Neuroscience Letters最新文献

{"title":"Prevention of memory impairment and hippocampal injury with blarcamesine in an Alzheimer’s disease model","authors":"Tangui Maurice","doi":"10.1016/j.neulet.2025.138349","DOIUrl":"10.1016/j.neulet.2025.138349","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ peptides and phospho-tau protein, and in anti-Aβ immunotherapy are suggesting that more early intervention will be more effective. Alternative therapeutic strategies to anti-Aß immunotherapy have received comparably less attention, yet one specific approach toward upstream neuroprotection by improvement of intracellular calcium homeostasis, activation of endogenous neuroprotection and restoration of autophagy through sigma-1 receptor activation recently demonstrated positive clinical data with oral blarcamesine in a phase IIb/III trial in 508 patients with early AD. AD-preventive approaches beyond lifestyle interventions become attractive candidates when meeting criteria of: (i) record of effective early intervention in mild disease, (ii) record of human safety, (iii) ease of administration, (iv) scalability to population level, (v) relative cost-effectiveness considering longer-term preventive use at population level. Here, we assessed blarcamesine’s efficacy at preventing memory impairment and brain oxidative injury in the mouse preclinical model induced by intracerebroventricular injection of aggregated Aβ_25-35 peptide, that permitted a clean preventive approach before administration of the pathology-inducing amyloidogenic Aβ fragment. We observed significant preventions of Aβ_25-35-induced memory impairments, for both spatial working and contextual long-term memories, and of Aβ_25-35-induced increase in lipid peroxidation in the mouse hippocampi. These new insights, together with blarcamesine’s clinical record in early AD render blarcamesine an attractive candidate for AD pharmacological prevention.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"865 ","pages":"Article 138349"},"PeriodicalIF":2.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dysregulation of high glucose-induced iPSC-neural stem cells differentiation by caspase-1.","authors":"Hsien-Hui Chung","doi":"10.1016/j.neulet.2025.138347","DOIUrl":"10.1016/j.neulet.2025.138347","url":null,"abstract":"<p><p>Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138347"},"PeriodicalIF":2.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hormonal and histological impacts of valproate in PTZ-kindled male rats: a focus on 5HT1A receptors","authors":"Mahdieh Shojaei ,&nbsp;Samad Nazemi ,&nbsp;Majid Khazaei ,&nbsp;Sajad Sahab Negah ,&nbsp;Bashir Sobhani ,&nbsp;Mohammad Rezaei ,&nbsp;Elham Khakshour ,&nbsp;Mohammad Mohammad-Zadeh","doi":"10.1016/j.neulet.2025.138335","DOIUrl":"10.1016/j.neulet.2025.138335","url":null,"abstract":"<div><h3>Introduction</h3><div>The occurrence of seizures and the use of valproate (VPA) both have sexual and hormonal side effects and ultimately cause infertility in males and females. Also, since VPA increases serotonin levels, it plays a role in the development of hormonal disorders in both sexes. Our aim was to investigate the role of 5-HT1A receptors in the impact of VPA on hormonal and cellular changes in pentylenetetrazol (PTZ)-kindled rats.</div></div><div><h3>Materials and methods</h3><div>Fifty male rats were divided into placebo (saline), PTZ + Saline, PTZ + VPA, PTZ + NAD, and PTZ + VPA + NAD groups. Hormone assays and histological examinations were performed at the end of kindling or after the fifteenth injection.</div></div><div><h3>Findings</h3><div>Changes in sex hormones due to epilepsy and VPA use in males decreased testosterone and increased estradiol. Progesterone increased in the kindled group and decreased in kindled rats receiving VPA. Histological changes due to kindling were observed, as were decreases in the number of spermatogonia, primary spermatocytes, Sertoli and Leydig cells, and seminiferous tubules; the diameter of seminiferous tubules was also smaller than in the saline group.