Brain, Behavior, and Immunity最新文献

{"title":"Loss of TLR4 on CRH neurons instead of OXT neurons in PVN induces anxiety-like behavior and obesity in mice","authors":"Shuqing Zhu ,&nbsp;Ying Zhou ,&nbsp;Ziyuan Ye ,&nbsp;Meng Sun ,&nbsp;Gang Shu ,&nbsp;Songbo Wang ,&nbsp;Qingyan Jiang ,&nbsp;Lina Wang","doi":"10.1016/j.bbi.2026.106469","DOIUrl":"10.1016/j.bbi.2026.106469","url":null,"abstract":"<div><div>Toll-like receptor 4 (TLR4) is a pattern recognition receptor involved in innate immune responses; it is widely expressed on microglia in the central nervous system and is involved in inflammatory responses. However, recent studies have shown that TLR4 is expressed on various types of neurons and participates in emotion regulation. CRH neurons and OXT neurons, two key neurons in the paraventricular nucleus (PVN) that regulate anxiety, have been widely studied. Here, we revealed that TLR4 is involved in anxiety regulation in the PVN and that knocking out PVN-TLR4 significantly increased anxiety-like behaviors in male and female mice. Furthermore, PVN^{CRH-TLR4 KO} significantly increased anxiety-like behavior and induced obesity in mice, whereas PVN^{OXT-TLR4 KO} had no significant effect on anxiety or obesity. We found that the absence of TLR4 significantly reduces the activity of CRH neurons and that the downstream nuclear projection of PVN-CRH neurons to the medial supramammillary nucleus (SuMM) is key to regulating anxiety. Activating the CRH projection SuMM circuit can significantly reverse anxiety-like behaviors in mice. Our research suggests that TLR4 deficiency in CRH neurons in the paraventricular nucleus, rather than in OXT neurons, is responsible for inducing anxiety and obesity, whereas inhibition of the CRH projection SuMM circuit is key to generating anxiety.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106469"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075712","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":"Lymphocyte-based inflammatory biomarkers during the postpartum period and postpartum depression symptoms in U.S. women","authors":"Kaipeng Xie","doi":"10.1016/j.bbi.2026.106466","DOIUrl":"10.1016/j.bbi.2026.106466","url":null,"abstract":"<div><h3>Background</h3><div>Postpartum depression (PPD) has multiple cascading negative effects on maternal and infant health. Inflammation is a potential factor for the development of PPD. However, lymphocyte-based inflammatory biomarkers, including platelet-to-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR), and PPD remains understudied, especially in U.S. women.</div></div><div><h3>Methods</h3><div>We conducted a cross-sectional study based on the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2020 pre-pandemic data. Based on demographics and reproductive questionnaires, two strategies were employed to include eligible postpartum women. PPD symptoms were assessed using the PHQ-9 questionnaire. Weighted logistic regression models, restricted cubic spline (RCS) models, eXtreme Gradient Boosting (XGBoost) machine learning (ML) model, subgroup analysis and sensitivity analyses were performed to analyze the relationships between these biomarkers and PPD symptoms.</div></div><div><h3>Results</h3><div>A total of 1,361 postpartum women within the 3-year postpartum period based on strategy 1, and 762 women ranges from one to twenty-eight months postpartum based on strategy 2 were included in analyses. After adjusted for all covariates, PLR during the postpartum period was significantly associated with the reduced risk of PPD symptoms based on both strategies (OR = 0.49, 95% CI: 0.26–0.94, <em>P</em> = 0.033; OR = 0.30, 95% CI: 0.15–0.60, <em>P</em> &lt; 0.001). There was a non-linear relationship between PLR and the risk of PPD symptoms (<em>P</em>-non-linear = 0.011, <em>P</em>-non-linear = 0.001). ML revealed PLR as one important variable for PPD symptoms. Interestingly, postpartum time modified the association between PLR and PPD symptoms (<em>P</em> for interaction = 0.026). The association was significant in women within 12 months postpartum (OR = 0.23, 95% CI: 0.11–0.49, <em>P</em> &lt; 0.001) but not in women with beyond 12 months postpartum. Sensitivity analyses validated the robustness of our findings.</div></div><div><h3>Conclusions</h3><div>PLR during the postpartum period is an independent risk factor for PPD symptoms in U.S. women, exhibiting its potential as a novel marker for PPD symptoms.