Brain, Behavior, and Immunity最新文献

{"title":"Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model","authors":"Hami Hemati ,&nbsp;Madison B. Blanton ,&nbsp;Heather E. True ,&nbsp;Jude Koura ,&nbsp;Rupak Khadka ,&nbsp;Kathleen A. Grant ,&nbsp;Ilhem Messaoudi","doi":"10.1016/j.bbi.2025.07.022","DOIUrl":"10.1016/j.bbi.2025.07.022","url":null,"abstract":"<div><div>Alcohol-induced dysregulation of microglial activity is associated with neuroinflammation, cognitive decline, heightened risk for neurodegenerative diseases, alcohol dependence, and escalation of alcohol drinking. Given the challenge of longitudinally sampling primary microglia, we optimized an <em>in vitro</em> method to differentiate peripheral blood mononuclear cells (PBMC) from rhesus macaque (RM) into induced microglia-like cells (RM-iMGLs). The RM-iMGLs displayed transcriptional profiles distinct from monocyte progenitors and closely resembling primary microglia. Notably, morphological features showed that differentiated RM-iMGLs derived from subjects with chronic alcohol consumption (CAC), while bigger, exhibited a bipolar-like morphology. Additionally, dysregulation in key inflammatory and regulatory markers, along with increased baseline phagocytic activity, was observed in CAC-derived RM-iMGLs. Phenotypic and functional assessments following LPS stimulation indicated the enrichment of a CD86⁺ hyper-inflammatory subpopulation in RM-iMGLs derived from ethanol-consuming animals, accompanied by an overall increase in immune reactivity, indicative of a heightened inflammatory state. Collectively, these findings demonstrate that <em>in vitro</em> differentiation of PBMCs offers a minimally invasive yet highly translational approach to studying the impact of CAC on microglial function and that CAC reshapes both functional and transcriptional profiles of RM-iMGLs, which require further investigation at the single-cell level.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 874-889"},"PeriodicalIF":7.6,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleeve gastrectomy alleviates anxiety-like behaviors in mice with high-fat diet induced obesity","authors":"Xianshu Wang ,&nbsp;Yuhan Zhang ,&nbsp;Chao Zhang ,&nbsp;Nan Zhang ,&nbsp;Yanli Yu ,&nbsp;Wei Liu","doi":"10.1016/j.bbi.2025.07.020","DOIUrl":"10.1016/j.bbi.2025.07.020","url":null,"abstract":"<div><div>The efficacy of bariatric surgery (BS) in alleviating obesity-associated anxiety symptoms remains unclear. This study aimed to investigate the impact of BS on anxiety using an obese mouse model, elucidating the complex interplay between obesity, anxiety, and related biological factors. Sleeve gastrectomy (SG) was performed on mice rendered obese via a high-fat diet to establish a BS model. The influence of SG on anxiety-like behaviors, amygdala gene expression, serum metabolite profiles, and gut microbiota composition was systematically evaluated. Behavioral analyses demonstrated that obesity intensified anxiety-like behaviors, whereas SG markedly mitigated these symptoms. Transcriptomic analysis revealed that SG altered gene transcription patterns in the amygdala, particularly affecting neurotransmitter and receptor genes. Serum metabolomics further validated these findings, indicating significant changes in neurotransmitter metabolite levels. Additionally, surgically treated mice exhibited elevated serum inosine concentrations, a microbial-derived metabolite, aligning with increased abundance of the inosine-producing bacterium <em>Akkermansia muciniphila</em> post-surgery. Given the rising global prevalence of obesity and associated mental health complications, understanding the potential mental health benefits of BS is critical. This study provides preclinical evidence supporting the anxiolytic effects of BS and underscores the need for further research to clarify its implications for human mental health.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 910-920"},"PeriodicalIF":7.