</div></div><div><h3>Conclusion</h3><div>The obtained results showed that the changes effected by the investigated drugs (VPA and NAD) increased when the receptor antagonist was injected with VPA. Therefore, maybe the activation of the 5-HT1A receptors has a protective effect in terms of the control of serotonin levels. When the 5HT1A receptor is inactive, the side effects caused by valproate become more pronounced.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"865 ","pages":"Article 138335"},"PeriodicalIF":2.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling Alzheimer's disease in mice: Gonadectomy combined with bilateral hippocampus dentate gyrus injection of Aβ_1-42 oligomers.","authors":"Yan Li, Qian Gao, Chenyu Zhuang, Yifan Zhou, Zixin Chang, Yingying Zhao, Shenfan Zhu, Yanqing Liu, Bo Zhang","doi":"10.1016/j.neulet.2025.138339","DOIUrl":"10.1016/j.neulet.2025.138339","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD.</p><p><strong>New method: </strong>This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice.</p><p><strong>Results: </strong>As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area.</p><p><strong>Comparison with existing methods: </strong>Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ_1-42 oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD.</p><p><strong>Conclusions: </strong>The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls.</p><p><strong>Significance statement: </strong>In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138339"},"PeriodicalIF":2.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal insulin administration shows limited tau-targeted effects in early-stage APP/PS1 Alzheimer's mice.","authors":"Yan Fang Mao, Liang Chen, Jun Yu Liu, Zhang Yu Guo, Pei Lin Lu, Yan Xing Chen","doi":"10.1016/j.neulet.2025.138337","DOIUrl":"10.1016/j.neulet.2025.138337","url":null,"abstract":"<p><p>Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138337"},"PeriodicalIF":2.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic analysis of TMEM230 variants in Han Chinese patients with Parkinson’s disease","authors":"Xinyue Deng ,&nbsp;Wen Zheng ,&nbsp;Hongbo Xu ,&nbsp;Yan Yang ,&nbsp;Zhi Song ,&nbsp;Qin Xiang ,&nbsp;Huarong Yang ,&nbsp;Hao Deng ,&nbsp;Lamei Yuan","doi":"10.1016/j.neulet.2025.138334","DOIUrl":"10.1016/j.neulet.2025.138334","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and gait disturbance. The transmembrane protein 230 gene (<em>TMEM230</em>) was initially identified as a disease-causing gene in autosomal dominant PD while the role of <em>TMEM230</em> in PD remains controversial. This study investigated the genetic role of <em>TMEM230</em> variants in PD. Whole exome sequencing and Sanger sequencing were performed on a cohort of 518 unrelated PD patients (388 sporadic and 130 familial) and 539 age- and sex-matched controls. Identified <em>TMEM230</em> variants were analyzed based on frequency assessments, bioinformatics prediction tools, and conservation analysis. The three-dimensional structures of the wild-type and mutated proteins were modeled using SWISS-MODEL and Missense3D, with visualization using PyMOL. Statistical analysis was performed to evaluate the association between <em>TMEM230</em> variants and PD. Eight rare heterozygous <em>TMEM230</em> variants were identified in sporadic PD patients and controls, including seven missense variants and a synonymous variant. Bioinformatics prediction analyses suggested that p.Gly16Trp and p.Arg23Gln were likely to have a damaging role, supporting their potential involvement in PD pathogenesis. The prevalence of <em>TMEM230</em> missense variants was significantly higher in PD cases compared to controls (1.93 % vs. 0.37 %, <em>P</em> = 0.017, odds ratio = 5.29, 95 % confidence interval: 1.15–24.24). This study enhances the understanding of the genetic landscape of <em>TMEM230</em> in the Han Chinese PD population and implies that <em>TMEM230</em> may function as an autosomal dominant disease-causing gene of PD with low penetrance, or as a susceptibility gene, though the pathogenicity of <em>TMEM230</em> variants is warranted by further investigation.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"865 ","pages":"Article 138334"},"PeriodicalIF":2.