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.
正念意识将注意力重定向到当下，这可能会减少与威胁相关的神经活动和下游炎症反应。社会评价性威胁，即自我受到他人的负面评价，是一种具有强烈炎症后果的压力源。作为一项随机对照试验（NCT05304052）的一部分，目前的研究测试了正念干预是否会降低神经对社会评价威胁的反应性，并减少下游的促炎信号。健康的年轻人被随机分配到等候名单控制组（n = 23）或为期6周的正念干预组（正念意识练习；MAPs; n = 26），这两组先前已被证明可以减轻压力和炎症。在干预前和干预后，我们在社会评估威胁任务（改进的蒙特利尔成像压力任务；MIST）中收集了血液样本和BOLD神经成像数据，重点关注三个与威胁相关的神经区域的活动：杏仁核、背前扣带皮层和前叶岛。使用基于启动子的生物信息学分析来分析白细胞全基因组RNA谱，以推断NF-κB转录因子活性，这是一个典型的促炎症信号通路。与等候名单对照相比，MAPs干预导致神经威胁反应的减少。与对照组相比，MAPs还降低了NF-κB的活性，在控制神经威胁反应的变化时，这种效果不再显著。结果表明，减少与威胁相关的神经活动可能有助于正念对炎症的有益影响。
{"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 , C.C. Boyle , N.I. Eisenberger , S.W. Cole , J.R.T. Korecki , A.J. Fuligni , 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":"2026-01-12","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bbi.2026.106277
Meiqin Li , Gaopeng Guan , Xin Li , Dingquan Zou , Wei Zhang , Kai Chen , Yanying Xiao , Yaping Wang , Meng Wang
Background
The trigeminal ganglion (TG) is a central hub for craniofacial injurious messaging, and its abnormal function is closely related to the pathogenesis of trigeminal neuralgia (TN). Bone morphogenetic protein 7 (BMP7), a pleiotropic cytokine with both neuroprotective and anti-inflammatory effects, has been shown to have therapeutic potential for neuropathic pain (NP) and neurodegenerative diseases. However, it remains to be elucidated whether BMP7 is involved in the pathological process of TN through the regulation of TG.
Objective
This study aimed to investigate whether BMP7 alleviates TN by modulating oxidative stress and activation in satellite glial cells (SGCs) of the TG.
Methods
A rat model of TN was established by chronic constriction injury of the distal infraorbital nerve (CCI-dION). Primary rat SGCs were activated with IL-1β to create an in vitro model. The role of BMP7 in regulating oxidative stress was assessed through in vivo knockdown and in vitro overexpression experiments. The NRF2 inhibitor ML385 was employed to validate the essential role of the NRF2/HO-1 pathway in BMP7-mediated SGC functional modulation.
Results
Following successful CCI-dION model establishment, TN rats showed significantly reduced mechanical pain thresholds, aggravated cold allodynia, and increased spontaneous pain behaviors, accompanied by decreased BMP7 expression, enhanced SGC activation, and elevated ROS levels in TG. These pathological phenotypes were consistently reproduced in BMP7-knockdown rats. In IL-1β-stimulated SGCs, BMP7 silencing mimicked pathological changes, while BMP7 overexpression reversed IL-1β effects − a rescue blocked by ML385. Critically, in vivo BMP7 overexpression attenuated CCI-dION-induced pain, oxidative stress, and SGC activation.
Conclusion
This study demonstrates that BMP7 alleviates TN by suppressing oxidative stress and activation of SGCs through activation of the NRF2/HO-1 pathway, highlighting its therapeutic potential for TN treatment.
{"title":"BMP7 alleviates trigeminal neuralgia by suppressing oxidative stress and activation of satellite glial cells via the NRF2/HO-1 pathway","authors":"Meiqin Li , Gaopeng Guan , Xin Li , Dingquan Zou , Wei Zhang , Kai Chen , Yanying Xiao , Yaping Wang , Meng Wang","doi":"10.1016/j.bbi.2026.106277","DOIUrl":"10.1016/j.bbi.2026.106277","url":null,"abstract":"<div><h3>Background</h3><div>The trigeminal ganglion (TG) is a central hub for craniofacial injurious messaging, and its abnormal function is closely related to the pathogenesis of trigeminal neuralgia (TN). Bone morphogenetic protein 7 (BMP7), a pleiotropic cytokine with both neuroprotective and anti-inflammatory effects, has been shown to have therapeutic potential for neuropathic pain (NP) and neurodegenerative diseases. However, it remains to be elucidated whether BMP7 is involved in the pathological process of TN through the regulation of TG.</div></div><div><h3>Objective</h3><div>This study aimed to investigate whether BMP7 alleviates TN by modulating oxidative stress and activation in satellite glial cells (SGCs) of the TG.</div></div><div><h3>Methods</h3><div>A rat model of TN was established by chronic constriction injury of the distal infraorbital nerve (CCI-dION). Primary rat SGCs were activated with IL-1β to create an <em>in vitro</em> model. The role of BMP7 in regulating oxidative stress was assessed through <em>in vivo</em> knockdown and <em>in vitro</em> overexpression experiments. The NRF2 inhibitor ML385 was employed to validate the essential role of the NRF2/HO-1 pathway in BMP7-mediated SGC functional modulation.</div></div><div><h3>Results</h3><div>Following successful CCI-dION model establishment, TN rats showed significantly reduced mechanical pain thresholds, aggravated cold allodynia, and increased spontaneous pain behaviors, accompanied by decreased BMP7 expression, enhanced SGC activation, and elevated ROS levels in TG. These pathological phenotypes were consistently reproduced in BMP7-knockdown rats. In IL-1β-stimulated SGCs, BMP7 silencing mimicked pathological changes, while BMP7 overexpression reversed IL-1β effects − a rescue blocked by ML385. Critically, <em>in vivo</em> BMP7 overexpression attenuated CCI-dION-induced pain, oxidative stress, and SGC activation.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that BMP7 alleviates TN by suppressing oxidative stress and activation of SGCs through activation of the NRF2/HO-1 pathway, highlighting its therapeutic potential for TN treatment.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106277"},"PeriodicalIF":7.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984470","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bbi.2026.106285
Tahani Alshehri , Yumeng Tian , Ruifang Li-Gao , Jeroen van der Velde , Saskia le Cessie , Frits R. Rosendaal , Brenda W.J.H. Penninx , Yuri Milaneschi , Dennis O. Mook-Kanamori
Background
Our study aimed to investigate the association of depressive mood and two depressive symptom profiles with the risk of cardiometabolic diseases (CMD) and to explore the underlying mechanisms of these associations through CMD-related metabolites and proteins.