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144727964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis","authors":"Zoë A. MacDowell Kaswan ,&nbsp;Alexandra K. Brooks ,&nbsp;Myrna Hurtado ,&nbsp;Emily Y. Chen ,&nbsp;Andrew J. Steelman ,&nbsp;Robert H. McCusker","doi":"10.1016/j.bbi.2025.07.017","DOIUrl":"10.1016/j.bbi.2025.07.017","url":null,"abstract":"<div><div>Viral encephalitis is a serious condition that causes acute neuroinflammation, neurodegeneration, cognitive deficits and behavioral changes, while putting patients at risk of developing seizures (ictogenesis) and post-encephalitis epilepsy. Intracerebral injection of C57BL/6 mice with Theiler’s murine encephalomyelitis virus (TMEV) is a model of viral encephalitis that causes behavioral seizures along with substantial neurodegeneration and neuroinflammation. This model is considered a benchmark preclinical paradigm for the investigation of hippocampal-dependent viral ictogenesis and temporal lobe epilepsy. Inflammation-induced <em>indolealine2,3-deoxygenase</em> (<em>Ido</em>) 1 and 2 initiate the conversion of tryptophan into kynurenine, which is subsequently converted into downstream neuroactive metabolites with the ability to modify behavioral seizures. Ido1 and Ido2 have also been shown to have non-redundant roles in modulating several inflammatory diseases. We have previously shown that Ido1 deficiency increases TMEV-induced behavioral seizure incidence using wild type (WT, C57BL/6J) mice. Here, we extend those findings to Ido2 deficiencies. We find that Ido2^KO (knockout) mice have equivalent TMEV-induced behavioral seizure incidence and hippocampal gene expression relative to wild type WT mice. However, while TMEV infection causes an increase in Iba1⁺ staining throughout the hippocampus (indicating microglial activation) this effect is ameliorated in Ido2^KO mice. Microglia, the resident innate immune cells of the brain, are critical for TMEV clearance but may also contribute to ictogenesis. Therefore, based on Ido2-dependent differences in microglia activation, we examined TMEV-induced ictogenesis in mice with microglial-specific Ido1 and Ido2 deficiencies. We found that microglial Ido2, but not Ido1, deficiency reduced ictogenesis but caused minimal changes in hippocampal gene expression. <em>In vitro</em> treatments revealed that microglia respond to TMEV infection via inflammatory signals rather than directly to viral infection itself. In sum, we demonstrate that Ido2 plays a key role in microglial response to TMEV and that, when the effects of Ido2 deficiency are limited to microglia, Ido2 deficiency is protective against ictogenesis.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 839-856"},"PeriodicalIF":8.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attenuation of Ca2+ signaling by overexpression of PMCA2 affects the microglial response to pathological events","authors":"Fan Zeng ,&nbsp;Sagun Tiwari ,&nbsp;Alaa Chok ,&nbsp;Yan Zhou ,&nbsp;Yue Zhao ,&nbsp;Xuezhen Chen ,&nbsp;Yue Hao ,&nbsp;Kaichuan Zhu ,&nbsp;Helmut Kettenmann ,&nbsp;Xianyuan Xiang","doi":"10.1016/j.bbi.2025.07.013","DOIUrl":"10.1016/j.bbi.2025.07.013","url":null,"abstract":"<div><div>Microglia strongly impact the pathologic course of brain diseases and injuries. Intracellular Ca²⁺ dynamics serve as central integrators, connecting microglial sensing capacity to their responses. We generated a mouse line with microglial overexpression of plasma membrane Ca²⁺-ATPase (PMCA)2, a central regulator of cytoplasmic Ca²⁺ homeostasis. This manipulation significantly attenuated ATP-evoked Ca²⁺ signals in vitro and spontaneous Ca²⁺ transients in vivo. Notably, in contrast to astrocytes, PMCA2 overexpression in microglia/macrophages did not affect animal behavior and survival. It had, however, a profound impact on microglial reactivity in pathological contexts, including reduced inflammatory responses following lipopolysaccharide challenge and diminished microglial proliferation at sites of acute injury. In an Alzheimer’s disease model, PMCA2 overexpression attenuated the disease-associated microglial signature, reducing amyloid plaque burden and plaque-associated neuritic dystrophy. These findings highlight the importance of Ca²⁺-mediated signaling for modulating the microglial response to pathologic events. Attenuating microglial Ca²⁺ signaling by PMCA2 overexpression is a potential strategy to promote beneficial microglial phenotypes in brain inflammation or degeneration.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 857-873"},"PeriodicalIF":7.