifang Kuang, Xu Zhang, Yuting Li, Jiarun Yang, Jun Ye, Xianda Ma, Qian Zhao, Ying Ding, Tatsuo Suzuki, Zhaohui Lan, Weidong Li
{"title":"Exploration of schizophrenia-related behavioral and molecular abnormalities in a mutant mouse model with a mutation in the TVV motif of the ErbB4 gene.","authors":"Abdul Aziz Khan, Shuai Wang, Ziying Wang, Zainab Rehman, Lei Chen, Yifang Kuang, Xu Zhang, Yuting Li, Jiarun Yang, Jun Ye, Xianda Ma, Qian Zhao, Ying Ding, Tatsuo Suzuki, Zhaohui Lan, Weidong Li","doi":"10.1186/s13041-025-01238-2","DOIUrl":"10.1186/s13041-025-01238-2","url":null,"abstract":"<p><p>The ErbB4 gene is a schizophrenia (SCZ) risk gene that interacts with PSD-95 via its C-terminus, a connection disrupted in SCZ patients. To investigate the functional significance of this interaction, we generated a zygotic mutant mouse lacking the terminal valine \"V\" residue from the ErbB4 TVV motif. The homozygous (homo) mice exhibited disrupted ErbB4‒PSD-95 interactions and SCZ-relevant behavioral deficits, including impairments in motor function, sensory processing, and memory performance. Structural computational analysis further revealed that the mutation altered the structural conformation of the ErbB4 C-terminus, which affected its binding affinity for PSD-95. Mechanistically, the mutation led to up-regulated but less activation of ErbB4 and down-regulated but overactivation of PSD-95, possibly representing a failed compensatory response aiming to maintain the ErbB4-PSD-95 interaction. Additionally, homo mice presented NMDAR2A subunit specific hypofunction and reduced GAD67 expression. These findings highlight that the ErbB4-PSD-95 interaction is a critical molecular link in the synaptic dysfunction and behavioral abnormalities associated with SCZ.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"78"},"PeriodicalIF":2.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12513098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258572","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":"Acupuncture improves depressive-like behaviors in CUMS rats by modulating lateral habenula synaptic plasticity via the BDNF/ERK/mTOR pathway.","authors":"Simin Yan, Jia Liu, Tiansheng Zhang, Jianguo Li, Jingyu Zeng, Meng Li, Muhammad Shahzad Aslam, Junliang Shen, Tao Tong, Zhuoran You, Siyu Liu, Peng Li, Jingxuan Li, Kaiyue Gong, Simiao Wei, Chongyao Hao, Xianjun Meng","doi":"10.1186/s13041-025-01247-1","DOIUrl":"10.1186/s13041-025-01247-1","url":null,"abstract":"<p><p>Acupuncture has been found to alleviate depressive behaviors caused by chronic unpredictable mild stress (CUMS) in rats. This study explores how acupuncture improves depressive behaviors by modulating synaptic plasticity in the lateral habenula through stimulation of Fengfu and Shangxing acupoints. Male Sprague-Dawley rats were divided into six groups, with the control group excluded. Undergoing a 28-day CUMS protocol, the intervention groups included sham needle stimulation, daily stimulation at the Fengfu (GV16) and Shangxing (GV23) acupoints on alternate days, fluoxetine (2.1 mg/kg, 0.21 mg/mL), or electroacupuncture treatment. All rats were weighed and subjected to behavioral tests. Western blotting was used to examine the expression of the BDNF/ERK/mTOR signaling pathway and associated proteins in the lateral habenula. The monoamine neurotransmitters in serum were measured using ELISA kits. Immunofluorescence staining was used to determine the expression levels of BDNF, TrkB, SYP, and PSD95 in the lateral habenula. Golgi staining was employed to quantify dendritic spine morphology. The study showed that CUMS led to depressive-like behaviors and downregulated the BDNF/ERK/mTOR signaling pathway in the lateral habenula. It also resulted in reduced expression of monoamine neurotransmitters in peripheral blood and changes in dendritic spine length and density. Importantly, both fluoxetine and acupuncture had varying degrees of preventive and restorative effects on these changes. The findings of this study suggest that acupuncture has the potential to activate the BDNF/ERK/mTOR signaling pathway in the lateral habenula of CUMS rats, thereby enhancing synaptic plasticity and exerting an antidepressant effect.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"77"},"PeriodicalIF":2.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251982","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}
Molecular BrainPub Date : 2025-10-01DOI: 10.1186/s13041-025-01248-0
Yuqian Liu, Ruiyun Guo, Ni Wang, Yue Yang, Jialu Li, Danyang Jing, Ruoyan Cui, Runchao Ma, Jun Ma
