Brain, Behavior, and Immunity最新文献

{"title":"Micro-encapsulation differentially impacts probiotic effects on brain structure and function in an elderly population – A randomised placebo-controlled trial","authors":"Julia Rode ,&nbsp;Ashley N. Hutchinson ,&nbsp;Myrto S. Chatzopoulou ,&nbsp;Sinéad B. Bleiel ,&nbsp;Rediet Fikru Gebresenbet ,&nbsp;Linda Andersson ,&nbsp;Jonas Persson ,&nbsp;Romain Daillère ,&nbsp;Benoît Beitz ,&nbsp;Bouthaina Ben Abdallah ,&nbsp;Lina Tingö ,&nbsp;Cecilia Bergh ,&nbsp;Robert J. Brummer","doi":"10.1016/j.bbi.2025.106113","DOIUrl":"10.1016/j.bbi.2025.106113","url":null,"abstract":"<div><div>Increasing evidence suggests that modulations of the gut-brain axis with probiotics impact healthy ageing. This double-blinded, randomised, placebo-controlled study compared effects of micro-encapsulated and non-encapsulated <em>Lacticaseibacillus rhamnosus</em> HN001 in 87 community-dwelling elderly (60–80 years). Resting state functional connectivity differed significantly in regions involved in visual processing and perception between the two probiotic groups (p &lt; 0.0001). Brain morphometry was not altered. Significant time*group effects (p &lt; 0.05) were observed for processing speed, non-significant effects were observed for short-term memory and anxiety symptoms, while other cognitive domains, depression, perceived stress, and sleep quality were unaffected. Distribution of available and stored peripheral serotonin was significantly affected (p &lt; 0.05), while levels of γ-aminobutyric acid and glutamate in striatum and circulating brain-derived neurotrophic factor did not show significant time*group effects. Micro-encapsulated probiotics target the gut differently, which impacts the effects on brain health assessed by (functional) magnetic resonance imaging in older adults.</div><div>The trial is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> under ID: NCT05801042.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106113"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111794","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":"Purinergic and extracellular vesicle signaling in alcohol-induced blood–brain barrier breakdown and neuroimmune activation","authors":"Namdev S. Togre ,&nbsp;Priyanka S. Bhoj ,&nbsp;Naveen Mekala,&nbsp;Rebecca Hancock,&nbsp;Jayshil Trivedi,&nbsp;Yuri Persidsky","doi":"10.1016/j.bbi.2025.106115","DOIUrl":"10.1016/j.bbi.2025.106115","url":null,"abstract":"<div><div>Chronic alcohol consumption is a major risk factor for neuroinflammation and cognitive decline, yet the molecular underpinnings connecting peripheral alcohol-induced injury to central nervous system (CNS) dysfunction remain poorly defined. Emerging evidence implicates purinergic P2X7 receptor (P2X7R) signaling and extracellular vesicles (EVs) as key mediators in peripheral–central communication. Ethanol exposure promotes oxidative stress, mitochondrial dysfunction, and blood–brain barrier (BBB) disruption, leading to sustained microglial activation and neuronal injury. Concurrently, alcohol-induced damage in the gut, liver, and lung, triggers systemic inflammation and EV release. These EVs, enriched in proinflammatory cytokines, miRNAs, mitochondrial DNA, and other DAMPs, can cross the compromised BBB and engage innate immune receptors, such as TLR4 and P2X7R, on glial cells, amplifying neuroimmune responses.</div><div>In this review, we integrated recent findings on EV biogenesis, P2X7R signaling, and neurovascular dysfunction in the context of alcohol use disorder. We proposed a mechanistic model in which ethanol-triggered P2X7R activation drives EV release, turning these vesicles into inflammatory couriers that carry peripheral injury signals to the brain. We emphasize EV cargo as promising biomarkers of alcohol-related neurodegeneration and explore emerging therapies that target EV pathways or P2X7R to curb alcohol-induced CNS damage.