Brain, Behavior, and Immunity最新文献

{"title":"Patient-derived monoclonal LGI1 autoantibodies elicit seizures, behavioral changes and brain MRI abnormalities in rodent models","authors":"Manoj Upadhya ,&nbsp;Alexander Stumpf ,&nbsp;Jack O’Brien-Cairney ,&nbsp;César Cordero Gómez ,&nbsp;Jan Döring ,&nbsp;Julius Hoffmann ,&nbsp;Susanne Mueller ,&nbsp;Yuko Fukata ,&nbsp;Scott van Hoof ,&nbsp;Divya Dhangar ,&nbsp;Max A. Wilson ,&nbsp;Arunvir Atwal ,&nbsp;Richard Rosch ,&nbsp;Gavin Woodhall ,&nbsp;Philipp Boehm-Sturm ,&nbsp;Masaki Fukata ,&nbsp;Jakob Kreye ,&nbsp;Dietmar Schmitz ,&nbsp;Sukhvir K. Wright ,&nbsp;Hans-Christian Kornau ,&nbsp;Harald Prüss","doi":"10.1016/j.bbi.2025.02.019","DOIUrl":"10.1016/j.bbi.2025.02.019","url":null,"abstract":"<div><h3>Objective</h3><div>Limbic encephalitis with leucine-rich glioma inactivated 1 (LGI1) protein autoantibodies is associated with cognitive impairment, psychiatric symptoms, and seizures, including faciobrachial dystonic seizures (FBDS). Patient-derived LGI1-autoantibodies cause isolated symptoms of memory deficits in mice and seizures in rats. Using a multimodal experimental approach, we set out to improve the validity of existing <em>in vivo</em> rodent models to further recapitulate the full clinical syndrome of anti-LGI1 antibody mediated disease.</div></div><div><h3>Methods</h3><div>A monoclonal anti-LGI1 antibody (anti-LGI1 mAb) derived from a patient’s CSF antibody-secreting cell was infused intracerebroventricularly (ICV) into rats and mice for one or two weeks, respectively. Cellular excitability of CA3 pyramidal neurons was determined in hippocampal slices. Structural changes in mouse brains were explored using MRI. Antibody effects on behavior and brain activity of rats were studied using video-EEG.</div></div><div><h3>Results</h3><div>Anti-LGI1 mAbs augmented the excitability of CA3 pyramidal neurons and elicited convulsive and non-convulsive spontaneous epileptic seizures in mice and rats. Mice displayed a hypoactive and anxious phenotype during behavioral testing. MRI revealed acutely increased hippocampal volume after ICV anti-LGI1 mAb infusion. Video-EEG recordings of juvenile rats uncovered two peaks of seizure frequency during the 7-day antibody infusion period resembling the natural progression of seizures in human anti-LGI1 encephalitis.</div></div><div><h3>Interpretation</h3><div>Our data strongly corroborate and extend our understanding of the direct pathogenic and epileptogenic role of human LGI1 autoantibodies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 342-355"},"PeriodicalIF":8.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinctive seizure signature in the first video case-control study of a naturally-occurring feline autoimmune encephalitis model","authors":"S.N.M. Binks ,&nbsp;A.H. Crawford ,&nbsp;E. Ives ,&nbsp;L.J. Davison ,&nbsp;A. Fower ,&nbsp;H. Fox ,&nbsp;A. Kaczmarska ,&nbsp;M. Woodhall ,&nbsp;P. Waters ,&nbsp;A.E. Handel ,&nbsp;S.R. Irani ,&nbsp;R. Gutierrez Quintana ,&nbsp;F.A. Chowdhury ,&nbsp;S.H. Eriksson ,&nbsp;A. Pakozdy","doi":"10.1016/j.bbi.2025.02.018","DOIUrl":"10.1016/j.bbi.2025.02.018","url":null,"abstract":"<div><h3>Background and objective</h3><div>Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear ‘Knut’, diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart.</div></div><div><h3>Methods</h3><div>We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors.</div></div><div><h3>Results</h3><div>The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=&lt;0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p &lt; 0.0001). Network analysis depicted complex and overlapping relationships between features, akin to the frequent and multifaceted seizures of human LGI1-Ab-E. Orofacial automatisms, mydriasis and temporal lobe localisation were predictive semiological features of feline LGI1-Ab-E.</div></div><div><h3>Significance</h3><div>Feline LGI1-Ab-E represents a clinically distinctive seizure disorder. Our findings highlight the value of studying naturally-occurring, biologically representative animal models which closely mimic human diseases. This bidirectional translational approach confers benefits across species and unites human and veterinary neurology.