Brain, Behavior, and Immunity最新文献

{"title":"The impact of adverse childhood experiences on gut microbiota and markers of inflammation is mediated by obesity and depression","authors":"Liisa Hantsoo ,&nbsp;Eileen Ford ,&nbsp;Elliot S. Friedman ,&nbsp;Fuhua Hao ,&nbsp;Andrew D. Patterson ,&nbsp;Kyle Bittinger ,&nbsp;Gary D. Wu ,&nbsp;Babette S. Zemel ,&nbsp;Ceylan Tanes","doi":"10.1016/j.bbi.2026.106479","DOIUrl":"10.1016/j.bbi.2026.106479","url":null,"abstract":"<div><h3>Background</h3><div>Adverse childhood experiences (ACEs) are associated with poor health outcomes in adulthood including obesity, psychiatric symptoms, and elevated levels of inflammatory markers. Our previous work found ACEs are associated with altered gut microbiota composition. In the present work, we examined ACE associations with gut microbiota and peripheral measures of inflammation in pregnant women with or without obesity, and explored potential modifying factors including diet and depressive symptoms.</div></div><div><h3>Methods</h3><div>Female participants were recruited in the third trimester of pregnancy as part of a larger growth study of African-American infants. Participants were categorized as healthy weight (BMI &lt; 25) or obese (BMI ≥ 30) based on their early pregnancy BMI. They completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and Center for Epidemiologic Studies Depression Scale (CES-D). Stool samples, blood, and dietary data were collected in the third trimester. Shotgun metagenomic sequencing was performed on DNA isolated from stool. Statistical models assessed relationships between gut microbiota and ACE. A false discovery rate (fdr) adjusted p-value q &lt; 0.1 was considered statistically significant.</div></div><div><h3>Results</h3><div>107 women completed questionnaires and provided stool in the third trimester. ACEs were positively associated with BMI and depressive symptom severity but not with gut microbiota composition. Depressive symptoms were significantly negatively associated with abundance of gut <em>Bifidobacterium longum</em> (q = 0.02) and positively associated with <em>Bacteroides thetaiotaomicron</em> (q = 0.02). Path analysis revealed that ACEs predicted pre-pregnancy BMI which predicted elevated inflammatory markers. ACEs also predicted more severe depressive symptoms in pregnancy, which was associated with gut microbiome composition. Finally, ACEs interacted with dietary intake of sugar and whole grains to impact markers of inflammation, the gut microbiome, and enzymes produced by gut microbiota.</div></div><div><h3>Discussion</h3><div>ACEs led to two risk pathways in pregnancy: one in which high pre-pregnancy BMI was linked with high levels of serum inflammatory markers during pregnancy, and the other in which greater depressive symptom severity was associated with alterations to the gut microbiome. Further, data suggested ACEs may influence the metabolic potential of the gut microbiome.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106479"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131149","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":"Rescuing prefrontal cortical excitation-inhibition imbalance with early-life microglial ablation ameliorates ASD-like behaviors in male BTBR mice.","authors":"Xinggao Zhang, Meifeng Gong, Zhenyang Chen, Jing Luo, Zijun Zhao, Zhirui Wu, Jinghui Zhao, Yuanyuan Ma, Lina Nie, Xiaotang Fan","doi":"10.1016/j.bbi.2026.106794","DOIUrl":"10.1016/j.bbi.2026.106794","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, alongside the presence of restricted and repetitive behaviors. Microglia, the resident immune cells of the central nervous system, play a crucial role in the development of ASD by regulating synaptic development and plasticity. In this study, we investigate the pharmacological effects and underlying cellular mechanisms of PLX3397 (PLX), a selective inhibitor of the colony-stimulating factor 1 receptor (CSF1R), for the pharmacological ablation of microglia in the context of ASD treatment. Our findings indicate that early postnatal treatment with PLX can enhance social abilities and reciprocal social behaviors while reducing repetitive and stereotyped autism-like behaviors, such as excessive grooming and marble burying. RNA sequencing analysis demonstrated that the neuroprotective effects of PLX are associated with reduced glutamatergic synaptic activity. This is further supported by the observation that PLX decreased vesicular glutamate transporter 1 (vGLUT1) expression, a marker of excitatory presynapses in the medial prefrontal cortex (mPFC). Additionally, we observed a reduction in dendritic spines and inhibition of excitatory synaptic transmission in the pyramidal neurons of the BTBR T + Itpr3tf/J (BTBR) mouse mPFC following early postnatal microglial depletion. Our findings highlight the therapeutic potential of PLX and provide valuable insights into the role of glutamatergic synapses in ASD.