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106115"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111778","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":"Stress, epigenetic remodeling and FKBP51: Pathways to chronic pain vulnerability","authors":"Oakley B. Morgan ,&nbsp;Samuel Singleton ,&nbsp;Roxana Florea ,&nbsp;Sara Hestehave ,&nbsp;Tim Sarter ,&nbsp;Eva Wozniak ,&nbsp;Charles A Mein ,&nbsp;Felix Hausch ,&nbsp;Christopher G. Bell ,&nbsp;Sandrine M. Géranton","doi":"10.1016/j.bbi.2025.106119","DOIUrl":"10.1016/j.bbi.2025.106119","url":null,"abstract":"<div><div>Chronic pain and post-traumatic stress disorder (PTSD) show striking similarities in their prevalence following injury and trauma respectively, with growing evidence suggesting shared vulnerability mechanisms, particularly through stress-related epigenetic regulation. The gene FK506 binding protein 5, <em>FKBP5,</em> is a critical regulator of the stress response which plays a well-established role in PTSD susceptibility and has recently emerged as a potential driver of chronic pain vulnerability. In our pre-clinical study, sub-chronic stress promoted the persistence of subsequent inflammation-induced primary hyperalgesia and accelerated the development of inflammation-driven anxiety in male and female mice. Global deletion of <em>Fkbp5</em> reduced stress-induced vulnerability to persistent pain, with a more pronounced protective effect in males than in females. To investigate the mechanisms underlying FKBP51-driven persistent pain vulnerability, we analysed male spinal cord tissue after stress exposure and found hypomethylation in the <em>Fkbp5</em> promoter site for the canonical FKBP51 transcript and other stress-related genes. However, most epigenetic changes in key regulatory regions did not correlate with changes in gene expression, suggesting that stress exposure had remodelled the epigenome without altering gene activity. FKBP51 pharmacological inhibition in males during stress exposure shortened the duration of subsequent inflammatory pain and reversed several stress-induced DNA methylation changes in promoter regions of genes associated with stress and nociception, but not <em>Fkbp5</em>. These results indicate that sub-chronic stress increases the susceptibility to chronic pain in an FKBP51-driven mechanism and leads to the hypomethylation of <em>Fkbp5</em>. However<em>,</em> reversing <em>Fkbp5</em> hypomethylation is not necessary to prevent chronic pain vulnerability, which is likely driven by complex epigenetic regulation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106119"},"PeriodicalIF":7.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111911","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":"The associations between glucose, inflammation, cognitive functions, and white matter structural connectivity in euthymic bipolar patients","authors":"Wei Hung Chang ,&nbsp;Tsung-Hua Lu ,&nbsp;Van San Bui ,&nbsp;Hui Hua Chang ,&nbsp;Jun-Cheng Weng ,&nbsp;Shih-Hsien Lin ,&nbsp;Shyh-Yuh Wei ,&nbsp;Huai-Hsuan Tseng ,&nbsp;Po See Chen","doi":"10.1016/j.bbi.2025.106109","DOIUrl":"10.1016/j.bbi.2025.106109","url":null,"abstract":"<div><h3>Background</h3><div>Previous studies have shown that human white matter structural connectivity is independently associated with glucose metabolism, inflammation, and cognitive function. However, an integrative understanding of these relationships in bipolar disorder (BD) remains unclear.</div></div><div><h3>Methods</h3><div>This study included 44 euthymic patients with BD and 59 healthy controls (HCs). White matter structural connectivity was assessed using diffusion tensor imaging (DTI). Metabolic parameters, including fasting glucose and high-sensitivity C-reactive protein (hsCRP), were measured. Cognitive function was evaluated using the Wisconsin Card Sorting Test (WCST).