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106466"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075713","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":"From non-specific biomarker to targeted action: transdiagnostic and sex-specific drivers of high-CRP status in severe mental illness across the FondaMental Advanced Centers of Expertise (FACE) cohorts","authors":"Tim Rietberg ,&nbsp;Susana Barbosa ,&nbsp;Pieter Meysman ,&nbsp;Bruno Aouizerate ,&nbsp;Frank Bellivier ,&nbsp;Fabrice Berna ,&nbsp;Delphine Capdevielle ,&nbsp;Isabelle Chereau ,&nbsp;Philippe Courtet ,&nbsp;Clément Dondé ,&nbsp;Caroline Dubertret ,&nbsp;Bruno Etain ,&nbsp;Wissam El Hage ,&nbsp;Mona Gerentes ,&nbsp;Jérôme Holtzmann ,&nbsp;Eric Fakra ,&nbsp;Emmanuel Haffen ,&nbsp;Noomane Bouaziz ,&nbsp;Antoine Lefrere ,&nbsp;Pierre-Michel Llorca ,&nbsp;Ophélia Godin","doi":"10.1016/j.bbi.2026.106464","DOIUrl":"10.1016/j.bbi.2026.106464","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Low-grade systemic inflammation contributes to the pathophysiology of severe mental illness (SMI) in a substantial subset of patients, who often experience greater disease burden and poorer treatment response. Elevated C-reactive protein (CRP), defined as CRP ≥ 3 mg/L, has been proposed to identify this group, but its non-specificity limits the biomarker’s ability to guide targeted intervention. We aimed to determine the most consistent drivers of high CRP across bipolar disorder (BD), schizophrenia (SZ) and major depressive disorder (MDD), and to translate these into clinically actionable intervention targets using robust data-driven methods.</div></div><div><h3>Methods</h3><div>We pooled and harmonised data from three large French national SMI cohorts (n = 7149: 4797 bipolar disorder, 1958 schizophrenia and 394 resistant major depression) and classified participants by CRP ≥ 3 mg/L, as well as an alternative cut-off of 5 mg/L. We applied penalised logistic regression (PLR), random forests (RF) and unsupervised clustering, using 28 biopsychosocial variables to identify robust drivers of high-CRP status. We then grouped these into actionable targets and assessed relative dominance.</div></div><div><h3>Results</h3><div>In total, 30.16% of participants had CRP ≥ 3 mg/L. PLR identified female sex (OR [95% CI]: 1.60 [1.27, 1.93]), higher BMI (OR: 1.09 [1.07, 1.13]), current nicotine dependence (OR: 1.05 [1.02, 1.09]), lower HDL cholesterol (OR: 0.57 [0.44, 0.73]) and smoking (ex-smoker status OR: 0.84 [0.66, 0.98]) as consistent drivers. RF highlighted a similar set of key drivers, also including waist circumference, triglycerides and cardiovascular comorbidities. Clustering of the high-CRP group was almost entirely driven by smoking status and nicotine dependence. When grouped into actionable targets, the identified drivers accounted for 16% of variance in CRP status, with obesity emerging as most dominant contributor. This pattern was most pronounced in females; in males it was more diffuse, with a more prominent role for smoking.</div></div><div><h3>Conclusions</h3><div>We propose a decision tree framework where CRP can serve as a first-line screening marker for inflammation in SMI, with subsequent steps focusing on the main contributing factors to guide targeted interventions. Priority should be given to targeting obesity and metabolic dysregulation. Among females, hyperuricemia represents the next most appropriate target, whereas in males, smoking warrants greater attention. This stepwise approach provides a route from a non-specific biomarker to targeted treatment strategies and should be validated in prospective studies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106464"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100109","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":"Multimodal imaging suggests potential immune-vascular contributions to altered regional brain perfusion and oxygen metabolism in Post-COVID-19 Syndrome","authors":"Daniel Martins ,&nbsp;Matthew Burrows ,&nbsp;Owen O’ Daily ,&nbsp;Ziyuan Cai ,&nbsp;Nicole Mariani ,&nbsp;Alessandra Borsini ,&nbsp;Valeria Mondelli ,&nbsp;Brandi Eiff ,&nbsp;Silvia Rota ,&nbsp;Timothy Nicholson ,&nbsp;Laila Rida ,&nbsp;Adam Hampshire ,&nbsp;Federico Turkheimer ,&nbsp;Catherine Morgan ,&nbsp;David J. Lythgoe ,&nbsp;Steven C.R. Williams ,&nbsp;Fernando Zelaya","doi":"10.1016/j.bbi.2026.106480","DOIUrl":"10.1016/j.bbi.2026.106480","url":null,"abstract":"<div><div>Post-COVID-19 Syndrome (PCS) frequently presents with persistent fatigue, cognitive impairment, and emotional symptoms. Although structural brain changes remain subtle, growing evidence implicates functional and metabolic disruptions in ongoing symptomatology. We used multimodal MRI to investigate cerebral perfusion and oxygen metabolism in PCS and examined their associations with cognitive function