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 289-296"},"PeriodicalIF":8.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis reveals mechanisms of FMT in Enhancing antidepressant effects of SSRIs","authors":"Ying Jiang ,&nbsp;Lingyi Shi ,&nbsp;Yucai Qu ,&nbsp;Mengmeng Ou ,&nbsp;Zhiqiang Du ,&nbsp;Zhenhe Zhou ,&nbsp;Hongliang Zhou ,&nbsp;Haohao Zhu","doi":"10.1016/j.bbi.2025.02.011","DOIUrl":"10.1016/j.bbi.2025.02.011","url":null,"abstract":"<div><h3>Objective</h3><div>This study explores the behavioral and molecular biological impacts of Fecal Microbiota Transplantation (FMT) on depressive mice unresponsive to treatment with Selective Serotonin Reuptake Inhibitors (SSRIs).</div></div><div><h3>Methods</h3><div>Healthy male C57BL/6 mice were used to establish a depression model through chronic restraint stress, treated with fluoxetine, and categorized into Response and Non-response groups. An FMT treatment was added to the Non-response group. Behavioral tests were conducted to assess symptoms of depression. The gut microbiome, plasma metabolites, and hippocampal tissue gene expression and function changes were analyzed using 16S rRNA gene sequencing, LC-MS, and RNA sequencing.</div></div><div><h3>Results</h3><div>FMT significantly improved the depressive symptoms in SSRIs-resistant mice. There was a partial restoration in the diversity and structure of the gut microbiota in the FMT group. Compared to the Non-response group, significant changes were noted in the metabolomic profiles of the FMT group, identifying various differential metabolites. Functional annotations indicated that these metabolites are involved in multiple metabolic pathways. In the Non-response group, certain gene expression levels were significantly restored. GO and KEGG enrichment analyses revealed that these differential genes mainly involve cytokine activity, receptor signaling regulation, and NOD-like receptor signaling pathways. Joint analysis suggested that FMT may exert its effects through an increase in the abundance of g__Paraprevotella, leading to decreased baicalin content and increased Tal2 expression.</div></div><div><h3>Conclusion</h3><div>FMT has potential in improving depressive symptoms unresponsive to SSRIs treatment. Its mechanism may be related to the modulation of the gut microbiota and its metabolites, subsequently affecting gene expression.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 176-188"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453914","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":"Hippocampal GPR35 is involved in the depression-like behaviors induced by inflammation and mediates the antidepressant effects of fluoxetine in mice","authors":"Xu Kang ,&nbsp;Zhi Xie ,&nbsp;Yan Yang ,&nbsp;Lei Wu ,&nbsp;Heng Xu ,&nbsp;Shuai Zhang ,&nbsp;YuSheng Liang ,&nbsp;Xian Wu","doi":"10.1016/j.bbi.2025.02.010","DOIUrl":"10.1016/j.bbi.2025.02.010","url":null,"abstract":"<div><h3>Background</h3><div>Neuroinflammation plays a pivotal role in the pathogenesis of depression. G protein-coupled receptor 35 (GPR35) is expressed in the brain and plays a role in regulating inflammatory processes. However, its specific role in depression remains unclear. Herein, we investigate the role of GPR35 in depressive behaviors induced by lipopolysaccharide (LPS) in mice.</div></div><div><h3>Methods</h3><div>We employed an LPS-induced depression mouse model and conducted behavioral tests, molecular analyses, and morphological assessments, along with chemogenetic techniques, to investigate the role of GPR35 in depression.</div></div><div><h3>Results</h3><div>Our results showed a significant increase in GPR35 expression in the brain of LPS-treated mice. Both pharmacological inhibition and genetic knockdown of GPR35 alleviated LPS-induced depressive-like behaviors by mitigating neuroinflammation, oxidative stress, synaptic plasticity deficits, and TLR4/NF-κB signaling in mice. Conversely, pharmacological activation of GPR35 notably exacerbated LPS-induced depressive-like behaviors in mice. Additionally, the GPR35 antagonist ML-145 effectively prevented LPS-induced inflammation responses in BV-2 microglia cells. Moreover, fluoxetine treatment effectively mitigated the upregulation of hippocampal GPR35 expression induced by LPS in mice. However, administration of the GPR35 agonist zaprinast reversed the antidepressant effects of fluoxetine. Chemogenetic activation of hippocampal glutamatergic neurons attenuated LPS-induced depression-like behaviors, accompanied by decreased GPR35 expression.