</div></div><div><h3>Results</h3><div>DTI analysis revealed that BD patients had significantly higher gamma (46.52 ± 2.89 vs. 45.21 ± 2.95, p = 0.026) and sigma (41.73 ± 2.30 vs. 40.58 ± 2.40, p = 0.016) metrics compared to HCs after adjusting for age, years of education, and body mass index. In the BD group, the gamma and sigma metrics of DTI showed significantly negative correlations with the total number of categories completed in the WCST. Furthermore, in BD patients, both gamma and sigma metrics were positively correlated with fasting glucose and hsCRP levels.</div></div><div><h3>Conclusions</h3><div>Cognitive deficits in patients with BD may be linked to over-segregated neuronal activities, as indicated by elevated gamma DTI metrics. These abnormalities appear to be associated with higher levels of inflammation and glucose metabolism.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106109"},"PeriodicalIF":7.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085142","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":"Dysregulated oxidative stress and lactate levels in treatment-resistant schizophrenia","authors":"Yehong Fang ,&nbsp;Tingkai Zhang ,&nbsp;Kai Xu ,&nbsp;Liangliang Wang ,&nbsp;Jingqi He ,&nbsp;Yanhui Liao ,&nbsp;Ning Yuan ,&nbsp;Jinsong Tang","doi":"10.1016/j.bbi.2025.106111","DOIUrl":"10.1016/j.bbi.2025.106111","url":null,"abstract":"<div><div>Schizophrenia is a severe and clinically heterogeneous mental disorder, with approximately 30 % of patients developing treatment resistance to standard antipsychotics. To elucidate the pathophysiological mechanisms underlying treatment-resistant schizophrenia (TRS), we performed a comparative proteomic analysis of plasma-derived extracellular vesicles (EVs) from TRS patients, non-TRS (NTRS) patients, and healthy controls (n = 29, 29, and 31, respectively). EVs from TRS and NTRS patients induced schizophrenia-like behavioral deficits in mice, such as impaired prepulse inhibition and reduced social interaction, while healthy control-derived EVs ameliorated these deficits in an MK-801-induced model. In vitro, TRS-EVs triggered concurrent proliferation and apoptosis in astrocytes and induced dendritic abnormalities in neurons more prominently than NTRS-EVs. Proteomic profiling revealed significant dysregulation in TRS-derived EVs, featuring decreased oxygen transport and antioxidant proteins (e.g., HBG1, HBB, PRDX2) and elevated glycolytic enzymes (e.g., LDHA, PKM), indicative of a metabolic shift toward lactate production. Consistent with this, TRS patients showed increased plasma lactate levels and reduced PRDX2 expression, which correlated with clinical severity. These metabolic perturbations were also observed in EV-treated mice and astrocytes. Importantly, pharmacological inhibition of lactate production with dichloroacetate (DCA) reversed the behavioral and neuronal deficits, underscoring the role of metabolic dysregulation in TRS and highlighting lactate modulation as a promising therapeutic strategy for treatment-resistant cases.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106111"},"PeriodicalIF":7.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079673","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-induced emotional alterations in mice are associated with impairments of tryptophan metabolism along the kynurenine and indole pathways","authors":"Nathalie Castanon ,&nbsp;Sylvie Vancassel ,&nbsp;Camille Amadieu ,&nbsp;Sofia Cussotto ,&nbsp;Quentin Leyrolle ,&nbsp;Céline Lucas ,&nbsp;Antoine Lefevre ,&nbsp;Patrick Emond ,&nbsp;Anne-Laure Dinel ,&nbsp;Lucile Capuron","doi":"10.1016/j.bbi.2025.106107","DOIUrl":"10.1016/j.bbi.2025.106107","url":null,"abstract":"<div><div>Chronic inflammatory conditions, such as obesity, are frequently associated with a high prevalence of mood disorders and a reduced response to conventional antidepressants. Therefore, identifying the biological substrates underlying these comorbidities is crucial, as it could help uncover new therapeutic strategies to improve current treatments. Growing evidence implicates inflammation-driven dysregulation of tryptophan breakdown along the kynurenine pathway (KP) as a key contributor, although the specific roles of its various metabolites remain unclear. Additionally, the involvement of