Brain Research Bulletin最新文献

{"title":"Gray matter and white matter functional connectivity changes induced by rTMS concurrent with cognitive training in Alzheimer’s disease","authors":"Jicheng Fang ,&nbsp;Yan Shi ,&nbsp;Li Ba ,&nbsp;Min Zhang ,&nbsp;Muwei Li ,&nbsp;Ning Zheng ,&nbsp;Yuanyuan Qin ,&nbsp;Wenzhen Zhu","doi":"10.1016/j.brainresbull.2025.111418","DOIUrl":"10.1016/j.brainresbull.2025.111418","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Primarily by targeting the gray matter (GM), repetitive transcranial magnetic stimulation (rTMS) has shown promise in improving cognitive function in individuals with Alzheimer’s disease (AD). However, the impact of rTMS on white matter (WM) remains poorly understood. This study aimed to investigate the functional connectivity (FC) changes in both GM and WM induced by rTMS, and explore their relationship with the clinical manifestation of the disease.</div></div><div><h3>Methods</h3><div>Sixteen patients with mild to moderate AD were enrolled and randomly assigned to either the real rTMS group (n = 8) or the sham treatment group (n = 8). Both groups received cognitive training in combination with rTMS. The real rTMS group received 10 Hz stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) followed by the left lateral temporal lobe (LTL), with each session lasting 20 min per day for 4 weeks, while sham with the coil positioned at a 90° angle. Resting-state BOLD signals were averaged to generate mean time series for each of the 82 GM regions and 48 WM bundles, both before and after treatment for each subject. We analyzed the resting-state fMRI data by using a 2 × 2 factorial design with “time” as the within-subjects factor and “group” as the between-subjects factor.</div></div><div><h3>Results</h3><div>In the analysis of 82 GM regions, when using left LTL as the seed, significant time main effect was observed in right ventral Posterior cingulate cortex (vPCC) (F=9.356, p = 0.009, η²=0.401) and right inferior temporal gyrus (ITG) (F=11.784, p = 0.004, η²=0.457). In the analysis of 48 WM bundles, when using left DLPFC as the seed, significant time × group interactions were found in right cingulum (hippocampus part, CGH) (F=12.123, p = 0.004, η²=0.464). The FC between left DLPFC and right cerebral peduncle (CBRP) demonstrated significant time main effect (F=15.569, p = 0.001, η²=0.527). Moreover, the FC between left DLPFC and right CGH was significantly correlated with MMSE scores changes (r = -0.610, p = 0.027), reflecting cognitive improvements after treatment.</div></div><div><h3>Conclusion</h3><div>The current study suggested that rTMS, when combined with cognitive training, can concurrently modulate functional activities in both GM and WM in patients with mild to moderate AD, which are associated with cognitive improvements. Notably, the limbic system appears to play a pivotal role in facilitating this therapeutic process.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"228 ","pages":"Article 111418"},"PeriodicalIF":3.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TBX21 knockdown attenuates neuroinflammation induced by intracerebral hemorrhage via the SIRT1-WDR5-H3K4me3 axis","authors":"Zhichao Zou ,&nbsp;Zhi Liu ,&nbsp;Zhanwei Zhang ,&nbsp;Xiaojing Li","doi":"10.1016/j.brainresbull.2025.111415","DOIUrl":"10.1016/j.brainresbull.2025.111415","url":null,"abstract":"<div><div>Neuroinflammation is a key contributor to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). This study aimed to elucidate the role and underlying mechanisms of T-box transcription factor 21 (TBX21), a known regulator of type I inflammatory responses, in ICH-induced neuroinflammation. An <em>in vitro</em> oxygen-glucose deprivation (OGD) model using BV2 microglia and an <em>in vivo</em> autologous blood injection-induced ICH rat model were used to modulate TBX21 and sirtuin 1 (SIRT1) expression. The results showed that TBX21 knockdown significantly suppressed the OGD-induced release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), decreased levels of the oxidative stress marker malondialdehyde (MDA), and restored the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In addition, TBX21 knockdown reversed the OGD-induced upregulation of TBX21, WDR5, H3K4me3, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS), while