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-33 promotes dopaminergic neuron survival and inhibits glial activation in Parkinson’s disease models","authors":"Chenye Shen ,&nbsp;Zhaolin Liu ,&nbsp;Fangzheng Chen ,&nbsp;Xinjie Zhu ,&nbsp;Guangchun Fan ,&nbsp;Penggang Ning ,&nbsp;Qing Li ,&nbsp;Xiaoshuang Zhang ,&nbsp;Hongtian Dong ,&nbsp;Yan Liu ,&nbsp;Mei Yu ,&nbsp;Jian Fei ,&nbsp;Fang Huang","doi":"10.1016/j.bbi.2025.07.010","DOIUrl":"10.1016/j.bbi.2025.07.010","url":null,"abstract":"<div><div>Interleukin-33 (IL33) plays a critical role in modulating immune and inflammatory responses across various diseases, yet its influence on Parkinson’s disease (PD) remains elusive. In this study, we provide substantial evidence that global depletion of <em>Il33</em> exacerbates PD pathology and motor deficits <em>in vivo</em>. Moreover, <em>Il33</em> deficiency diminishes the communication between astrocytes and microglia, leading to a more profound injury to primary neurons <em>in vitro</em>. Notably, the application of recombinant IL33 (rIL33) following MPTP treatment or α-synuclein^A53T overexpression partially inhibits the reduction in TH expression, glial activation, and the motor dysfunctions <em>in vivo</em>. Collectively, our findings demonstrate the opposed effects of <em>Il33</em> deletion and rIL33 administration on neuroinflammation in PD, emphasizing the therapeutic potential of IL33 in regulating neuroinflammation and neuronal viability in the central nervous system (CNS).</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 787-800"},"PeriodicalIF":8.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal alcohol exposure induces microglia to release exosomes with an elevated level of MIP-1α that participates in apoptotic process of stress-regulatory proopiomelanocortin neurons via glutamate excitotoxicity","authors":"Prashant Tarale ,&nbsp;Shaista Chaudhary ,&nbsp;Dipak K. Sarkar","doi":"10.1016/j.bbi.2025.07.016","DOIUrl":"10.1016/j.bbi.2025.07.016","url":null,"abstract":"<div><div>Microglia are known to participate in ethanol-activated neuronal death of stress-regulatory proopiomelanocortin (POMC) neurons in the hypothalamus leading to hyper corticosterone response to stress and anxiety-like behaviors in a rat model of fetal alcohol spectrum disorder. We recently reported that ethanol-activated microglia release small membrane-bound vesicles called exosomes, which carry various neuroinflammatory molecules involved in POMC neuronal death. Here, we determined if macrophage inflammatory protein (MIP)-1α, a neuroinflammatory chemokine participates in ethanol-induced POMC neuronal death during the developmental period. We used an in vitro model, consisting of primary culture of hypothalamic microglia prepared from postnatal day 2 (PND2) rat and treated with or without 50 mM ethanol for 24 h, and an in vivo animal model in which hypothalamic microglia were obtained from PND6 rats fed daily with 2.5 mg/kg ethanol or control milk formula between PND2-6. We found that ethanol elevated MIP-1α level in microglial exosomes both in vitro and in vivo models. Ethanol-activated microglial exosomes when introduced into primary cultures of β-endorphin-producing POMC neurons, increased cellular levels of MIP-1α and chemokine receptor CCR5 related signaling molecules including glutamate transporter-1 and NMDA receptor subunit genes, calcium influx, inflammatory cytokines and apoptotic genes causing apoptotic death of POMC neurons. These effect of microglial exosomes on POMC neurons were suppressed by a CCR5 antagonist Maraviroc. Maraviroc administrated in postnatal PAE rats, reduces the ethanol-induced death of POMC neurons in developing hypothalamus and suppressed stress-related corticosterone hyperresponse and anxiety-like behaviors during adulthood. These findings indicate that alcohol exposure during the developmental period increases MIP-1α levels in microglial exosomes, which activate CCR5 signaling and cause apoptosis in POMC neurons, leading to hormonal and behavioral stress response abnormalities in animals.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 818-828"},"PeriodicalIF":8.