and peripheral biomarkers. We enrolled 40 individuals with prior mild SARS-CoV-2 infection, including 20 with persistent fatigue and 20 recovered controls matched for age, sex, BMI, and acute COVID-19 severity. Participants underwent structural MRI, arterial spin labelling (ASL) to quantify regional cerebral blood flow (CBF), and asymmetric spin echo imaging to estimate oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO₂). We assessed cognition using an online battery and measured serum levels of TNF-α, IL-6, IL-8, IL-13, IFN-γ, GFAP, and S100β, alongside blood routine tests. We performed ANCOVAs on predefined regions of interest (hippocampus, anterior cingulate cortex [ACC], insula, amygdala, striatum), followed by Bayesian inference and exploratory whole-brain analyses. PCS participants showed increased CMRO₂ in the hippocampus and decreased CMRO₂ in the ACC. Subfield analysis revealed elevated OEF and CMRO₂ across most hippocampal regions, excluding the entorhinal cortex. Whole-brain analyses identified increased perfusion in salience-related regions (insula, ACC, thalamus) and decreased perfusion in posterior cortical and cerebellar areas, in the absence of grey matter volume differences. Higher hippocampal metabolism positively correlated with cognitive performance, suggesting compensatory adaptation to sustain function. In contrast, lower ACC CMRO₂ correlated with depressive symptoms, reduced motivation, and elevated TNF-α and GFAP, consistent with neurovascular uncoupling possibly driven by immune-glial activation. These findings reveal distinct physiological disruptions in PCS, with potential implications for stratified, metabolism-focused interventions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106480"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164179","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":"Obesity, low-grade inflammation, and inflammatory response to immune challenge modulate willingness to expend effort for reward","authors":"Iris Ka-Yi Chat ,&nbsp;Lina S Hansson ,&nbsp;Mats Lekander ,&nbsp;Charlotta Jacobsen ,&nbsp;Sven Benson ,&nbsp;Johannes Hebebrand ,&nbsp;Vera Bender ,&nbsp;Analena Handke ,&nbsp;Till Hasenberg ,&nbsp;Michael Treadway ,&nbsp;Harald Engler ,&nbsp;Robert Dantzer ,&nbsp;Manfred Schedlowski ,&nbsp;Julie Lasselin","doi":"10.1016/j.bbi.2026.106548","DOIUrl":"10.1016/j.bbi.2026.106548","url":null,"abstract":"<div><h3>Background</h3><div>Inflammation is increasingly considered a vulnerability factor for deficits in reward motivation. It remains unclear if such motivational changes differ between acute and chronic low-grade inflammation. Given obesity’s link to chronic low-grade inflammation, the present study <em>a priori</em> tested the effects of obesity and low-grade inflammation (elevated CRP concentrations), as well as acute inflammation (experimental immune challenge using lipopolysaccharide), on motivation for a monetary reward. Moreover, the wear-and-tear induced by chronic inflammation could amplify motivational changes induced by immune challenge. Thus, we also tested the <em>a priori</em> hypotheses that acute inflammation is associated with more strongly altered reward motivation for individuals with higher low-grade inflammation, and for obese than normal-weight individuals.</div></div><div><h3>Methods</h3><div>Obese (n = 14) and normal-weight (n = 21) young adults, all without current or past history of medical or psychiatric conditions, were intravenously injected with a bacterial endotoxin (lipopolysaccharide, LPS [0.8 ng/kg body weight]) to trigger an acute inflammatory response, and placebo (saline) in a counterbalanced, randomized, crossover design. The Effort Expenditure for Reward Task (EEfRT) was administered 2 h following each injection to assess reward motivation. Blood was sampled pre- and post-injection to quantify concentrations of inflammatory proteins (interleukin [IL]-6 and C-reactive protein [CRP]).</div></div><div><h3>Results</h3><div>Obesity and higher low-grade inflammation (baseline CRP) were associated with overall reduced motivation to expend effort for reward in the placebo condition. Interactions with reward magnitude were observed, so that this effect occurred at smaller reward values, but not when reward values increased. However, these interaction effects were not significant in <em>a posteriori</em> sensitivity analyses. LPS-induced inflammatory responses (IL-6 concentrations during EEfRT) were associated with a weaker influence of reward magnitude on increasing effort. Unexpectedly, we did not detect the amplification effect of obesity and its associated low-grade inflammation on the ability of lipopolysaccharide to modulate reward motivation.