enhancing SIRT1 expression. Mechanistically, TBX21 could directly bind to the promoter region of SIRT1 and suppress its transcription, and the protective effects of TBX21 knockdown were abolished by SIRT1 knockdown. In the ICH rat model, TBX21 knockdown or SIRT1 overexpression led to improvements in neurological severity scores, reductions in hematoma volume, and restoration of tight junction protein expression (occludin, claudin-3, and ZO-1). Collectively, these findings indicate that TBX21 promotes post-ICH neuroinflammation by repressing SIRT1, thereby enhancing WDR5-mediated H3K4me3 epigenetic modifications. TBX21 may therefore serve as a promising therapeutic target for mitigating SBI after ICH.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"229 ","pages":"Article 111415"},"PeriodicalIF":3.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reverses depressive-like behavior in a mouse model of post-traumatic stress disorder","authors":"Haneen Amawi ,&nbsp;Tayma Makhlouf ,&nbsp;Alaa M. Hammad ,&nbsp;Sahar Alsheyab ,&nbsp;Rawan Alhazaimeh ,&nbsp;F. Scott Hall ,&nbsp;Joyeeta T. Khan ,&nbsp;Bahaa Al-Trad ,&nbsp;Amit K. Tiwari","doi":"10.1016/j.brainresbull.2025.111414","DOIUrl":"10.1016/j.brainresbull.2025.111414","url":null,"abstract":"<div><h3>Background</h3><div>Post-traumatic stress disorder (PTSD) is a psychological condition characterized by consistent psychological distress resulting from the experience of intense traumatic events, such as warfare or natural disasters. Benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are widely prescribed treatments for PTSD, but their adverse side effects are a significant concern and they have only limited efficacy as a symptomatic treatment for PTSD. Moreover, they have no effect on the core underlying causes of PTSD Studies have reported a potential neuroprotective effect for Sodium-Glucose Cotransporter-2 Inhibitors (SGLTi). This study utilized the single-prolonged stress (SPS) mouse model of PTSD, which involved sequential exposure to different stressors (2 hours of restraint, 20 minutes of forced swimming, 15 minutes of rest, and 1–2 minutes of diethyl ether exposure), to investigate the therapeutic potential of Dapagliflozin (DAPA), a novel SGLTi, in mitigating the SPS-induced depressive-like behavior.</div></div><div><h3>Methods</h3><div>Male mice were randomly assigned to four experimental groups: Control group, SPS group, DAPA group (dapagliflozin; 1 mg/kg/day by oral gavage for 7 days), and SPS+DAPA group. Behavioral assessments for depressive-like behaviors were evaluated using the forced swim test and the tail suspension test. Blood and brain tissue samples were collected for analysis stress markers.</div></div><div><h3>Results</h3><div>SPS-treated mice showed significant depressive-like behavior on the seventh day post-treatment, which was reversed by DAPA treatment (1 mg/kg/day). Significant increases in brain tissue mRNA expression of <em>Crh, Bax, Il1b, and Bdnf</em>, as well as serum corticosterone, were observed in the SPS group, while DAPA reversed these effects.</div></div><div><h3>Conclusion</h3><div>This data indicates that DAPA (1 mg/kg) has potential therapeutic effects for the treatment of PTSD-induced depressive-like symptoms.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"228 ","pages":"Article 111414"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The activity of glutamatergic neurons in the dorsal-ventral poles of the dentate gyrus regulates distinct phenotypes of depression in mice","authors":"Jinping Wang ,&nbsp;Hongjie Li ,&nbsp;Yusi Hua ,&nbsp;Lanyu Zhang ,&nbsp;Xiaoqin Jiang ,&nbsp;Xinchuan Wei","doi":"10.1016/j.brainresbull.2025.111413","DOIUrl":"10.1016/j.brainresbull.2025.111413","url":null,"abstract":"<div><div>Depression is a heterogeneous mental disorder. The dorsal and/or ventral dentate gyrus (DG) has been implicated in the pathophysiology of depression. However, it remains unclear whether the activities of glutamatergic neurons in the dorsal and ventral DG contribute to the heterogeneity of depression. In the present study, we conduct a series of depression-related behavior tests by activating or inhibiting the activity of glutamatergic neurons in the dorsal and ventral DG using chemical genetic methods. It is