</div></div><div><h3>Conclusion</h3><div>Hippocampal GPR35 is closely associated with depressive behaviors in the inflammatory model, highlighting its potential as a therapeutic target for antidepressant drug development.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 189-213"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464582","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":"PARP14 inhibits microglial activation via NNT to alleviate depressive-like behaviors in mice","authors":"Xiaoyu Yu ,&nbsp;Tingting Yang ,&nbsp;Di Wu ,&nbsp;Chenxue Xu ,&nbsp;Zhuoran Li ,&nbsp;Ao Sun ,&nbsp;Shulei Gao ,&nbsp;Heng Li ,&nbsp;Zhenyu Fan ,&nbsp;Rongrong Huang","doi":"10.1016/j.bbi.2025.02.017","DOIUrl":"10.1016/j.bbi.2025.02.017","url":null,"abstract":"<div><div>Microglial inflammation has been implicated in the pathophysiology of major depressive disorder; however, the underlying biological mechanisms remain inadequately understood. Consequently, we conducted a screening of the Poly ADP-ribose (PAR) polymerase (PARP) family expression in the hippocampus of chronic unpredictable stress (CUS) mouse models and investigated the specific role of PARP14 in microglial inflammation and its association with depression. Here, this study demonstrated the elevated PARP14 expression in the hippocampus of CUS mice. The knockdown of PARP14 in the hippocampus did not mitigate depressive-like behaviors in mice, whereas overexpression of PARP14 significantly mitigated these behaviors. Furthermore, PARP14 was abundant in microglia, and microglial-targeted PARP14 overexpression significantly alleviated depressive-behaviors in CUS, reduced microglial activation, and inhibited the central inflammatory responses. Mechanistically, PARP14 positively regulated nicotinamide nucleotide transhydrogenase (NNT) expression in microglia, and the inflammatory response of microglia induced by PARP14 knockdown was suppressed through NNT overexpression. Additionally, deficiency in NNT led to an accumulation of reactive oxygen species (ROS) and subsequent microglial inflammation, which was effectively inhibited by the ROS inhibitor N-Acetylcysteine. These findings suggest that PARP14 alleviates depressive-like behaviors in mice by inhibiting microglial activation via NTT-mediated clearance of ROS.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 235-246"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464491","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 TNIP1 as a new therapeutic avenue for major depressive disorder","authors":"Yi-Yung Hung ,&nbsp;Ching-Yi Tsai ,&nbsp;Chien-Te Lee ,&nbsp;Hung-Chun Fu ,&nbsp;Chen-Kai Chou ,&nbsp;Yi-Chien Yang ,&nbsp;Jia-Feng Chen ,&nbsp;Hong-Yo Kang","doi":"10.1016/j.bbi.2025.02.015","DOIUrl":"10.1016/j.bbi.2025.02.015","url":null,"abstract":"<div><div>TNFAIP3-interacting protein 1 (TNIP1) is a polyubiquitin-binding protein that functions as a negative regulator of NF-κB pathway and alleviates inflammation, but little is known about its role in major depressive disorder (MDD). After discovering an elevated TNIP1 expression in monocytes from individuals with MDD after antidepressant treatment, our analyses further uncovered a significant rise in TNIP1 mRNA expression among patients experiencing remission after antidepressant treatment, particularly in those who received duloxetine. We aimed to explore the potential of TNIP1 as a potential therapeutic target for treatment of MDD. In vitro cell line studies showed that TNIP1 is induced by duloxetine to suppress TNF-α through increasing PPAR-γ receptor expression as anti-inflammatory effects and combined treatment of PPAR-γ agonist pioglitazone