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delayed administration of rapamycin inhibits glial scar formation through upregulating matrilin-3 in an autophagy-dependent manner in ischemic stroke","authors":"Yi Guo ,&nbsp;Aiping Qin ,&nbsp;Li Sun ,&nbsp;Jinzhi He ,&nbsp;Yuping Shan ,&nbsp;Xinyi Wang ,&nbsp;Tongxin Zhang ,&nbsp;Min Li ,&nbsp;Yuqi Ma ,&nbsp;Shigang Qiao ,&nbsp;Huiling Zhang","doi":"10.1016/j.neulet.2025.138333","DOIUrl":"10.1016/j.neulet.2025.138333","url":null,"abstract":"<div><div>Glial scar formation is one of the major pathological mechanisms following ischemic stroke. Rapamycin is a potent specific mTOR inhibitor and an autophagy activator. Although it has neuroprotective effects against acute ischemic stroke, it is unknown whether delayed administration of rapamycin can reduce ischemic stroke-induced pathogenesis such as glial scar formation, independent on its effects of acute administration. We recently reported that matrilin-3, an extracellular matrix component, provides neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation and glial scar formation. Here, in rat models of middle cerebral artery occlusion and reperfusion (I/R), rapamycin was administered for consecutive 7 or 14 days starting at day 1 post-reperfusion; and in an oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced primary astrocyte or human astrocyte injury model, rapamycin was given upon reoxygenation. We found that rapamycin improved I/R-mediated rats’ neurological dysfunction, accompanied by reduced glial scar formation and neuronal loss. To our surprise, rapamycin increased the levels of matrilin-3 in the <em>peri</em>-infarct region of rats and in OGD/Re-treated astrocytes associating with restoring autophagic flux. In contrast, the autophagy inhibitors wortmannin and bafilomycin A1 blocked autophagic flux, decreased the levels of matrilin-3 and enhanced glial scar formation, respectively. Overexpression of matrilin-3 significantly reduced the glial scar formation. Mechanistically, rapamycin could decrease the ADAMTS-4 and ADAMTS-5 levels, two hydrolases responsible for the breakdown of matrilin-3, thus upregulating the matrilin-3 levels. Our results reveal that delayed administration of rapamycin suppresses the glial scar formation by upregulating the astrocytic matrilin-3 related to restoring autophagic flux in ischemic stroke.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"865 ","pages":"Article 138333"},"PeriodicalIF":2.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-423-3p alleviates sevoflurane-induced learning and memory dysfunction and nerve damage via negative regulation of GPX4.","authors":"Liquan Qiu, Licai Zhang, Bin Fan, Xue Luo","doi":"10.1016/j.neulet.2025.138332","DOIUrl":"10.1016/j.neulet.2025.138332","url":null,"abstract":"<p><strong>Background: </strong>Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-3p. However, the association between miR-423-3p and neurological damage remains to be elucidated.</p><p><strong>Aim: </strong>To investigate the effect of miR-423-3p on the rats after sevoflurane anesthesia and related molecular mechanisms.</p><p><strong>Methods: </strong>RT-qPCR was utilized to quantify the levels of miR-423-3p, GPX4 and oxidative stress indicators in rat hippocampus. Cognitive function was assessed through the Morris water maze and novel object recognition tests. ELISA was applied to detect the levels of inflammatory factors.</p><p><strong>Results: </strong>In the Sev group, miR-423-3p expression was significantly elevated, while GPX4 expression was markedly reduced. Down-regulated miR-423-3p negatively regulated GPX4 to shorten escape latency while increasing crossing times of the platform, time spend in the target quadrant, relative occupancy of exploring new objects and time to explore new objects. Furthermore, down-regulated miR-423-3p reduced ROS and MDA levels and increased GSH levels in nerve-injured rats, which could be reversed by inhibited GPX4. miR-423-3p inhibition reduced the levels of NLRP3, Caspase-1, IL-8, and IL-1β, which could be rescued by inhibition of GPX4.</p><p><strong>Conclusion: </strong>Down-regulation of miR-423-3p attenuated cognitive deficits in nerve-injured rats. Moreover, repressed miR-423-3p mitigated oxidative stress and inflammation by negatively regulating GPX4.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138332"},"PeriodicalIF":2.