the gut-derived indole pathway (IP) of tryptophan metabolism is still poorly understood, despite increasing evidence linking gut microbiota metabolites to mood regulation. To address these questions, we assessed depressive-like and anxiety-like behaviors in C57BL/6J mice chronically exposed to high-fat diet (HFD), a reliable preclinical model of inflammatory depression. We also measured plasma and brain (hippocampus, frontal cortex, striatum) levels of a broad panel of KP and IP metabolites. HFD increased emotional behaviors and altered plasma and brain levels of tryptophan metabolites. Notably, it promoted a systemic neurotoxic-neuroprotective KP imbalance favoring neurotoxicity. It also drastically reduced indole production, with significant repercussions on brain indole-3 sulfate levels. Importantly, these metabolomic changes correlated with the severity of emotional alterations, with distinct metabolite-behavior relationships depending on the specific neuropsychiatric symptom dimensions assessed. In conclusion, this study offers valuable novel insights into the role of KP- and IP-derived tryptophan metabolites as key mediators between obesity and depression, and thus potential new promising therapeutic targets to improve neuropsychiatric comorbidities of obesity.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106107"},"PeriodicalIF":7.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079740","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":"Choroid plexus alterations in autism spectrum disorder: A PET-MRI study","authors":"Ylind Lila ,&nbsp;Chieh-En Jane Tseng ,&nbsp;Emma G. Johnston ,&nbsp;Camila Canales ,&nbsp;Christopher J. McDougle ,&nbsp;Jacob M. Hooker ,&nbsp;Nicole R. Zürcher","doi":"10.1016/j.bbi.2025.106110","DOIUrl":"10.1016/j.bbi.2025.106110","url":null,"abstract":"<div><div>The choroid plexus (CP), primarily known as the production site of cerebrospinal fluid (CSF), constitutes one of the sites of the blood-CSF barrier and plays a unique role in inflammation propagation, serving as a key regulator of immune responses. Recent work has shown CP enlargement in neurological and psychiatric disorders with immune involvement. To investigate potential neuroimmune and structural alterations <em>in vivo</em> in autism spectrum disorder (ASD), we assessed the CP-localized expression of mitochondrial translocator protein (TSPO) and CP volume in autistic adults. Sixty-five participants, which included 36 autistic participants and 29 non-autistic controls (CON), completed a simultaneous positron emission tomography-magnetic resonance imaging (PET-MRI) scan with the TSPO radiotracer [¹¹C]PBR28. The CP was segmented using subject-level anatomical scans. We observed CP volume enlargement in ASD (mean group difference: 677.8, 95 % CI [331.0, 1025.0], p = 0.0002). In particular, the CP volume of ∼30 % of autistic adults was more than 2 standard deviations above the average CP volume of CON. Exploratory analysis considering sex showed that CP volume was associated with more severe ASD symptoms in autistic males (estimated beta: 153.10, 95 % CI [50.03, 256.30], p = 0.005) and that TSPO in the CP was elevated in autistic females (mean group difference 0.12, 95 % CI [0.03, 0.21], p = 0.01). Our findings reveal volumetric alterations of the human CP in ASD, providing novel insights into the involvement of the CP in ASD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106110"},"PeriodicalIF":7.6,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074442","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":"Salivary cytokines in stress research: Reactivity kinetics in response to placebo-controlled acute psychosocial stress and associations with plasma cytokines and endocrine stress markers","authors":"Marvin Fischer ,&nbsp;Lisa-Marie Walther ,&nbsp;Angelina Gideon ,&nbsp;Christine Sauter ,&nbsp;Christiane Waller ,&nbsp;Ivano Amelio ,&nbsp;Petra H. Wirtz","doi":"10.1016/j.bbi.2025.106100","DOIUrl":"10.1016/j.bbi.2025.106100","url":null,"abstract":"<div><h3>Background/objectives</h3><div>In