found that inhibiting the dorsal DG glutamatergic neurons induces social deficits, as well as learning and memory dysfunction, while activating them improves social behaviors and alleviated social deficits induced by chronic stress. Conversely, inhibiting the ventral DG glutamatergic neurons increases anxiety and despair-like symptoms, and activating them reduces anxiety and despair-like symptoms and alleviates these symptoms caused by chronic stress. Our study highlights the necessity of incorporating dorsoventral axis-specific analyses of DG in subsequent investigations to better understand the pathophysiological heterogeneity of depression.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"228 ","pages":"Article 111413"},"PeriodicalIF":3.5,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artesunate alleviates cerebral ischemia/reperfusion injury by suppressing FUNDC1-mediated excessive mitophagy","authors":"Fei Wang,&nbsp;Wenji Zhou,&nbsp;Liqing Huang,&nbsp;Li Sun,&nbsp;Lujun Deng,&nbsp;Liping Li","doi":"10.1016/j.brainresbull.2025.111407","DOIUrl":"10.1016/j.brainresbull.2025.111407","url":null,"abstract":"<div><div>Cerebral ischemia-reperfusion (I/R) injury represents a debilitating neurological disorder with significant morbidity. Artesunate, a water-soluble hemisuccinate derivative, has emerged as a potential therapeutic agent for cerebral I/R injury. Our investigation endeavors to assess the efficacy of artesunate in this context while elucidating its mechanisms of action. We established the middle cerebral artery occlusion/refusion (MACO) rat model and oxygen-glucose deprivation/reperfusion (OGD/R)-stimulated PC12 cells model. Mitophagy was analyzed by transmission electron microscope, mitochondrial membrane potential detection, western blotting, and real-time quantitative polymerase chain reaction (RT-qPCR). The underlying mechanism was investigated by cell viability, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The results suggested that artesunate inhibited apoptosis and excessive mitophagy. Mechanically, artesunate regulated FUN14 domain containing 1 (FUNDC1)-mediated mitophagy via the AMPK (AMP-activated protein kinase)-mTOR (mechanistic target of rapamycin)-TFEB (transcription factor EB) signaling pathway. Additionally, artemether reduced the infarct size in MCAO rats, inhibited neurological dysfunction, and enhanced memory performance. In summary, our data revealed a novel mechanism whereby artesunate suppresses apoptosis by inhibiting excessive mitophagy. These findings offered a new promising therapy for cerebral I/R injury.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"228 ","pages":"Article 111407"},"PeriodicalIF":3.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dopaminergic neurons in the ventral periaqueductal gray projecting to the dorsal lateral septum regulate comorbid pain and anxiety","authors":"Shaoshan Wang ,&nbsp;Yani Guo ,&nbsp;Bingdi Wei ,&nbsp;Rukun Lu ,&nbsp;Zhixuan Tan ,&nbsp;Chaojun Wei","doi":"10.1016/j.brainresbull.2025.111409","DOIUrl":"10.1016/j.brainresbull.2025.111409","url":null,"abstract":"<div><div>The comorbidity of pain and anxiety is one of the most prevalent mental health disorders globally. However, its underlying etiological mechanisms remain incompletely understood. This study revealed that the dorsal lateral septum (LSD) and its associated neural circuits play key roles in pain and/or anxiety regulation. Using chemical genetic techniques, we found that the specific inhibition of LSD GABAergic neurons significantly alleviated pain responses and anxiety-like behaviors. Conversely, the specific activation of LSD GABAergic neurons induced hyperalgesia and anxiety-like behaviors in mice. Furthermore, our study showed that dopaminergic neurons in the ventral periaqueductal gray (vPAG) play a crucial role in regulating pain and anxiety comorbidity through their projections to the LSD. This regulatory mechanism depends on the release of dopamine and its binding to the D2 receptor of LSD. In summary, this study highlights the critical role of LSD GABAergic neurons and their associated neural circuits in the comorbidity of pain and anxiety, thereby providing a new theoretical foundation and research direction for developing potential therapeutic strategies.