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paeonol facilitates the repair of neuronal damage in the mPFC caused by chronic stress via the Rho GTPases-cofilin1 signaling pathway","authors":"Xiuling Zhu ,&nbsp;Yegui Zhang ,&nbsp;Xili Yan ,&nbsp;Yingdi Zhao ,&nbsp;Liangbin Shi ,&nbsp;Zihang Sun ,&nbsp;Kang Meng ,&nbsp;Yongli Zong ,&nbsp;Qiang Li ,&nbsp;Zhiliang Xu","doi":"10.1016/j.neulet.2025.138329","DOIUrl":"10.1016/j.neulet.2025.138329","url":null,"abstract":"<div><h3>Background</h3><div>The Rho GTPases-cofilin1 signalling axis preserves neuronal morphology and synaptic plasticity by modulating actin homeostasis. However, the potential role of paeonol—a bioactive compound derived from Paeonia suffruticosa—in mitigating CUMS-induced neuronal injury via this pathway remains unelucidated.</div></div><div><h3>Objective</h3><div>This study investigates the neuroprotective mechanisms of paeonol against CUMS-associated neuronal injury in the medial prefrontal cortex (mPFC), focusing on the Rho GTPases-cofilin1 signalling axis.</div></div><div><h3>Methods</h3><div>60 male Sprague-Dawley rats were divided into five groups: Control, CUMS, Fluoxetine-treated (Flu), low-dose paeonol (LDP, 25 mg/kg), and high-dose paeonol (HDP, 80 mg/kg). Depressive-like phenotypes were induced via a 4-week CUMS paradigm, followed by daily gavage of fluoxetine or paeonol. Behavioral assessments quantified depressive-like phenotypes. Histology used HE and Nissl staining; dendritic morphology was assessed via Golgi impregnation. Protein levels of Rac1, Cdc42, RhoA, Cofilin1, and p-Cofilin1 in mPFC were quantified by Western blot.</div></div><div><h3>Results</h3><div>CUMS-exposed rats displayed prolonged immobility duration and delayed feeding initiation; paeonol and fluoxetine attenuated these deficits. Golgi analysis showed CUMS reduced total dendritic length, apical dendrite extension, branching complexity and mature dendritic spines (mushroom/branched), while increasing filopodial protrusions in mPFC pyramidal neurons. Both treatments rescued these alterations. Western blot showed CUMS decreased p-cofilin1 levels and downregulated Rac1 and Cdc42 expression, while increasing cofilin1. Paeonol normalized p-cofilin1 phosphorylation, restored Rac1 and Cdc42 expression and reduced cofilin1 levels.</div></div><div><h3>Conclusion</h3><div>Paeonol alleviates CUMS-induced behavioural impairments, potentially through modulating the Rho GTPases-cofilin1 signaling axis.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"865 ","pages":"Article 138329"},"PeriodicalIF":2.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep-layer neurons compensate for the loss of layer 4 sensory recipient cells in the developing neocortex","authors":"Pei-Shan Hou ,&nbsp;Carina Hanashima","doi":"10.1016/j.neulet.2025.138330","DOIUrl":"10.1016/j.neulet.2025.138330","url":null,"abstract":"<div><div>Layer 4 cortical neurons are key sensory recipients of thalamocortical inputs, facilitating higher-order information processing. Layer 4 cell fate is determined by intrinsic transcriptional programs and extrinsic cues, yet the extent to which layer 4 cell identity is fixed remains unclear. Here, we investigate cortical fate plasticity using a tamoxifen-inducible conditional ablation to selectively eliminate layer 4-destined neurons at their earliest postmitotic stage. We found that, despite the depletion of these cells, the overall layer 4 neuron population remains intact, suggesting a compensatory mechanism. Birthdate labeling and molecular analysis revealed that earlier-born deep-layer neurons, rather than later-born upper-layer neurons, adopt a layer 4 identity in response to this loss. This fate shift is associated with altered Foxg1 downregulation and Nr2f1 upregulation, suggesting a molecular switch governing adaptive neurogenesis. Collectively, these findings provide new insights into the temporal and spatial constraints of cortical fate determination and reveal a compensatory mechanism that preserves cortical circuit formation despite early neuronal loss.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"865 ","pages":"Article 138330"},"PeriodicalIF":2.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}