Methods
In the Netherlands Epidemiology of Obesity study, depressive mood was measured with the Inventory of Depressive Symptomatology questionnaire, and two depressive symptom profiles, namely atypical energy-related symptom (AES) and melancholic, were created. The AES profile was derived by summing the score of five items: increased sleepiness, increased appetite, weight gain, low energy level and leaden paralysis. The melancholic symptom profile was used as another clinically established symptom profile for comparison with AES. The incidence of CMD (defined as development of cardiovascular diseases or type 2 diabetes (T2D)) was identified during a median follow-up of 6.7 years. Cox proportional hazards models assessed the association between depressive symptom profiles and CMD incidence, adjusted for confounders, while linear regression models examined associations with CMD-related proteins and metabolites identified in the UK Biobank.
Results
Compared to participants without depressive mood, those in the severe depressive mood group had the highest risk of developing CMD, with a hazard ratio (HR) of 1.65 (95% CI: 1.22–2.22). Regarding depressive symptom profiles, individuals with a severe AES profile showed a significantly increased risk of T2D (HR: 2.87, 95% CI: 1.92–4.30) compared to those without symptoms, whereas no significant association was observed for the melancholic symptom profile. The AES profile was more strongly associated with CMD-related metabolites, including glycoprotein acetyls, isoleucine and lipoproteins, and proteins predominantly enriched in the cytokine-cytokine receptor interaction pathway.
Conclusion
The AES profile is specifically associated with the incidence of T2D, and some specific metabolites and proteins were suggested to influence such association. Acknowledging the heterogeneity of depression may aid in tailoring CMD prevention.
{"title":"Symptomatology of depression and onset of cardiometabolic diseases − A 7-year follow-up study","authors":"Tahani Alshehri , Yumeng Tian , Ruifang Li-Gao , Jeroen van der Velde , Saskia le Cessie , Frits R. Rosendaal , Brenda W.J.H. Penninx , Yuri Milaneschi , Dennis O. Mook-Kanamori","doi":"10.1016/j.bbi.2026.106285","DOIUrl":"10.1016/j.bbi.2026.106285","url":null,"abstract":"<div><h3>Background</h3><div>Our study aimed to investigate the association of depressive mood and two depressive symptom profiles with the risk of cardiometabolic diseases (CMD) and to explore the underlying mechanisms of these associations through CMD-related metabolites and proteins.</div></div><div><h3>Methods</h3><div>In the Netherlands Epidemiology of Obesity study, depressive mood was measured with the Inventory of Depressive Symptomatology questionnaire, and two depressive symptom profiles, namely atypical energy-related symptom (AES) and melancholic, were created. The AES profile was derived by summing the score of five items: increased sleepiness, increased appetite, weight gain, low energy level and leaden paralysis. The melancholic symptom profile was used as another clinically established symptom profile for comparison with AES. The incidence of CMD (defined as development of cardiovascular diseases or type 2 diabetes (T2D)) was identified during a median follow-up of 6.7 years. Cox proportional hazards models assessed the association between depressive symptom profiles and CMD incidence, adjusted for confounders, while linear regression models examined associations with CMD-related proteins and metabolites identified in the UK Biobank.</div></div><div><h3>Results</h3><div>Compared to participants without depressive mood, those in the severe depressive mood group had the highest risk of developing CMD, with a hazard ratio (HR) of 1.65 (95% CI: 1.22–2.22). Regarding depressive symptom profiles, individuals with a severe AES profile showed a significantly increased risk of T2D (HR: 2.87, 95% CI: 1.92–4.30) compared to those without symptoms, whereas no significant association was observed for the melancholic symptom profile. The AES profile was more strongly associated with CMD-related metabolites, including glycoprotein acetyls, isoleucine and lipoproteins, and proteins predominantly enriched in the cytokine-cytokine receptor interaction pathway.</div></div><div><h3>Conclusion</h3><div>The AES profile is specifically associated with the incidence of T2D, and some specific metabolites and proteins were suggested to influence such association. Acknowledging the heterogeneity of depression may aid in tailoring CMD prevention.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106285"},"PeriodicalIF":7.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973186","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}
Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions characterized by persistent deficits in social interaction, communication, and repetitive behavior. Although the etiology of ASD has traditionally been linked to neuronal dysfunctions, emerging evidence highlights the significance of non-neuronal cells, particularly microglia and astrocytes, in the pathophysiology of ASD. Although both glial cell types exhibit diverse functional states, microglia are primarily associated with eliminating unused neurons and synapses during early brain development, whereas astrocytes in the tripartite synapse mainly support synapse formation and actively regulate excitatory and inhibitory neurotransmission. Together, microglia and astrocytes complement each other in shaping a dynamic excitatory/inhibitory (E/I) network in the developing brain. Abnormal glial function during critical neurodevelopmental periods is emerging as a significant, and possibly even a leading factor in the E/I imbalance underlying ASD. In this review we highlight recent findings on how microglia and astrocytes contribute to E/I imbalance and other neuronal dysfunctions in ASD, particularly during the vulnerable prenatal period. GABAergic transmission, with a shift in the polarity of GABA action early in development, represents a particularly vulnerable target for aberrant modulation by glia. Recent transcriptomic and multi-omics studies show that signaling pathways thought to be neuron-specific can also be activated in glia at distinct developmental time points, shaping their unique contributions to ASD. This growing knowledge opens new perspectives for using glia-targeted therapeutic approaches for mitigating debilitating aspects of ASD.
{"title":"Non-neuronal mechanisms in autism spectrum disorder (ASD): Microglia and astrocytes at the crossroads with neurons","authors":"Henna Jäntti , Susanne Michels , Enrico Cherubini , Rashid Giniatullin , Tarja Malm","doi":"10.1016/j.bbi.2026.106275","DOIUrl":"10.1016/j.bbi.2026.106275","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions characterized by persistent deficits in social interaction, communication, and repetitive behavior. Although the etiology of ASD has traditionally been linked to neuronal dysfunctions, emerging evidence highlights the significance of non-neuronal cells, particularly microglia and astrocytes, in the pathophysiology of ASD. Although both glial cell types exhibit diverse functional states, microglia are primarily associated with eliminating unused neurons and synapses during early brain development, whereas astrocytes in the tripartite synapse mainly support synapse formation and actively regulate excitatory and inhibitory neurotransmission. Together, microglia and astrocytes complement each other in shaping a dynamic excitatory/inhibitory (E/I) network in the developing brain. Abnormal glial function during critical neurodevelopmental periods is emerging as a significant, and possibly even a leading factor in the E/I imbalance underlying ASD. In this review we highlight recent findings on how microglia and astrocytes contribute to E/I imbalance and other neuronal dysfunctions in ASD, particularly during the vulnerable prenatal period. GABAergic transmission, with a shift in the polarity of GABA action early in development, represents a particularly vulnerable target for aberrant modulation by glia. Recent transcriptomic and multi-omics studies show that signaling pathways thought to be neuron-specific can also be activated in glia at distinct developmental time points, shaping their unique contributions to ASD. This growing knowledge opens new perspectives for using glia-targeted therapeutic approaches for mitigating debilitating aspects of ASD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106275"},"PeriodicalIF":7.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984473","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bbi.2026.106280
Shaaban A. Mousa , Mohammed Shaqura , Doaa Mohamed , Xueqi Hong , Susanne M. Krug , Elsayed Y. Metwally , Chalid Assaf , Sascha Treskatsch , Michael Schäfer
Objective
Perineural invasion − a hallmark of cancers such as prostate and pancreatic − is strongly associated with severe, treatment-resistant pain. To dissect the neuron-specific mechanisms underlying this pain, we established a rat model of prostate cancer–associated perineural invasion to get insights into neuroinflammatory processes arising from direct tumor–nerve interactions and to provide a platform for evaluating targeted therapeutic strategies.
Methods
GFP-expressing AT-1 prostate cancer cells were directly microinjected into the perineurium of the sciatic nerve in syngeneic Copenhagen rats. Over 21 days, we assessed tumor progression, macrophage infiltration, and expression of pro-tumorigenic and pro-inflammatory mediators. Nociceptive behavior was monitored for mechanical, heat and cold stimuli. The MEK/ERK pathway was inhibited pharmacologically using the intrathecal phosphor-ERK1/2 inhibitor.