stress research, the measurement of cytokines from saliva may provide a non-invasive alternative to blood sampling. However, current research is limited by methodological shortcomings, including lack of placebo-stress control groups, comparison with plasma cytokine stress reactivity, infrequent sampling, and insufficient control for salivary flow rate. The aim of this study was to investigate repeatedly measured salivary cytokine responses to the Trier-Social-Stress-Test (TSST) compared to a placebo-TSST (PlacTSST), and to explore associations with plasma cytokines and endocrine stress markers.</div></div><div><h3>Methods</h3><div>In this placebo-controlled, single-blind, between-subject study, healthy young men were randomized to a stress condition (TSST;<em>n</em> = 30) or a placebo-stress condition (PlacTSST;<em>n</em> = 20). Salivary interleukin-(IL)-6, IL-1β, tumor-necrosis-factor-(TNF)-α were measured at baseline and repeatedly up to 30 min post-stress, with correction for salivary flow rate. Plasma cytokines were assessed up to 90 min post-stress. Salivary cortisol, epinephrine, and norepinephrine were assessed to explore potential endocrine mechanisms.</div></div><div><h3>Results</h3><div>The TSST induced significantly greater increases in salivary IL-6 (<em>p</em> = 0.024, η_p² = 0.07) and IL-1β (<em>p</em> = 0.031, η_p² = 0.07) compared to the PlacTSST, with peak responses at + 1 min post-stress and return to baseline by + 30 min. TNF-α was not stress-reactive, neither in saliva (<em>p</em> = 0.35) nor in plasma (<em>p</em> = 0.16). Higher total salivary IL-6 reactivity predicted higher plasma IL-6 reactivity (β = 0.48, <em>p</em> &lt; 0.001, ΔR² = 0.31), with salivary responses preceding those in plasma. Higher norepinephrine increases related to higher salivary IL-1β responses (β = 0.45, <em>p</em> = 0.018, ΔR² = 0.15), pointing to a potential noradrenergic modulation.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that acute psychosocial stress induces rapid and transient independent increases in salivary IL-6 and IL-1β but not TNF-α that relate to plasma cytokine and endocrine changes. These results support the utility of salivary cytokine assessment as a sensitive and non-invasive and less cost-intensive alternative to plasma sampling. Further research is warranted to elucidate underlying regulatory mechanisms and extend findings to different populations.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106100"},"PeriodicalIF":7.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044054","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":"CD300f enables microglial damage sensing, efferocytosis, and apoptotic cell metabolization after brain injury","authors":"Luciana Negro-Demontel ,&nbsp;Frances Evans ,&nbsp;Fabio Andrés Cawen ,&nbsp;Zachary Fitzpatrick ,&nbsp;Hannah D. Mason ,&nbsp;Daniela Alí-Ruiz ,&nbsp;Rubèn López-Vales ,&nbsp;Natalia Lago ,&nbsp;Hugo Peluffo","doi":"10.1016/j.bbi.2025.106105","DOIUrl":"10.1016/j.bbi.2025.106105","url":null,"abstract":"<div><div>Microglia, the resident phagocytes of the central nervous system (CNS), continuously survey the parenchyma and its borders, acting as first responders to brain injury. Their ability to detect and react to environmental changes is mediated by a repertoire of surface receptors collectively known as the<!--> <!-->microglial sensome.</div><div>Here, we identify the lipid-sensing immunoreceptor CD300f as a key regulator of microglial responses to tissue damage and apoptotic cells. Using intravital two-photon microscopy, we show that CD300f^−/− microglia fail to extend processes toward a laser-induced cortical lesion, indicating impaired detection of damage-associated cues.</div><div>In models of mild traumatic brain injury (mTBI) and intracortical injection of apoptotic cells, CD300f deficiency led to reduced recognition and clearance of dying cells resulting in the accumulation of cellular debris within the parenchyma. At later stages, apoptotic remnants were retained within CD300f^−/− microglia <em>in vivo</em> and bone marrow–derived macrophages <em>in vitro</em>, suggesting defective intracellular degradation.