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"228 ","pages":"Article 111409"},"PeriodicalIF":3.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the nexus: Sleep's role in ferroptosis and health","authors":"Peng-cheng Zhao ,&nbsp;Zhen-yu Wu ,&nbsp;Yu-hang Zhu ,&nbsp;Tao-wu Gong ,&nbsp;Zhao-qiong Zhu","doi":"10.1016/j.brainresbull.2025.111412","DOIUrl":"10.1016/j.brainresbull.2025.111412","url":null,"abstract":"<div><div>Sleep is an important physiological process to maintain physiological health, which involves the regulation of many systems in the body, which is not only closely related to hormone balance, immune system and nervous system function in the body. Recent studies have emphasized the complex relationship between sleep and cell death mechanisms. Ferroptosis is a form of iron-dependent cell death, which is related to a variety of neurodegenerative diseases. Sleep plays an important role in regulating brain metabolism, immune function and overall intracellular homeostasis. New evidence suggests that there is a two-way interaction between sleep and ferroptosis. Sleep interruption may enhance the ferroptosis pathway, which in turn may change the quality of sleep. Understanding this interaction is essential to reveal the underlying mechanisms of neurodegeneration and to develop potential therapeutic interventions.</div><div>This review combines the results of current studies on the molecular and cellular mechanisms of ferroptosis and the extensive role of sleep in brain health. Special attention is paid to the effects of sleep deprivation on iron metabolism and oxidative stress, which play an important role in ferroptosis. The review also explores the role of sleep in regulating iron homeostasis and how sleep disorders promote iron accumulation in the brain, which may accelerate the process of ferroptosis.</div><div>Sleep disorders, especially chronic sleep deprivation, may create a favorable environment for ferroptosis by affecting iron metabolism and oxidative stress levels in the brain. Conversely, cell death associated with siderosis disrupts normal sleep patterns, forming a circulatory relationship that exacerbates neurodegenerative diseases. Understanding the complex mechanisms of sleep and ferroptosis will provide valuable insights into aging and age-related diseases. In addition, the pathways involved in sleep regulation and ferroptosis can provide new methods for the prevention and treatment of neurodegenerative diseases and other ferroptosis-related pathology.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"228 ","pages":"Article 111412"},"PeriodicalIF":3.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the pain pathway: The VPL–S1HL–ACC circuit's role in central post-stroke pain","authors":"Panyang Li ,&nbsp;Chaofan Lu ,&nbsp;Mingliang Wang ,&nbsp;Yuanyuan Mao ,&nbsp;Xi Wang ,&nbsp;Yi Liu ,&nbsp;Jingjing Zhang ,&nbsp;Sen Zhao","doi":"10.1016/j.brainresbull.2025.111406","DOIUrl":"10.1016/j.brainresbull.2025.111406","url":null,"abstract":"<div><div>Central post-stroke pain (CPSP) is a chronic neuropathic condition driven by central sensitization, often resulting in poor clinical outcomes. Neural circuits play a critical role in modulating chronic pain. To elucidate the mechanisms underlying CPSP, we established a mouse model via intracranial injection of type IV collagenase. cFos immunofluorescence and <em>in vivo</em> calcium imaging identified pain-associated activated nuclei. Using viral tracing, optogenetics, chemogenetics, and behavioral assays, we mapped a neural circuit comprising the ventral posterolateral thalamic nucleus (VPL), the hindlimb primary somatosensory cortex (S1HL), and the anterior cingulate cortex (ACC). In CPSP mice, ipsilateral S1HL^CaMKIIα and ACC^CaMKIIα neurons exhibited robust activation. Chemogenetic manipulation further demonstrated that activation of these neurons induced pain behaviors, whereas their inhibition alleviated pain. Notably, specific activation of the S1HL^CaMKIIα–ACC^CaMKIIα circuit produced mechanical allodynia, and optogenetic stimulation of VPL^CaMKIIα projections to S1HL similarly evoked pain responses while enhancing ACC neuronal firing. These findings underscore the critical role of the VPL–S1HL–ACC circuit in pain abnormalities and provide novel insights into the central sensitization underlying CPSP, suggesting promising therapeutic strategies for its management.