Results
Perineural AT-1 cell injection induced progressive tumor growth accompanied by increased polarized macrophage infiltration with a predominance of M1 macrophages and their associated pro-inflammatory cytokines (IL-1β, TNF-α). This response was further characterized by elevated levels of pro-tumorigenic (RANTES, IL-1ra, TIMP-1, VEGF, Ki67) along with upregulation of neuronal injury markers (ATF-3, NGF, and GDNF) in the sciatic nerve. In parallel, sustained upregulation of cAMP as well as phosphorylation of CREB and ERK1/2 was observed along pain pathways over a 21-dayperiod. Mechanical and heat hyperalgesia as well as cold allodynia progressively intensified over 21 days. Importantly, MEK/ERK inhibition with intrathecal PD98059 reversed perineural tumor-induced mechanical allodynia.
Conclusion
This model provides insight into neuroinflammatory tumor–macrophage–nerve interactions associated with neuronal hyperexcitability. Although focused in scope, it enables stepwise investigation of tumor-induced neuronal responses and offers a useful platform for evaluating neuroinflammatory mechanisms of tumor invasion and for identifying potential therapeutic targets.
{"title":"Tumor–Macrophage–Nerve interactions drive neuroinflammation and neuropathic pain in prostate cancer perineural invasion","authors":"Shaaban A. Mousa , Mohammed Shaqura , Doaa Mohamed , Xueqi Hong , Susanne M. Krug , Elsayed Y. Metwally , Chalid Assaf , Sascha Treskatsch , Michael Schäfer","doi":"10.1016/j.bbi.2026.106280","DOIUrl":"10.1016/j.bbi.2026.106280","url":null,"abstract":"<div><h3>Objective</h3><div>Perineural invasion − a hallmark of cancers such as prostate and pancreatic − is strongly associated with severe, treatment-resistant pain. To dissect the neuron-specific mechanisms underlying this pain, we established a rat model of prostate cancer–associated perineural invasion to get insights into neuroinflammatory processes arising from direct tumor–nerve interactions and to provide a platform for evaluating targeted therapeutic strategies.</div></div><div><h3>Methods</h3><div>GFP-expressing AT-1 prostate cancer cells were directly microinjected into the perineurium of the sciatic nerve in syngeneic Copenhagen rats. Over 21 days, we assessed tumor progression, macrophage infiltration, and expression of pro-tumorigenic and pro-inflammatory mediators. Nociceptive behavior was monitored for mechanical, heat and cold stimuli. The MEK/ERK pathway was inhibited pharmacologically using the intrathecal phosphor-ERK1/2 inhibitor.</div></div><div><h3>Results</h3><div>Perineural AT-1 cell injection induced progressive tumor growth accompanied by increased polarized macrophage infiltration with a predominance of M1 macrophages and their associated pro-inflammatory cytokines (IL-1β, TNF-α). This response was further characterized by elevated levels of pro-tumorigenic (RANTES, IL-1ra, TIMP-1, VEGF, Ki67) along with upregulation of neuronal injury markers (ATF-3, NGF, and GDNF) in the sciatic nerve. In parallel, sustained upregulation of cAMP as well as phosphorylation of CREB and ERK1/2 was observed along pain pathways over a 21-dayperiod. Mechanical and heat hyperalgesia as well as cold allodynia progressively intensified over 21 days. Importantly, MEK/ERK inhibition with intrathecal PD98059 reversed perineural tumor-induced mechanical allodynia.</div></div><div><h3>Conclusion</h3><div>This model provides insight into neuroinflammatory tumor–macrophage–nerve interactions associated with neuronal hyperexcitability. Although focused in scope, it enables stepwise investigation of tumor-induced neuronal responses and offers a useful platform for evaluating neuroinflammatory mechanisms of tumor invasion and for identifying potential therapeutic targets.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106280"},"PeriodicalIF":7.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973185","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bbi.2026.106278
Yu-Ling Gan , Shang-Hsuan Lin , Yu-Ping Kang , Jia-Zhen Zhou , Wei-Hsuan Huang , Ping-Hua Sung , Chia-Chi Hung , Pei-Chien Hsu , Shu-Yin Chu , Feng-Shiun Shie , I-Hui Lee , Chung-Jiuan Jeng , Yi-Hsuan Lee
FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular stress responses and inflammatory signaling through the NF-κB pathway. Although FKBP51 is upregulated in reactive astrocytes, its role in epilepsy and excitotoxic neuroinflammation remains unknown. Excessive astrogliosis and impaired glutamate transporter-1 (GLT-1)-mediated glutamate clearance promote excitotoxicity and increase seizure susceptibility. Here, we investigated how both global and astrocyte-specific Fkbp5 deletions influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global Fkbp5 knockout (Fkbp5-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific Fkbp5 conditional knockout (aFkbp5-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved GLT-1 expression in hippocampal CA3. Glia–neuron mixed cultures derived from Fkbp5-KO brains showed reduced NMDA-induced neurotoxicity and astrogliosis, accompanied by decreased NF-κB p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51–NF-κB interaction inhibited proinflammatory lipopolysaccharide-induced astrogliosis and NF-κB activation. Transcriptomic analysis of Fkbp5-KO hippocampi further confirmed suppression of NF-κB-driven inflammatory pathways. In summary, astrocytic FKBP51 mediates reactive astrogliosis and GLT-1 downregulation, linking excitotoxic neuroinflammation with seizure susceptibility and cognitive impairment, and represents a potential intervention target for epilepsy.