</div></div><div><h3>Conclusions</h3><div>Lipopolysaccharide-induced and low-grade inflammation may alter how effort is allocated towards reward: low-grade inflammation reduced the willingness to expend effort, while acute inflammation dampened reward sensitivity. This study offers a nuanced understanding of inflammatory processes underlying alterations in reward motivation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"136 ","pages":"Article 106548"},"PeriodicalIF":7.6,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462644","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":"Neural mechanisms of mindfulness: reduced neural reactivity to social-evaluative threat accounts for mindfulness intervention effects on inflammatory gene expression","authors":"R.B. Blades ,&nbsp;C.C. Boyle ,&nbsp;N.I. Eisenberger ,&nbsp;S.W. Cole ,&nbsp;J.R.T. Korecki ,&nbsp;A.J. Fuligni ,&nbsp;J.E. Bower","doi":"10.1016/j.bbi.2026.106284","DOIUrl":"10.1016/j.bbi.2026.106284","url":null,"abstract":"<div><div>Mindful awareness redirects attention toward the present moment, which may reduce threat-related neural activity and downstream inflammation in response to stress. Social-evaluative threat, where the self is negatively judged by others, is a stressor with potent inflammatory consequences. As part of a randomized controlled trial (NCT05304052), the current study tested whether a mindfulness intervention reduced neural reactivity to social-evaluative threat and reduced downstream pro-inflammatory signaling. Healthy young adults were randomly assigned to a waitlist control group (n = 23) or a 6-week mindfulness intervention (Mindful Awareness Practices; MAPs; n = 26) that has previously been shown to reduce stress and inflammation. Pre- and post-intervention, we collected blood samples and BOLD neuroimaging data during a social-evaluative threat task (modified Montreal Imaging Stress Task; MIST), focusing on activity in three threat-related neural regions: amygdala, dorsal anterior cingulate cortex, and anterior insula. Leukocyte genome-wide RNA profiles were analyzed using promoter-based bioinformatic analyses to infer NF-κB transcription factor activity, a canonical pro-inflammatory signaling pathway. Relative to waitlist control, the MAPs intervention led to reductions in neural threat reactivity. MAPs also reduced NF-κB activity relative to the control condition, and this effect was no longer significant when controlling for changes in neural threat reactivity. Results suggest that reductions in threat-related neural activity may contribute to the beneficial effects of mindfulness on inflammation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106284"},"PeriodicalIF":7.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973184","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":"Metabolomic signatures of electroconvulsive therapy in schizophrenia: Mitochondrial energy metabolism and inflammation as therapeutic targets","authors":"Yan Li ,&nbsp;Guangfa Wang ,&nbsp;Xinyu Fang ,&nbsp;Yuru Ling ,&nbsp;Chao Zhou ,&nbsp;Jin Fang ,&nbsp;Renliang Cai ,&nbsp;Yunshan Hu ,&nbsp;Chaoran Wu ,&nbsp;Shaotong Zhang ,&nbsp;Ayesha Zafar Iqbal ,&nbsp;Yu Wang ,&nbsp;Kuan-Pin Su ,&nbsp;Xiangrong Zhang","doi":"10.1016/j.bbi.2025.106235","DOIUrl":"10.1016/j.bbi.2025.106235","url":null,"abstract":"<div><h3>Background</h3><div>Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.</div></div><div><h3>Methods</h3><div>We conducted untargeted metabolomics analyses (GC–MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.</div></div><div><h3>Results</h3><div>Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.</div></div><div><h3>Conclusions</h3><div>This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT’s therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106235"},"PeriodicalIF":7.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809675","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":"Deletion of the microglial phagocytic receptor MerTK mimics early-life adversity-induced changes in synapses and behavior in male mice","authors":"Madison M. Garvin ,&nbsp;Urjoshi Kar ,&nbsp;Cassandra L. Kooiker ,&nbsp;Jessica L. Bolton","doi":"10.1016/j.bbi.2025.106246","DOIUrl":"10.1016/j.bbi.2025.106246","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Early-life adversity (ELA) is a significant risk factor for emotional disorders like depression, likely due to changes in stress-related circuit development. We have previously shown that ELA increases the number of excitatory synapses onto corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus (PVN) by decreasing microglial synapse engulfment. Here, we hypothesize that ELA induces microglial dysfunction via inhibition of the microglial phagocytic receptor, MerTK, thus resulting in the observed changes in synapses and stress-related behavior. To determine whether deleting MerTK in microglia phenocopies the effects of ELA, microglia-specific conditional knockout (m)MerTK-KO (CX3CR1-Cre&lt;sup&gt;+&lt;/sup&gt;::MerTK&lt;sup&gt;fl/fl&lt;/sup&gt;) mice were crossed with ‘wild-type’ (CX3CR1-Cre&lt;sup&gt;-&lt;/sup&gt;::MerTK&lt;sup&gt;fl/fl&lt;/sup&gt;) mice, and their litters were reared in either a control or ELA (induced by limited bedding and nesting) environment, from postnatal days (P)2–10. Excitatory synapses in the PVN were assessed at P10, microglial engulfment was assessed at P8, and adult offspring were tested in a behavioral battery to measure threat-response (known to be dependent on PVN-CRH+ neurons) and anxiety-like behavior, followed by acute restraint stress to measure the neuroendocrine stress response. Following ELA at P10, we find that excitatory, but not inhibitory, synapses in the PVN are increased in males, which is mimicked by mMerTK-KO in control males, but causes no further increase in ELA males. Correspondingly, ELA and mMerTK-KO decrease microglial engulfment of excitatory presynaptic terminals at P8 in males. In contrast, females already have higher numbers of excitatory synapses at baseline, and exhibit no further increase with ELA or mMerTK-KO. Remarkably, the pattern of threat-response behavior in males closely matches the excitatory synapses, with mMerTK-KO control males escaping more from the simulated predator threat in the looming-shadow threat task, similar to ELA males. Again, females do not show any significant changes due to ELA or mMerTK-KO in the threat-response, although they do exhibit ELA-induced changes in anxiety-like behavior. ELA provokes a greater corticosterone response to acute stress in males, but not females, although females were again already higher at baseline. In sum, our results demonstrate that ELA provokes decreased microglial engulfment during development, leading to increased excitatory synapses in the PVN and an increased active response to threat in the looming-shadow test in males only. Deleting MerTK specifically from microglia recapitulates both the synaptic and behavioral effects in control males, but does not have an effect in ELA males or control females, suggesting that the MerTK pathway is already inhibited by ELA in males and less active in females at baseline. Our work is the first to elucidate the mechanisms underlying the male-biased microglial dysfunction caused by ELA, with prom","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106246"},"PeriodicalIF":7.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846487","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":"C-reactive protein levels and behavioural outcomes in mid-childhood in very preterm and term born children","authors":"Ira Kleine ,&nbsp;Alexandria O’Reilly Mescall ,&nbsp;Laila Hadaya ,&nbsp;Zeyuan Sun ,&nbsp;Naghmeh Nikkheslat ,&nbsp;Andrew Lawrence ,&nbsp;Emily Simonoff ,&nbsp;Serena Counsell ,&nbsp;Paola Dazzan ,&nbsp;A David Edwards ,&nbsp;Carmine Pariante ,&nbsp;Chiara Nosarti","doi":"10.1016/j.bbi.2025.106213","DOIUrl":"10.1016/j.bbi.2025.106213","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Preterm birth has been associated with long-term physical, cognitive, behavioural and emotional challenges. Preterm infants are often exposed to significant inflammation in early life, which has been studied in relation to adverse neurodevelopmental outcomes. In later childhood, inflammation has been associated with psychiatric symptoms. However, the developmental processes underlying the association between inflammation and mental health outcomes, particularly in preterm children, are not fully understood. We aimed to investigate the association between inflammation and behavioural outcomes in mid-childhood in preterm- and term-born children.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This study used data collected as part of the Brain, Immunity and Psychopathology following very Preterm Birth (BIPP) study, a prospective cohort study assessing very preterm-born (&lt;33 weeks’ gestation) and term-born children at a median age of 9.2 years (range 7.0 – 13.7 years). Children received behavioural and cognitive assessments and provided saliva samples for C-reactive protein (CRP) analysis as a marker of chronic inflammation. Clinical neonatal discharge summaries were available for the very preterm participants, from which a perinatal inflammatory risk score was devised. Missing behavioural and cognitive outcome scores were imputed. Generalised linear mixed models were used to test the association between CRP or perinatal inflammatory risk score and each behavioural/cognitive outcome variable in turn, controlling for age, sex, neighbourhood deprivation, ethnicity and prematurity. In models that showed an effect of CRP, the interaction between prematurity and CRP was also examined.