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"227 ","pages":"Article 111406"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding autism: Causes, diagnosis, and advancing therapies","authors":"Min Wang ,&nbsp;Xiaozhuang Zhang ,&nbsp;Liyan Zhong ,&nbsp;Liqin Zeng ,&nbsp;Ling Li ,&nbsp;Paul Yao","doi":"10.1016/j.brainresbull.2025.111411","DOIUrl":"10.1016/j.brainresbull.2025.111411","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) is a neurodevelopmental condition marked by difficulties in social communication, languages, and repetitive behaviors. Its rising prevalence has made it a critical global public health issue. ASD is believed to arise from a combination of genetic and environmental influences. While some gene mutations associated with ASD have been identified, most cases lack clear genetic explanations. Evidence increasingly points to early-life environmental factors as key contributors to ASD, including advanced parental age, maternal diabetes during pregnancy, infections, hormonal imbalances, certain medications, and exposure to air pollution. Currently, ASD diagnosis relies on behavioral assessments, but the absence of specific molecular biomarkers poses significant obstacles to early detection and targeted therapies. Encouragingly, research has identified potential biomarkers, such as neuroimaging classifiers, electroencephalography patterns, eye-tracking data, digital analytics, gene expression profiles, inflammatory and chemokine markers, proteomic and metabolomic profiles, and gut microbiota characteristics. Potential therapeutical strategies under investigation include digital therapies, non-invasive brain stimulation, antioxidants, oxytocin, AVPR1a antagonists, PPAR agonists, and mTOR inhibitors. This review explores ASD across five areas: epidemiological trends, genetic mechanisms, early-life environmental factors and their potential roles, diagnostic biomarkers, and therapeutic approaches.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"227 ","pages":"Article 111411"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144167769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP3 in the dorsal raphe nucleus manipulates the depressive-like behaviors","authors":"Junchao Cai ,&nbsp;Jiarong Zhao ,&nbsp;Rui Peng ,&nbsp;Heming Yu ,&nbsp;Yong He ,&nbsp;Qigang Zhou ,&nbsp;Yue Wang ,&nbsp;Peng Xie","doi":"10.1016/j.brainresbull.2025.111405","DOIUrl":"10.1016/j.brainresbull.2025.111405","url":null,"abstract":"<div><div>Major depressive disorder is one of the most common psychiatric disorders, and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in depression. Dorsal raphe nucleus (DRN), as the main origin of producing serotonin in the brain, is an important functional brain region in depressive disorders. However, the relationship between NLRP3 in the DRN and depression has not been clarified in previous studies. So, we focus on demonstrating the role of NLRP3 expressed in DRN in depression. In this study, the male C57BL/6 J mice were exposed to chronic unpredictable mild stimulation and the expression and cellular localization of NLRP3 in DRN were analyzed. Subsequently, the mice were treated with the NLRP3 inhibitor MCC950 to inhibit NLRP3 inflammasome, and the expression of NLRP3 was knocked down in certain cells within the DRN of NLRP3^fl/fl mice to investigate the role of NLRP3 in regulating depressive phenotype. Compared with the control group, the expression of NLRP3 in DRN of CUMS group was significantly increased, especially in the microglia and neuron. Furthermore, treatment with the NLRP3 inhibitor induced a significant antidepressant effect, and the depressive phenotype of NLRP3^fl/fl mice was rescued after knocking down NLRP3 in the microglia or neuron. In addition, the expression levels of related molecules in the NLRP3 inflammasome pathway were significantly higher in the CUMS group compared to the control group. These results illustrated that NLRP3 played an important role in regulating depressive phenotype in DRN, and suggested a new therapy target for depression.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"227 ","pages":"Article 111405"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}