{"title":"Astrocytic FKBP5 regulates neuroinflammation and cognitive outcomes in male mouse models of excitotoxic epilepsy","authors":"Yu-Ling Gan , Shang-Hsuan Lin , Yu-Ping Kang , Jia-Zhen Zhou , Wei-Hsuan Huang , Ping-Hua Sung , Chia-Chi Hung , Pei-Chien Hsu , Shu-Yin Chu , Feng-Shiun Shie , I-Hui Lee , Chung-Jiuan Jeng , Yi-Hsuan Lee","doi":"10.1016/j.bbi.2026.106278","DOIUrl":"10.1016/j.bbi.2026.106278","url":null,"abstract":"<div><div>FK506-binding protein 51 (FKBP51, encoded by <em>FKBP5</em>) is a multisignaling cochaperone that regulates cellular stress responses and inflammatory signaling through the NF-κB pathway. Although FKBP51 is upregulated in reactive astrocytes, its role in epilepsy and excitotoxic neuroinflammation remains unknown. Excessive astrogliosis and impaired glutamate transporter-1 (GLT-1)-mediated glutamate clearance promote excitotoxicity and increase seizure susceptibility. Here, we investigated how both global and astrocyte-specific <em>Fkbp5</em> deletions influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global <em>Fkbp5</em> knockout (<em>Fkbp5</em>-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific <em>Fkbp5</em> conditional knockout (a<em>Fkbp5</em>-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved GLT-1 expression in hippocampal CA3. Glia–neuron mixed cultures derived from <em>Fkbp5</em>-KO brains showed reduced NMDA-induced neurotoxicity and astrogliosis, accompanied by decreased NF-κB p65 phosphorylation. Notably, overexpression of an <em>Fkbp5</em> quadruple mutant that disrupts the FKBP51–NF-κB interaction inhibited proinflammatory lipopolysaccharide-induced astrogliosis and NF-κB activation. Transcriptomic analysis of <em>Fkbp5</em>-KO hippocampi further confirmed suppression of NF-κB-driven inflammatory pathways. In summary, astrocytic FKBP51 mediates reactive astrogliosis and GLT-1 downregulation, linking excitotoxic neuroinflammation with seizure susceptibility and cognitive impairment, and represents a potential intervention target for epilepsy.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106278"},"PeriodicalIF":7.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984433","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bbi.2026.106282
Noa van Zwieten , George Aalbers , Femke Lamers , Erik J. Giltay , Manon H.J. Hillegers , Brenda W.J.H. Penninx
Background
Daily life stress is associated with biological dysregulations including elevated inflammatory markers and poorer metabolic (immunometabolic) health, but it remains unclear how they are connected to daily life affect and behaviors. We examined whether daily life affect and behaviors were associated with immunometabolic health, and whether associations were moderated by the presence of a current depression/anxiety diagnosis.
Methods
In the Netherlands Study of Depression and Anxiety, participants (n = 357) with and without depression/anxiety self-reported positive affect (PA) and negative affect (NA) 5x/day while continuously wearing a research-grade actigraphy device for 14 days. We quantified four affect variables (i.e., M and SD of PA and NA) and three behavioral variables (i.e., minutes spent in moderate-to-vigorous physical activity [MVPA], sleep duration, and relative amplitude [RA; measure of circadian rhythmicity]), averaged across 14 days. We used linear regression analyses to explore their associations with three immunometabolic health outcomes: (1) inflammation index (based on C-Reactive Protein and Interleukin-6 levels), (2) metabolic index (based on five metabolic syndrome components), and (3) BMI (Body Mass Index), and examined if these associations were moderated by the presence of a current depression/anxiety diagnosis.
Results
Analyses showed that higher MVPA and RA were consistently associated with lower inflammation index (B = −0.19; B = −0.12), metabolic index (B = −0.14, B = −0.15), and BMI (B = −1.23; B = −1.30) (all p’s < 0.011). Longer sleep duration was associated with lower BMI (B = −0.80, p = 0.027). Affect variables were not associated with immunometabolic health outcomes (p’s > 0.05). Associations were independent of mental health status (p’s > 0.05).
Conclusions
Our findings suggest that more minutes spent in MVPA and a more pronounced circadian rhythm, assessed with actigraphy, are important correlates of better immunometabolic health, and highlight the potential of ambulatory assessment in understanding immunometabolic health.