and duloxetine exerts synergistic effects on TNIP1 expression. Furthermore, an animal study also demonstrated duloxetine-induced TNIP1 expression in CA3 region of hippocampus, suggesting the TNIP1 expression is up-regulated by antidepressants. We further investigated the potential effect of TNIP1 as a therapeutic target in alleviating depressive-like behavior in chronic mild stress model C57BL/6 mice overexpressing TNIP1 in the hippocampal CA3 region. The results showed that overexpression of TNIP1 in the CA3 region of the hippocampus through cerebral microdialysis significantly reduces depressive-like behavior in mice. In contrast, TNIP1 knockdown in the CA3 region of the hippocampus causes depressive-like behavior and Duloxetine failed to rescue depressive-like behavior in TNIP1-knockdown mice. Together, these data suggest targeting TNIP1 as a novel therapeutic regiment may provide a promising future for pharmacological development of antidepressants in remitting MDD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 214-224"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dectin-1 participates in neuroinflammation and dopaminergic neurodegeneration through synergistic signaling crosstalk with TLR4","authors":"Feng Xue ,&nbsp;Mei Zhang ,&nbsp;Rui-Yue Zhao ,&nbsp;Xiao-Wen Wang ,&nbsp;Yu Gu ,&nbsp;Ye Yang ,&nbsp;Wen-Fang Chen","doi":"10.1016/j.bbi.2025.02.013","DOIUrl":"10.1016/j.bbi.2025.02.013","url":null,"abstract":"<div><div>Neuroinflammation mediated by microglial activation plays a prominent role in the pathogenesis of Parkinson’s disease (PD). Dendritic cell-associated C-type lectin-1 (Dectin-1) is a pattern recognition receptor that is involved in innate immunity. However, the role of Dectin-1 on dopaminergic neuronal damage remains unclear. Our results demonstrated that the expression of Dectin-1 was significantly increased in the microglia of the LPS-induced PD mouse model. Inhibition of Dectin-1 by laminarin (LAM) attenuated LPS-induced dopaminergic neuronal damage in substantia nigra (SN) and behavioral deficits and promoted the phenotypic transformation of microglia from M1 to M2. Moreover, inhibition or knockdown of Dectin-1 significantly decreased LPS-induced phosphorylation of Syk and P65 as well as the production of COX-2 and iNOS in BV2 cells. Knockdown of Syk also significantly decreased LPS-induced protein expressions of COX-2 and iNOS. Mechanistically, both TLR4 inhibitor and NF-κB inhibitor could antagonize LPS-induced Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays showed a physical binding of NF-κB/P65 to Dectin-1 promoter, which further indicated the regulatory effect of toll-like receptor 4 (TLR4)/NF-κB signaling pathway on Dectin-1 expression. Furthermore, the present study provided the first evidence that Dectin-1 activation by hot-alkali treated depleted zymosan <strong>(</strong>d-Zymosan) could induce dopaminergic neurotoxicity and motor dysfunction, and promote up-regulation of TLR4, iNOS and Iba-1 in C57BL/6J mice. In conclusion, Dectin-1-Syk synergistic signaling crosstalk with TLR4/NF-κB promotes and maintains inflammatory phenotypes of M1 microglia which induces dopaminergic neuronal damage in SN. These findings provide novel insights into the pivotal role of Dectin-1 in neuroinflammation, suggesting its potential as a novel therapeutic target for PD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 260-273"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467018","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":"Developmental stage of childhood trauma exposure and markers of inflammation at age 24","authors":"Jennifer Murphy ,&nbsp;Colm Healy ,&nbsp;David Mongan ,&nbsp;Subash R. Susai ,&nbsp;Mary Cannon ,&nbsp;David R. Cotter","doi":"10.1016/j.bbi.2025.02.020","DOIUrl":"10.1016/j.bbi.2025.02.020","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;It is largely unknown whether the specific developmental stage at which childhood trauma occurs is related to inflammatory dysregulation in adulthood. We aimed to explore if trauma exposure at distinct developmental stages in childhood is differentially associated with the novel marker of chronic inflammation − soluble urokinase plasminogen activator receptor (suPAR), as well as with C-Reactive Protein (CRP) and Interleukin-6 (IL-6) levels in early adulthood.