{"title":"Integrated molecular data analysis confirms PDK1 as a candidate risk factor in ALS pathophysiology.","authors":"Yuqian Liu, Ruiyun Guo, Ni Wang, Yue Yang, Jialu Li, Danyang Jing, Ruoyan Cui, Runchao Ma, Jun Ma","doi":"10.1186/s13041-025-01248-0","DOIUrl":"10.1186/s13041-025-01248-0","url":null,"abstract":"<p><p>Combining cellular, animal, and MR analyses from three independent cohorts, we identified PDK1 as a consistent risk factor for ALS development, highlighting its potential as a therapeutic target. To further elucidate PDK1's pathogenic mechanisms, we conducted transcriptomic profiling. Samples were stratified into PDK1 high- and low-expression groups. GO and KEGG analyses demonstrated that upregulated DEGs were enriched in pathways involving β-CATENIN, cell adhesion and Ribosome, suggesting a potential role for WNT/β-catenin signaling activation in ALS pathogenesis. To further validate the consistent risk association of PDK1 with ALS across multiple datasets, we utilized 4-month-old SOD1G93A transgenic mice, 4-month-old C9orf72 transgenic mice, and SOD1-overexpressing HEK293T cells. Significant upregulation of PDK1 mRNA was observed in all models, and a significant increase in protein abundance was found in SOD1G93A. This provides strong experimental evidence for the results of the MR study. These results indicate that PDK1 may affect the pathogenesis of amyotrophic lateral sclerosis through genetic variations and transcriptional dysregulation, and may play an important role in the occurrence and development of the disease.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"76"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206834","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-astrocyte crosstalk following ischemic stroke.","authors":"Shangsong Yang, Yuxiong Chen, Jialin Tang, Yicheng Cui, Wei Wei, Zhongnan Hao, Zhipeng Xiao, Yongli Pan, Qinyuan Tian, Wenqiang Xin, Meihua Li","doi":"10.1186/s13041-025-01244-4","DOIUrl":"10.1186/s13041-025-01244-4","url":null,"abstract":"<p><p>Ischemic stroke, the most prevalent form of stroke, severely impacts human health due to its high incidence, disability, and mortality rates. The complex pathological response to ischemic stroke involves the interplay of various cells and tissues. Among these, astrocytes and microglia, as essential components of nervous system, play significant roles in the pathological processes of ischemic stroke. In addition to their individual functions, an increasing number of studies have revealed that the interaction between astrocytes and microglia is crucial following ischemic stroke. It integrates current research reports to examine and clarify the effects of interaction between the microglia and astrocytes on the nervous system after ischemic stroke, aiming to provide new insights and approaches for future academic research and disease treatment.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"75"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206905","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}
Molecular BrainPub Date : 2025-09-30DOI: 10.1186/s13041-025-01245-3
Xiaojing Su, Liangbiao Wang, Xiaoqing Liu, Yan Zhang
{"title":"Identification of VGLUT3-expressing LTMRs-recruited spinal circuits for itch inhibition.","authors":"Xiaojing Su, Liangbiao Wang, Xiaoqing Liu, Yan Zhang","doi":"10.1186/s13041-025-01245-3","DOIUrl":"10.1186/s13041-025-01245-3","url":null,"abstract":"<p><p>Itch is a common symptom among patients suffering dermatological and systemic diseases, yet effective clinical treatments are currently lacking. Previous research has suggested that vesicular glutamate transporter 3 (VGLUT3)-lineage sensory neurons may play a role in inhibiting itch, but the circuit mechanisms within the spinal cord remain unclear. In this study, we employed optogenetic techniques to activate VGLUT3-lineage sensory afferents in mice and observed a significant reduction in scratching behaviors elicited by both pruritogens and mechanical stimuli. Moreover, aversive component of chemical itch assessed by conditioned place aversion (CPA) was abrogated. Viral tracing combined with electrophysiological recordings revealed synaptic connections between VGLUT3<sup>+</sup> sensory neurons and spinal dynorphin (SC<sup>DYN</sup>) /neuropeptide Y-expressing (SC<sup>NPY</sup>) neurons. Further pharmacological studies indicated that intrathecal injection of antagonists of neuropeptide Y1 receptor and kappa opioid receptor (KOR) separately diminished VGLUT3<sup>+</sup> neurons-mediated inhibitory effects on mechanical and chemical itch, respectively. In summary, our findings suggest that VGLUT3<sup>+</sup> sensory neurons participate in itch regulation through interactions with two classes of inhibitory neurons in the spinal cord, shedding light on potential therapeutic targets for distinct forms of itch management.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"74"},"PeriodicalIF":2.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200252","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}