{"title":"Daily affect and behavior in relation to inflammatory and metabolic health: An ambulatory assessment study","authors":"Noa van Zwieten , George Aalbers , Femke Lamers , Erik J. Giltay , Manon H.J. Hillegers , Brenda W.J.H. Penninx","doi":"10.1016/j.bbi.2026.106282","DOIUrl":"10.1016/j.bbi.2026.106282","url":null,"abstract":"<div><h3>Background</h3><div>Daily life stress is associated with biological dysregulations including elevated inflammatory markers and poorer metabolic (immunometabolic) health, but it remains unclear how they are connected to daily life affect and behaviors. We examined whether daily life affect and behaviors were associated with immunometabolic health, and whether associations were moderated by the presence of a current depression/anxiety diagnosis.</div></div><div><h3>Methods</h3><div>In the Netherlands Study of Depression and Anxiety, participants (n = 357) with and without depression/anxiety self-reported positive affect (PA) and negative affect (NA) 5x/day while continuously wearing a research-grade actigraphy device for 14 days. We quantified four affect variables (i.e., M and SD of PA and NA) and three behavioral variables (i.e., minutes spent in moderate-to-vigorous physical activity [MVPA], sleep duration, and relative amplitude [RA; measure of circadian rhythmicity]), averaged across 14 days. We used linear regression analyses to explore their associations with three immunometabolic health outcomes: (1) inflammation index (based on C-Reactive Protein and Interleukin-6 levels), (2) metabolic index (based on five metabolic syndrome components), and (3) BMI (Body Mass Index), and examined if these associations were moderated by the presence of a current depression/anxiety diagnosis.</div></div><div><h3>Results</h3><div>Analyses showed that higher MVPA and RA were consistently associated with lower inflammation index (B = −0.19; B = −0.12), metabolic index (B = −0.14, B = −0.15), and BMI (B = −1.23; B = −1.30) (all <em>p</em>’s < 0.011). Longer sleep duration was associated with lower BMI (B = −0.80, <em>p</em> = 0.027). Affect variables were not associated with immunometabolic health outcomes (<em>p</em>’s > 0.05). Associations were independent of mental health status (<em>p</em>’s > 0.05).</div></div><div><h3>Conclusions</h3><div>Our findings suggest that more minutes spent in MVPA and a more pronounced circadian rhythm, assessed with actigraphy, are important correlates of better immunometabolic health, and highlight the potential of ambulatory assessment in understanding immunometabolic health.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106282"},"PeriodicalIF":7.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973932","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}
Pub Date : 2026-01-11DOI: 10.1016/j.bbi.2026.106274
Clara Bourgon , Laetitia Merle-Nguyen , Juliette Jacquelin , Isis Leguay , Luc Jouneau , Bernard Klonjkowski , Sophie Le Poder , Nicolas Meunier
The loss of smell has been a hallmark of the COVID-19 pandemic. Odorant detection relies on neurons present in the olfactory epithelium supported by sustentacular cells. The latter are massively infected by SARS-CoV-2 along with infiltration of innate immune cells and desquamation of the olfactory epithelium. This destruction leads to release of olfactory epithelium cells into the lumen of the nasal cavity, but the extent of the loss of mature olfactory neurons remains to be clarified. In this study, we compared the spatiotemporal evolution of the olfactory epithelium during SARS-CoV-2 infection with associated smell impairment in hamsters. The olfactory performance of infected hamsters decreases as early as 2 days post-infection (dpi), then gradually recovers through 17 dpi. While the infection is mostly resolved after 4 dpi in the nasal cavity, we observed a subacute decrease of the mature olfactory neuron population which almost completely disappear at 11 dpi. Furthermore, regeneration of the olfactory epithelium does not start until 8 dpi and leads to a high fraction of immature olfactory neurons. The delayed regeneration and persistent alteration of the olfactory neuron population was correlated with a prolonged expression of inflammatory cytokines and a rapid decrease of the levels of anti-inflammatory markers linked to regeneration. Overall, our results suggest that the regeneration process is altered in some areas of the olfactory epithelium leading to delayed recovery of the epithelium. The later may explain the prolonged smell alteration linked to SARS-CoV-2 infection.
嗅觉丧失是COVID-19大流行的一个标志。气味检测依赖于存在于嗅觉上皮中的神经元，由支撑细胞支持。后者被SARS-CoV-2大量感染，伴随着先天免疫细胞的浸润和嗅上皮的脱屑。这种破坏导致嗅觉上皮细胞释放到鼻腔腔内，但成熟嗅觉神经元损失的程度仍有待澄清。在这项研究中，我们比较了仓鼠在SARS-CoV-2感染期间嗅觉上皮的时空演变和相关的嗅觉损伤。感染仓鼠的嗅觉性能最早在感染后2 d （dpi）下降，然后在感染后17 d逐渐恢复。虽然鼻腔感染在4 dpi后基本消失，但我们观察到成熟嗅觉神经元数量亚急性减少，在11 dpi时几乎完全消失。此外，嗅觉上皮的再生直到8 dpi才开始，并导致高比例的未成熟嗅觉神经元。嗅觉神经元群的延迟再生和持续改变与炎症细胞因子的延长表达和与再生相关的抗炎标志物水平的迅速下降有关。总的来说，我们的研究结果表明，再生过程在嗅觉上皮的某些区域发生了改变，导致上皮的恢复延迟。后者可以解释与SARS-CoV-2感染有关的长期气味改变。
{"title":"Subacute loss of olfactory neurons following SARS-CoV-2 infection in hamsters","authors":"Clara Bourgon , Laetitia Merle-Nguyen , Juliette Jacquelin , Isis Leguay , Luc Jouneau , Bernard Klonjkowski , Sophie Le Poder , Nicolas Meunier","doi":"10.1016/j.bbi.2026.106274","DOIUrl":"10.1016/j.bbi.2026.106274","url":null,"abstract":"<div><div>The loss of smell has been a hallmark of the COVID-19 pandemic. Odorant detection relies on neurons present in the olfactory epithelium supported by sustentacular cells. The latter are massively infected by SARS-CoV-2 along with infiltration of innate immune cells and desquamation of the olfactory epithelium. This destruction leads to release of olfactory epithelium cells into the lumen of the nasal cavity, but the extent of the loss of mature olfactory neurons remains to be clarified. In this study, we compared the spatiotemporal evolution of the olfactory epithelium during SARS-CoV-2 infection with associated smell impairment in hamsters. The olfactory performance of infected hamsters decreases as early as 2 days post-infection (dpi), then gradually recovers through 17 dpi. While the infection is mostly resolved after 4 dpi in the nasal cavity, we observed a subacute decrease of the mature olfactory neuron population which almost completely disappear at 11 dpi. Furthermore, regeneration of the olfactory epithelium does not start until 8 dpi and leads to a high fraction of immature olfactory neurons. The delayed regeneration and persistent alteration of the olfactory neuron population was correlated with a prolonged expression of inflammatory cytokines and a rapid decrease of the levels of anti-inflammatory markers linked to regeneration. Overall, our results suggest that the regeneration process is altered in some areas of the olfactory epithelium leading to delayed recovery of the epithelium. The later may explain the prolonged smell alteration linked to SARS-CoV-2 infection.