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Participants were 264 children (n = 195 very preterm and n = 69 control). After excluding participants with high salivary CRP levels (predicted serum CRP &gt; 10 mg/L), indicative of acute infection/inflammation (n = 3), 202 children had complete salivary CRP data: 47.9 % were male. There was no significant difference in salivary CRP value in mid-childhood between very preterm and term participants. When controlling for covariates, neither very preterm birth nor perinatal inflammatory risk score were associated with salivary CRP level in mid-childhood. Salivary CRP in mid-childhood was associated with lower externalising symptoms (B = -0.26, p = 0.037) and higher anxiety symptoms (B = 0.06, p = 0.022). Perinatal inflammatory risk score was not associated with behavioural or cognitive outcome measures.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;We show no evidence that prematurity or perinatal inflammation are associated with salivary CRP in mid-childhood, nor that perinatal inflammatory insults are related to later behavioural outcomes in our cohort of preterm children. Our findings support an association between salivary CRP and behavioural outcomes in mid-childhood. Further research is needed to understand the interpl","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106213"},"PeriodicalIF":7.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707435","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":"Cytokines, Somatosensory Functioning, and Psychological Distress in Post-Breast Cancer Surgery Pain: A longitudinal study","authors":"Amber De Groote ,&nbsp;Mira Meeus ,&nbsp;Lenny Coppens ,&nbsp;Samir Kumar-Singh ,&nbsp;Lore Dams ,&nbsp;Jade Mosselmans ,&nbsp;Wiebren Tjalma ,&nbsp;An De Groef ,&nbsp;Mertens Michel GCAM","doi":"10.1016/j.bbi.2026.106281","DOIUrl":"10.1016/j.bbi.2026.106281","url":null,"abstract":"<div><div>Approximately 40% of breast cancer (BC) patients experience pain during a curative treatment episode. While the biological impact of surgery and adjuvant therapies is central to pain onset, patients’ pain intensity and persistence are further shaped by its interplay with psychosocial factors. Here we explored cytokine levels, somatosensory functioning, and psychological distress as biomarkers for pain in BC patients at one and three months post-surgery. Specifically, we compared these factors in BC patients with and without pain at both time points and examined their associations with pain intensity and their change over time (delta pain).</div><div>Thirty-seven BC patients were measured at one and three months post-surgery. Pain intensity was assessed using the Visual Analogue Scale. Fifty-six cytokines were measured using a multiplex electrochemiluminescence-based immunoassay, somatosensory functioning through quantitative sensory testing, including thermal detection and pain thresholds, conditioned pain modulation, and temporal summation, and psychological distress (i.e., pain catastrophizing, depression, anxiety, stress, resilience, positive and negative affect) using validated questionnaires. Group comparisons and correlation analyses were conducted between these biopsychosocial factors and (delta) pain intensity.</div><div>Patients in the pain group displayed higher warmth detection thresholds at the tibialis anterior muscle at both time points. At three months post-surgery, nine cytokines, anxiety and pain catastrophizing were elevated in the pain group. Correlation analysis showed that seven out of the nine elevated cytokines and anxiety positively correlated with pain intensity at three months post-surgery, supporting their potential as candidate biomarkers. Furthermore, Interleukin (IL)-17f, IL-22, IL-33, and granulocyte colony-stimulating factor (at one month) and C-reactive protein (at three months post-surgery) were positively correlated with delta pain intensity. Our findings support novel cytokine candidates for future research.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106281"},"PeriodicalIF":7.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988335","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}