Molecular BrainPub Date : 2025-09-26DOI: 10.1186/s13041-025-01246-2
Hyunjin Shin, Seunghwan Choi, Geehoon Chung, Sun Kwang Kim
{"title":"Analgesic effects of transcutaneous auricular vagus nerve stimulation on partial sciatic nerve ligation-induced neuropathic pain in mice via serotonergic pathways.","authors":"Hyunjin Shin, Seunghwan Choi, Geehoon Chung, Sun Kwang Kim","doi":"10.1186/s13041-025-01246-2","DOIUrl":"10.1186/s13041-025-01246-2","url":null,"abstract":"<p><p>Current treatments for neuropathic pain often provide limited relief and are associated with significant side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) shows promise as a non-pharmacological analgesic approach; however, its optimal therapeutic configuration and underlying brain mechanisms remain incompletely understood. This study investigated the analgesic effects of taVNS on neuropathic pain in a mouse model induced by partial sciatic nerve ligation (PSL), exploring mechanisms and optimizing configurations. PSL-induced neuropathic pain in mice, characterized by mechanical allodynia, was significantly alleviated by taVNS. The most robust analgesic effects were observed with multiple bilateral taVNS sessions, administered once daily for three consecutive days, with effects persisting for at least 48 h post-stimulation. Immunohistochemical analysis of c-Fos expression revealed that taVNS increased neural activity in the dorsal raphe nucleus (DRN), a key source of serotonin, while simultaneously reducing activity in the central amygdala (CeA), a region critical for pain processing and affective responses. Further experiments demonstrated that the analgesic effects of taVNS were abolished by systemic administration of p-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings underscore the critical role of serotonin signaling in mediating taVNS-induced analgesia for neuropathic pain. The study also highlights the importance of stimulation parameters, identifying a multiple bilateral configuration as particularly effective. Our results suggest that taVNS, potentially acting via the DRN-serotonergic system to modulate limbic structures like the CeA, holds significant potential as a non-pharmacological therapeutic option for managing neuropathic pain.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"73"},"PeriodicalIF":2.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176883","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":"Voluntary running improves synaptic degeneration of the anterior cingulate cortex in knee osteoarthritis.","authors":"Ryo Miyake, Manabu Yamanaka, Wataru Taniguchi, Naoko Nishio, Yuki Matsuyama, Takeru Ueno, Yuta Kaimochi, Terumasa Nakatsuka, Hiroshi Yamada","doi":"10.1186/s13041-025-01207-9","DOIUrl":"https://doi.org/10.1186/s13041-025-01207-9","url":null,"abstract":"<p><p>Osteoarthritis of the knee (knee OA) causes chronic pain involving peripheral tissues, the spinal cord, and the brain. Neuropathic pain leads to changes in synaptic plasticity in the anterior cingulate cortex (ACC). However, whether such changes occur in knee OA mice and their association with exercise therapy remains unclear. Therefore, this study investigated these aspects using electrophysiological and behavioral approaches. We found no induction of pre- or post-long-term potentiation (LTP) in the ACC of knee OA mice. Application of ZD7288 and zeta inhibitory peptide (ZIP) reduced the amplitude of evoked excitatory postsynaptic currents, indicating pre-existing changes in synaptic plasticity in the ACC. Microinjection of ZD7288 and ZIP improved pain-escape and anxiety-like behaviors. Voluntary running exercise induced pre- and post-LTP and improved these behaviors in knee OA mice. Exercise therapy for knee OA may alter synaptic plasticity in the ACC, contributing to behavioral improvements.</p>","PeriodicalId":18851,"journal":{"name":"Molecular Brain","volume":"18 1","pages":"72"},"PeriodicalIF":2.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961937","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}