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106274"},"PeriodicalIF":7.6,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965370","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}
Background: The mechanisms underlying the increased risk of depression following mild traumatic brain injury (mTBI) remain poorly understood, particularly the synergistic interaction between the initial injury and subsequent environmental stress. This study aims to elucidate the molecular cascade governing this "injury-stress" synergy.
Methods: We developed a "two-hit" mouse model combining mTBI with chronic unpredictable mild stress (CUMS) to investigate their interaction. Our approach integrated behavioral testing with molecular, immunohistochemical, and targeted genetic manipulations (AAV-mediated) in the medial prefrontal cortex (mPFC) to establish causal links.
Results: We found that mTBI alone did not induce significant behavioral deficits but instead established a state of latent vulnerability by driving persistent microglial priming in the mPFC. Sustained release of High-Mobility Group Box 1 (HMGB1) post-mTBI was identified as the key driver of this priming. Mechanistically, we demonstrate that chronic stress did not act by further increasing HMGB1 levels, but by amplifying downstream signaling efficiency through the selective upregulation of its receptor, RAGE. Bidirectional genetic interventions confirmed that RAGE is the critical molecular switch that translates the "second-hit" of stress into pathological amplification, culminating in exacerbated neuroinflammation, synaptic loss, and severe behavioral deficits.
Conclusion: Our study untangles a "priming-triggering" mechanism of injury-environment interaction, identifying the HMGB1-RAGE axis as its key molecular mediator. This finding not only enhances our understanding of how latent vulnerability transitions into overt neuropsychiatric disease, but also provides a promising target for preventive intervention.
{"title":"Injury-environment interaction: microglial priming by mTBI creates vulnerability to subsequent stress via the HMGB1-RAGE axis.","authors":"Jing Qiu, Guang Yang, Jingling Cai, Chen Chen, Shiting Liang, Haohao Huang, Lianting Ma","doi":"10.1016/j.bbi.2026.106273","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.106273","url":null,"abstract":"<p><strong>Background: </strong>The mechanisms underlying the increased risk of depression following mild traumatic brain injury (mTBI) remain poorly understood, particularly the synergistic interaction between the initial injury and subsequent environmental stress. This study aims to elucidate the molecular cascade governing this \"injury-stress\" synergy.</p><p><strong>Methods: </strong>We developed a \"two-hit\" mouse model combining mTBI with chronic unpredictable mild stress (CUMS) to investigate their interaction. Our approach integrated behavioral testing with molecular, immunohistochemical, and targeted genetic manipulations (AAV-mediated) in the medial prefrontal cortex (mPFC) to establish causal links.</p><p><strong>Results: </strong>We found that mTBI alone did not induce significant behavioral deficits but instead established a state of latent vulnerability by driving persistent microglial priming in the mPFC. Sustained release of High-Mobility Group Box 1 (HMGB1) post-mTBI was identified as the key driver of this priming. Mechanistically, we demonstrate that chronic stress did not act by further increasing HMGB1 levels, but by amplifying downstream signaling efficiency through the selective upregulation of its receptor, RAGE. Bidirectional genetic interventions confirmed that RAGE is the critical molecular switch that translates the \"second-hit\" of stress into pathological amplification, culminating in exacerbated neuroinflammation, synaptic loss, and severe behavioral deficits.</p><p><strong>Conclusion: </strong>Our study untangles a \"priming-triggering\" mechanism of injury-environment interaction, identifying the HMGB1-RAGE axis as its key molecular mediator. This finding not only enhances our understanding of how latent vulnerability transitions into overt neuropsychiatric disease, but also provides a promising target for preventive intervention.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106273"},"PeriodicalIF":7.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948459","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}
Pub Date : 2026-01-08DOI: 10.1016/j.bbi.2025.106247
Kate Merritt , Edward R. Palmer , Pedro Luque Laguna , Arjun Sethi , Jack C. Rogers , C. John Evans , Abraham Reichenberg , Golam M. Khandaker , Rachel Upthegrove , Glyn Lewis , Derek Jones , Anthony S. David
Aims
Inflammation is a risk factor for psychosis, yet the mechanisms underlying this association remain unclear. Elevated levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) in childhood have been associated with increased risk of developing later psychotic experiences (PEs) and psychotic disorders. This study investigates whether CRP and IL-6 levels at age 9 are associated with brain grey matter volume at age 20, and whether this association differs between individuals with and without PEs. We hypothesise that childhood inflammation will be linked to altered grey matter volumes in adulthood, and this association will be strongest among those who develop PEs.