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Participants were drawn from the Avon Longitudinal Study of Parents and Children (n = 3272). The trauma variables represent any trauma exposure within early (0–4.9 years), middle (5–10.9 years), or late (11–17 years) childhood, and were derived from the responses to 121 questions collected via standardised questionnaires regarding traumatic experiences including physical abuse, sexual abuse, emotional abuse, emotional neglect, domestic violence, and bullying. Plasma suPAR, CRP and IL-6 samples were collected at age 24. Linear regression models assessed the relationship between trauma exposure at different developmental stages and the inflammatory markers, adjusting for sex, socio-economic status (SES) and child ethnicity. Latent profile analysis (LPA) identified age 24 inflammatory profiles and multinomial logistic regressions identified associations between childhood trauma and these latent groups.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;After adjustment for confounders, late childhood trauma was significantly associated with age 24 suPAR (β = 0.06, 95 % CI [.03, 0.1], p = 0.001), CRP (β = 0.09, 95 % CI [.01, 0.17], p = 0.04) and IL-6 (β = 0.1, 95 % CI [.02, 0.19], p = 0.02). The relationship between late trauma and suPAR survived additional adjustment for prior trauma (β = 0.06, 95 % CI [.01, 0.11], p = 0.03). Middle childhood trauma was significantly associated with IL-6 (β = 0.1, 95 % CI [.02, 0.18], p = 0.02). This attenuated after additionally adjusting for prior trauma (β = 0.11, 95 % CI [-0.09, 0.3], p = 0.29). There was little evidence of an association between early trauma and any inflammatory marker. Exposure to any trauma from 0-17 years was associated with elevated suPAR (β = 0.04, 95 % CI [.005, 0.07], p = 0.025) and IL-6 (β = 0.1, 95 % CI [.02, 0.18], p = 0.02) after adjustment for confounders. Additionally, LPA identified three distinct inflammatory profiles: 1. no inflammatory dysregulation; 2. elevated CRP and IL-6 levels; and 3. a high inflammatory group characterised by elevated levels of suPAR, CRP and IL-6. After adjustment for confounders, individuals with trauma either in early (RR = 2.31, 95 % CI [1.16, 4.6], p = 0.017), middle (RR = 2.72, 95 % CI [1.4, 5.29], p = 0.003) or late (RR = 3.37, 95 % CI [1.7, 6.64], p &lt; 0.001) childhood had an increased risk of being in the high inflammatory group. The association between late childhood trauma and this high inflammatory group survived adjustment for prior t","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 225-234"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hormonal contraceptives in adolescence impact the neuroimmune environment of the medial prefrontal cortex and hippocampus in female rats","authors":"Rachel A. Gilfarb ,&nbsp;Sanjana Ranade ,&nbsp;Elizabeth Dybas ,&nbsp;Abigail Biddle ,&nbsp;Meredith Stewart ,&nbsp;Abhishek Rajesh ,&nbsp;Benedetta Leuner ,&nbsp;Kathryn M. Lenz","doi":"10.1016/j.bbi.2025.02.016","DOIUrl":"10.1016/j.bbi.2025.02.016","url":null,"abstract":"<div><div>Adolescence is a period of protracted neurodevelopment, during which the prefrontal cortex (PFC) undergoes significant remodeling. Microglia are integral to neurodevelopment and are sensitive to gonadal hormones, which increase during adolescence. Microglia and gonadal hormones can interact to influence adolescent development of the PFC (or medial prefrontal cortex [mPFC] in rodents). In females, gonadal hormones can be perturbed by using hormonal contraceptives (HCs). We predicted that HC administration over adolescence could affect microglia, other immunocompetent cells, and the neuroimmune environment of the developing mPFC. We also assessed HC effects on neuroimmune measures in the hippocampus, as the hippocampus also matures throughout adolescence and is sensitive to ovarian hormones. Intact post-pubertal female Sprague-Dawley rats received daily subcutaneous injections