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surgery-induced reduction in inflammation relates to improved neural inhibitory control in obesity","authors":"Lisa-Katrin Kaufmann ,&nbsp;Emma Custers ,&nbsp;Debby Vreeken ,&nbsp;Jessica Snabel ,&nbsp;Martine C. Morrison ,&nbsp;Robert Kleemann ,&nbsp;Maximilian Wiesmann ,&nbsp;Eric J. Hazebroek ,&nbsp;Esther Aarts ,&nbsp;Amanda J. Kiliaan","doi":"10.1016/j.bbi.2025.07.012","DOIUrl":"10.1016/j.bbi.2025.07.012","url":null,"abstract":"<div><div>Obesity is associated with impaired inhibitory control and low-grade systemic inflammation. Systemic inflammation adversely affects neurocognitive performance. Here, we investigate the effects of metabolic bariatric surgery on systemic inflammation and its influence on neural mechanisms underlying inhibitory control. In a sample of 47 individuals with severe obesity, we assessed inhibitory control processing pre- and 2 years post-bariatric surgery by probing neural activation and connectivity during an fMRI Stroop task. We investigated whether surgery-induced changes in plasma markers of systemic inflammation were related to changes in altered neural responses. Data were collected as part of the BARICO (Bariatric surgery Rijnstate and Radboudumc neuroimaging and Cognition in Obesity) study. Longitudinal analyses revealed decreased Stroop-related activation in the caudate nucleus and the left insula following surgery. These activation changes were accompanied by inflammation-related changes in functional coupling with medial superior frontal regions. Specifically, greater post-surgery decreases in leptin (pro-inflammatory) were associated with decreased connectivity between the anterior insula and the medial superior frontal regions, while increases in macrophage migration inhibitory factor (MIF, potentially neuroprotective) were linked to enhanced connectivity between the caudate nucleus and the medial superior frontal gyrus. Importantly, improved functional coupling between the caudate nucleus and the medial superior frontal gyrus was predictive of better task performance. Our findings suggest that surgery-induced reductions in systemic inflammation may improve inhibitory control in individuals with obesity by promoting neural changes in inflammation-sensitive brain regions and their functional interactions.</div><div>This protocol was prospectively registered with the Dutch Trial Register <span><span>Onderzoekmetmensen.nl</span><svg><path></path></svg></span>, with trial number NTR29050.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 829-838"},"PeriodicalIF":8.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting RelA/NLRP3/CCL3 axis mitigates microglia inflammatory response and promotes recovery after spinal cord injury","authors":"Wei Song ,&nbsp;Runhan Fu ,&nbsp;Zhongze Yuan ,&nbsp;Yanchun Liu ,&nbsp;Yanbing Kao ,&nbsp;Renjie Zhang ,&nbsp;Guangjin Gu ,&nbsp;Hanming Zhu ,&nbsp;Haoyun Liu ,&nbsp;Zhihao Zhang ,&nbsp;Xiaohong Kong ,&nbsp;Shiqing Feng","doi":"10.1016/j.bbi.2025.07.015","DOIUrl":"10.1016/j.bbi.2025.07.015","url":null,"abstract":"<div><div>Spinal cord injury (SCI) leads to loss of motor and sensory function below the lesion site, presenting a lifelong burden of disability. During the acute phase of SCI, microglia develop an inflammatory phenotype, characterized by the NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling activation, exacerbating tissue damage and impeding trauma recovery. However, the molecular mechanisms underlying this process remain unclear. Here we show that conditional knockout of <em>Nlrp3</em> in microglia using <em>Nlrp3^fl/fl</em>; <em>Cx3cr1</em>-CreERT; <em>Rosa26</em>-tdTomato mice (<em>Nlrp</em>3ΔMG) confers neuroprotection by preserving neuron survival and mitigating tissue damage during the acute phase of SCI. Mechanistically, <em>Nlrp3</em> ablation in microglia attenuates the activation of pyroptosis-related signaling pathways in microglia and suppresses the production of inflammatory cytokines (IL-1β, IL-18, CCL3, and CCL5). Furthermore, we identify RelA as a transcriptional regulator of <em>Nlrp3</em>, binding to its promoter and upregulating its expression in activated microglia. Inhibition of RelA using pyrrolidine dithiocarbamate ammonium (PDTC), a blood–brain barrier permeable drug, effectively downregulates NLRP3 expression and suppresses spinal cord inflammation, thereby contributing to neuroprotection. Our findings demonstrate the crucial role of RelA/NLRP3/CCL3 axis in modulating microglial inflammation and highlight its potential as a therapeutic target to promote recovery post SCI.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 801-817"},"PeriodicalIF":8.