Methods
In the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, MRI scans were acquired at age 20 years in participants with PEs (n = 71) and controls without PEs (n = 173). Voxel-based morphometry examined the association between childhood CRP or IL-6 and grey matter volume in adulthood, with interaction analyses testing for group differences by PEs status.
Results
In all participants (PEs and controls) elevated IL-6 in childhood was associated with smaller grey matter volume in adulthood, in several cortical regions which did not reach significance. After excluding 4 subjects with potential acute infection, IL-6 was associated with smaller grey matter volume in the left supramarginal gyrus (pFWE = 0.028, Z = 4.24, family-wise error (FWE) corrected), right parahippocampal gyrus (pFWE = 0.047; Z = 4.21; 292 voxels), and left precuneus (pFWE = 0.035; Z = 3.65). No interaction between IL-6 and PEs group on grey matter volume was found.
A significant interaction between CRP and PEs group was observed on grey matter volume (pFWE = 0.013, Z = 4.13). Elevated CRP levels in childhood were associated with larger right superior frontal gyrus volume in individuals with PEs, whereas CRP did not impact grey matter volume in controls. Effect sizes reduced after excluding 5 subjects with potential acute infection.
Conclusions
These findings suggest that individuals who go on to develop PEs were more vulnerable to the effects of circulating CRP on grey matter volume, consistent with a possible disease-specific pathway linking inflammation to psychosis. In contrast, IL-6 was associated with smaller volume in regions of the default mode network regardless of PEs, suggesting a more general effect on brain development.
{"title":"Inflammatory markers (IL-6 and CRP) in childhood and their association with brain structure and psychotic experiences in adulthood","authors":"Kate Merritt , Edward R. Palmer , Pedro Luque Laguna , Arjun Sethi , Jack C. Rogers , C. John Evans , Abraham Reichenberg , Golam M. Khandaker , Rachel Upthegrove , Glyn Lewis , Derek Jones , Anthony S. David","doi":"10.1016/j.bbi.2025.106247","DOIUrl":"10.1016/j.bbi.2025.106247","url":null,"abstract":"<div><h3>Aims</h3><div>Inflammation is a risk factor for psychosis, yet the mechanisms underlying this association remain unclear. Elevated levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) in childhood have been associated with increased risk of developing later psychotic experiences (PEs) and psychotic disorders. This study investigates whether CRP and IL-6 levels at age 9 are associated with brain grey matter volume at age 20, and whether this association differs between individuals with and without PEs. We hypothesise that childhood inflammation will be linked to altered grey matter volumes in adulthood, and this association will be strongest among those who develop PEs.</div></div><div><h3>Methods</h3><div>In the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, MRI scans were acquired at age 20 years in participants with PEs (n = 71) and controls without PEs (n = 173). Voxel-based morphometry examined the association between childhood CRP or IL-6 and grey matter volume in adulthood, with interaction analyses testing for group differences by PEs status.</div></div><div><h3>Results</h3><div>In all participants (PEs and controls) elevated IL-6 in childhood was associated with smaller grey matter volume in adulthood, in several cortical regions which did not reach significance. After excluding 4 subjects with potential acute infection, IL-6 was associated with smaller grey matter volume in the left supramarginal gyrus (<em>p</em>FWE = 0.028, <em>Z</em> = 4.24, family-wise error (FWE) corrected), right parahippocampal gyrus (<em>p</em>FWE = 0.047; <em>Z</em> = 4.21; 292 voxels), and left precuneus (<em>p</em>FWE = 0.035; <em>Z</em> = 3.65). No interaction between IL-6 and PEs group on grey matter volume was found.</div><div>A significant interaction between CRP and PEs group was observed on grey matter volume (<em>p</em>FWE = 0.013, <em>Z</em> = 4.13). Elevated CRP levels in childhood were associated with larger right superior frontal gyrus volume in individuals with PEs, whereas CRP did not impact grey matter volume in controls. Effect sizes reduced after excluding 5 subjects with potential acute infection.</div></div><div><h3>Conclusions</h3><div>These findings suggest that individuals who go on to develop PEs were more vulnerable to the effects of circulating CRP on grey matter volume, consistent with a possible disease-specific pathway linking inflammation to psychosis. In contrast, IL-6 was associated with smaller volume in regions of the default mode network regardless of PEs, suggesting a more general effect on brain development.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106247"},"PeriodicalIF":7.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948443","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}
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