of vehicle or 10 ug ethinyl estradiol + 20 ug levonorgestrel (HCs) throughout adolescence from postnatal day (PND) 35–56. On PND 57 or 58, brains were collected for immunohistochemistry and qPCR. In the mPFC, HC-treated rats showed less Iba1 (microglia) immunolabeling and fewer Iba1⁺ cells. HC treatment also altered microglia morphology and reduced the spacing between microglia in the mPFC. In the hippocampus, HC-treated rats had reduced Iba1 immunolabeling in the dorsal CA1 and reductions in microglial cell complexity in dorsal CA1, ventral CA1, and ventral CA3. There were no effects of HCs on GFAP (astrocyte) immunolabeling in the mPFC or on astrocytes in any hippocampal subregion analyzed, except an increase in astrocyte number in the dorsal dentate gyrus. mPFC expression of genes related to phagocytosis (<em>Cd68, Trem2</em>) and neuroimmune signaling (<em>Cx3cr1, Cx3cl1</em>) were reduced in rats treated with HCs, but no gene expression changes were seen in the hippocampus. These data provide the first evidence that HCs given during the critical developmental period of adolescence can affect microglia properties in limbic brain regions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"127 ","pages":"Pages 315-328"},"PeriodicalIF":8.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467019","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":"Serum metabolites and inflammation predict brain functional connectivity changes in Obsessive-Compulsive disorder","authors":"Guoqing Chen ,&nbsp;Xiao Zhao ,&nbsp;Minyao Xie ,&nbsp;Haocheng Chen ,&nbsp;Chenchen Shao ,&nbsp;Xuedi Zhang ,&nbsp;Yu Wu ,&nbsp;Na Liu ,&nbsp;Ning Zhang","doi":"10.1016/j.bbi.2025.01.013","DOIUrl":"10.1016/j.bbi.2025.01.013","url":null,"abstract":"<div><div>Currently, our understanding of the metabolic and immune pathways involved in obsessive–compulsive disorder (OCD), as well as the precise mechanisms by which metabolism and immunity impact brain activity and function, is limited. This study aimed to examine the alterations in serum metabolites, inflammatory markers, brain activity, and brain functional connectivity (FC) among individuals with OCD and investigate the relationship between these factors. The study included 55 individuals with moderate-to-severe OCD (either drug-naïve or not taking medication for at least eight weeks) and 54 healthy controls (HCs). The High-Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS) technique was used to detect serum metabolites, whereas the enzyme-linked immunosorbent assay (ELISA) was utilized to identify inflammatory markers. The FC of the brain was investigated using resting-state functional magnetic resonance immaging(rs-fMRI). The findings demonstrated that individuals with OCD exhibited significant alterations in 11 metabolites compared to HCs. In particular, 10 of these metabolites exhibited an increase, while one metabolite displayed a decrease. Additionally, individuals with OCD experienced a marked elevation in the levels of five inflammatory factors (TNF-α, IL-1β, IL-2, IL-6, and IL-12). Rs-fMRI analysis revealed that individuals with OCD exhibited atypical FC in various brain regions, such as the postcentral gyrus, angular gyrus, and middle temporal gyrus. These specific brain areas are closely associated with sensory-motor processing, cognitive control, and emotion regulation. Further stepwise multiple regression analysis revealed that serum metabolite levels, particularly phosphatidylcholine, and inflammatory markers such as IL-1β could predict alterations in brain FC among individuals diagnosed with OCD. In summary, this study uncovered that individuals with OCD exhibit alterations in serum metabolites, inflammatory markers, brain activity, and FC. The findings suggest that these metabolites and inflammatory markers might play a role in the development and progression of OCD by affecting brain activity and the FC of neural networks.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"126 ","pages":"Pages 113-125"},"PeriodicalIF":8.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419509","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}