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upadacitinib regulates pain-related pathways and BDNF expression in human monocyte-derived microglial-like cells","authors":"M. Vomero ,&nbsp;E. Corberi ,&nbsp;O. Berardicurti ,&nbsp;D. Currado ,&nbsp;F. Trunfio ,&nbsp;F. Saracino ,&nbsp;A. Marino ,&nbsp;L. Frascà ,&nbsp;M. Gatti ,&nbsp;G. Imperatori ,&nbsp;L. La Barbera ,&nbsp;P. Krashia ,&nbsp;M. D’Amelio ,&nbsp;R. Giacomelli ,&nbsp;L. Navarini","doi":"10.1016/j.bbi.2025.07.007","DOIUrl":"10.1016/j.bbi.2025.07.007","url":null,"abstract":"<div><div>Chronic pain is one of the most critical symptoms reported by patients with inflammatory arthritis, and even when joint inflammation improves, disabling residual pain may persist in a significant number of patients. Microglial cells, by producing different pro-inflammatory cytokines and pain-related molecules, including IL-1β and BDNF, are involved in neuroinflammation process. Treatment with Upadacitinib (upa), a JAK1 inhibitor, has been shown to be effective in improving disease activity and quickly relieving pain; however, the biological mechanisms underlying its efficacy against pain perception still require further investigation. This study aims to investigate whether and how upa may influence the production of pain and neuroinflammation-related molecules in pro-inflammatory human monocyte-derived microglia-like (M1-MDMi) model, specifically regarding BDNF. JAK1 inhibition by <em>in vitro</em> upa treatment downregulated BDNF expression and secretion by the modulation of P2X4 receptor, thus affecting a central mechanism involved in pain perception. Moreover, transcriptomic analysis showed that upa promoted an anti-nociceptive profile in the human glial model, by reducing the expression of neuroinflammatory, acute, and chronic pain-related pathways.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 778-786"},"PeriodicalIF":8.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astroglial TNFR2 signaling regulates hippocampal synaptic function and plasticity in a sex dependent manner","authors":"Brianna N. Carney ,&nbsp;Placido Illiano ,&nbsp;Taylor M. Pohl ,&nbsp;Haritha L. Desu ,&nbsp;Antonella Mini ,&nbsp;Shwetha Mudalegundi ,&nbsp;Andoni I. Asencor ,&nbsp;Shika Jwala ,&nbsp;Maureen C. Ascona ,&nbsp;Praveen K. Singh ,&nbsp;David J. Titus ,&nbsp;Burcu A. Pazarlar ,&nbsp;Lei Wang ,&nbsp;Laura Bianchi ,&nbsp;Jens D. Mikkelsen ,&nbsp;Coleen M. Atkins ,&nbsp;Kate L. Lambertsen ,&nbsp;Roberta Brambilla","doi":"10.1016/j.bbi.2025.07.006","DOIUrl":"10.1016/j.bbi.2025.07.006","url":null,"abstract":"<div><div>Astrocytes participate in synaptic transmission and plasticity through tightly regulated, bidirectional communication with pre- and post-synaptic neurons, as well as microglia and oligodendrocytes. A key component of astrocyte-mediated synaptic regulation is the cytokine tumor necrosis factor (TNF). TNF signals via two cognate receptors, TNFR1 and TNFR2, both expressed in astrocytes. While TNFR1 signaling in astrocytes has long been shown as necessary for physiological synaptic function, the role of astroglial TNFR2 was never explored. Here, we show that astroglial TNFR2 is essential for maintaining hippocampal synaptic function and plasticity in physiological conditions. Indeed, <em>Gfap^creERT2:Tnfrsf1b^fl/fl</em> mice with selective ablation of TNFR2 in astrocytes exhibited dysregulated expression of neuronal and glial proteins (e.g., upregulation of SNARE complex molecules, glutamate receptor subunits, glutamate transporters) essential for hippocampal synaptic transmission and plasticity. This was most evident in male mice compared to females. In the hippocampus, <em>Gfap^creERT2:Tnfrsf1b^fl/fl</em> male mice but not females showed elevated numbers of astrocytes and microglia, as well as increased glial reactivity measured by TSPO autoradiography. These cellular alterations ultimately translated into functional deficits, specifically learning and memory impairments measured by novel object recognition and Morris water maze tests, and suppressed long-term potentiation (LTP). Finally, RNA sequencing of sorted hippocampal astrocytes showed that, in <em>Gfap^creERT2:Tnfrsf1b^fl/fl</em> male mice, genes and pathways implicated in synaptic plasticity as well as astrocyte-neuron and astrocyte-oligodendrocyte communication were downregulated compared to <em>Tnfrsf1b^fl/fl</em> control mice.</div><div>Together, our findings indicate that TNFR2 signaling in astrocytes is essential for proper astrocyte-neuron communication at the basis of synaptic function, and that this mechanism is regulated in a sex-dependent manner.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 757-777"},"PeriodicalIF":8.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}