</div><div>Proteomic analysis after a controlled cortical injury (CCI) contusion model revealed widespread dysregulation of autophagy-related and metabolic pathways, consistent with impaired efferocytosis and phagolysosomal processing. In parallel, we observed upregulation of the UDP-degrading ectonucleotidase ENTPD6 protein and downregulation of the microglial purinergic receptor P2ry6 mRNA, indicating a dysfunctional UDP–P2RY6 axis that may underlie impaired damage sensing and phagocytic initiation.</div><div>Despite greater histological preservation, CD300f^−/− mice exhibited worse long-term functional recovery after brain injury.</div><div>Together, these findings highlight CD300f as a key damage-associated molecular pattern (DAMP) receptor that integrates purinergic signaling, efferocytosis, and metabolic adaptation, highlighting its essential role in coordinating microglial responses to CNS injury.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106105"},"PeriodicalIF":7.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038877","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":"Blood transcriptomic analysis reveals a distinct molecular subtype of treatment resistant depression compared to non-treatment resistant depression","authors":"Anna Sirés ,&nbsp;Jorge Domínguez-Barragán ,&nbsp;Nicola Lorenzon ,&nbsp;Oumayma Meskini ,&nbsp;Lisa Buson ,&nbsp;Rosana Carvalho Silva ,&nbsp;Marco Bortolomasi ,&nbsp;Giulia Perusi ,&nbsp;Valentina Menesello ,&nbsp;Massimo Gennarelli ,&nbsp;Bernardo Carpiniello ,&nbsp;Ewa Ferensztaj-Rochowiak ,&nbsp;Filip Rybakowski ,&nbsp;Ferran Sanz ,&nbsp;Claudia Pisanu ,&nbsp;Alessio Squassina ,&nbsp;Mirko Manchia ,&nbsp;Mara Dierssen ,&nbsp;PROMPT Study Group,&nbsp;Bernhard T. Baune ,&nbsp;Júlia Perera-Bel","doi":"10.1016/j.bbi.2025.106103","DOIUrl":"10.1016/j.bbi.2025.106103","url":null,"abstract":"<div><div>Treatment-resistant depression (TRD) is a severe condition characterized by chronic and recurrent depressive symptoms, leading to significant morbidity and a considerable socio-economic impact. Genetic and biological studies suggest that TRD is associated with distinct biological characteristics. In this study, we analysed whole-transcriptome differences in 293 patients with major depressive disorder (MDD) to compare TRD (N = 150) vs non-TRD (N = 143) cases. We identified 5,746 differentially expressed genes (DEGs), with an adjusted p-value &lt; 0.05. Functional analysis and Weighted Gene Co-expression Network Analysis (WGCNA) revealed that upregulated transcripts in TRD were enriched for non-coding RNAs (ncRNA) and associated with ncRNA processing and ribosomal biogenesis. In contrast, downregulated transcripts in TRD were predominantly protein-coding genes associated with immune system processes, epigenetic regulation, and RNA and DNA processing. Consistently, cell type deconvolution analysis revealed distinct immune cell proportions in TRD patients, with lower levels of neutrophils, mast cells and natural killer (NK) cells, but a higher proportion of CD4 T cells.</div><div>In a subgroup analysis comparing non-TRD remitters and TRD non-remitters, representing the extreme phenotypes of treatment response, 1,213 DEGs were identified with 96 % overlapping those found in the broader TRD versus non-TRD analysis. This substantial overlap underscores shared molecular features underlying TRD. Overall, the findings suggest that TRD represents a distinct molecular subtype characterized by unique immune and epigenetic signatures. These results indicate that patients with TRD may be identifiable at a molecular level, potentially paving the way for more personalised treatment approaches.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106103"},"PeriodicalIF":7.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032820","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}