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106794"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810862","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":"Inflammatory biomarkers as predictors of fetal brain resilience or vulnerability to prenatal maternal anxiety","authors":"Xiang Zhou ,&nbsp;Die Zhang ,&nbsp;Chaoqiang Liu ,&nbsp;Helen Chen ,&nbsp;Yap-Seng Chong ,&nbsp;Marielle V. Fortier ,&nbsp;Peter D. Gluckman ,&nbsp;Anqi Qiu","doi":"10.1016/j.bbi.2026.106477","DOIUrl":"10.1016/j.bbi.2026.106477","url":null,"abstract":"<div><div>Prenatal maternal anxiety has been associated with altered neurodevelopmental outcomes in offspring, yet the biological mechanisms underlying this relationship remain poorly understood. This study investigated whether maternal inflammatory biomarkers moderate the association between prenatal anxiety and offspring brain and behavioral development. Using data from a prospective longitudinal cohort, we assessed maternal anxiety and circulating inflammatory markers at late mid-pregnancy, followed by neonatal brain MRI (n = 159) and cognitive assessments at 24 months (n = 340). Our findings revealed that interferon-gamma (IFN-γ) moderated the association between prenatal maternal anxiety and neonatal right globus pallidus volume, with higher IFN-γ levels linked to a larger pallidus volume and better cognitive outcomes at 24 months, even in the context of elevated anxiety. Similarly, both high and low levels of maternal monocyte chemoattractant protein-1 (MCP-1) altered the relationship between prenatal anxiety and neonatal brain morphology within the striatal–cortical circuit, including bilateral caudate volumes and cortical thickness in the sensorimotor and temporal regions. These results suggest that extreme MCP-1 levels may amplify vulnerability or promote resilience in fetal brain development. Higher MCP-1 levels were also associated with improved language development at 24 months. Together, these findings highlight the potential roles of inflammatory biomarkers in shaping the fetal brain’s sensitivity to maternal anxiety, offering potential mechanisms for early risk identification and intervention strategies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106477"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149099","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":"Midbrain microglial and macrophage mRNAs distinguish neuroinflammatory schizophrenia from bipolar disorder","authors":"Gerardo Mendez-Victoriano ,&nbsp;Yunting Zhu ,&nbsp;Yasmine Kostoglou ,&nbsp;Adam K. Walker ,&nbsp;Frank Middleton ,&nbsp;Paul T. Massa ,&nbsp;Bart J.L. Eggen ,&nbsp;Maree J. Webster ,&nbsp;Iris E.C. Sommer ,&nbsp;Cynthia S. Weickert","doi":"10.1016/j.bbi.2026.106276","DOIUrl":"10.1016/j.bbi.2026.106276","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Increased microglial/macrophage transcripts are found in the midbrains of people with a neuroinflammatory subtype of schizophrenia. However, it is unknown in which immune cell population these transcripts are mostly expressed, nor do we know if transcriptional changes in microglial/macrophage markers are also found in the midbrain of neuroinflammatory bipolar disorder.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Here, we determined the extent of microglial/macrophage changes in the ventral midbrain (at the level of the oculomotor nerve exit) of a large cohort of people with schizophrenia and bipolar disorder, defined as either low or high-inflammation, compared to controls. We aimed to confirm in which cell-type cluster our transcripts were expressed (microglia vs macrophages). First, we mapped the cellular expression of putative microglial/macrophage markers via snRNA-seq. Then, mRNA levels of 11 microglial/macrophage markers were measured and compared via RT-PCR from human post-mortem midbrains of 61 healthy controls, 63 schizophrenia cases, and 33 bipolar disorder cases.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;7/11 mRNAs (&lt;em&gt;IBA1&lt;/em&gt;, &lt;em&gt;CD11B&lt;/em&gt;, &lt;em&gt;CX3CR1&lt;/em&gt;, &lt;em&gt;P2RY12&lt;/em&gt;, &lt;em&gt;CD64&lt;/em&gt;, &lt;em&gt;CD40&lt;/em&gt;, &amp; &lt;em&gt;TMEM119&lt;/em&gt;) were mainly expressed in microglial cell clusters; 2 mRNAs were in the macrophage cell cluster (&lt;em&gt;CD32C, CD86&lt;/em&gt;); 1 mRNA was broadly expressed (&lt;em&gt;HEXB&lt;/em&gt;), and &lt;em&gt;CD68&lt;/em&gt; mRNA was too low to confirm cellular source by snRNA-seq. Across groups, transcripts associated with microglia activation and motility were significantly increased in high-inflammation schizophrenia (&lt;em&gt;IBA1, CD11B&lt;/em&gt;; all &lt;em&gt;p&lt;/em&gt; ≤ 0.001) and significantly decreased in high-inflammation bipolar disorder (&lt;em&gt;P2RY12&lt;/em&gt;, &lt;em&gt;CX3CR1&lt;/em&gt;; all &lt;em&gt;p&lt;/em&gt; ≤ 0.01) compared to low-inflammation controls. Transcripts associated with microglial and macrophage activation via FcγR-IgG/Immune complex antigen binding were significantly increased in high-inflammatory schizophrenia (&lt;em&gt;CD64&lt;/em&gt; &amp; &lt;em&gt;CD32C&lt;/em&gt;) and high-inflammatory bipolar disorder (&lt;em&gt;CD32C&lt;/em&gt;) (all &lt;em&gt;p&lt;/em&gt; ≤ 0.01). Transcripts associated with increased cytokine response (&lt;em&gt;CD40 &amp; CD86&lt;/em&gt;) and phagocytosis (&lt;em&gt;CD68&lt;/em&gt;) were significantly increased in high-inflammatory schizophrenia and divergently changed in high-inflammatory bipolar disorder (&lt;em&gt;CD40&lt;/em&gt; increased&lt;em&gt;/CD86&lt;/em&gt; decreased) (all &lt;em&gt;p&lt;/em&gt; ≤ 0.05). Overall, the number of CD68 + cells with reactive-like morphology was increased in high-inflammation schizophrenia compared to all the low-inflammation groups (all p ≤ 0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Our findings strengthen the contention that microglia and macrophages are activated in schizophrenia and disrupted in bipolar disorder midbrains of high-inflammatory subgroups. This suggests that optimal immune-based treatments targeting schizophrenia and bipolar disorder patients may differ when restor","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106276"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997279","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":"Altered gene expression associated with postoperative delirium in patients undergoing surgery and anesthesia","authors":"Maria Heinrich ,&nbsp;Anna-Rosa Krüger ,&nbsp;Sreyoshi Chatterjee ,&nbsp;Anna Fournier ,&nbsp;Florian Lammers-Lietz ,&nbsp;Roland Krause ,&nbsp;Peter Nürnberg ,&nbsp;Reinhard Schneider ,&nbsp;Georg Winterer ,&nbsp;Maik Pietzner ,&nbsp;Claudia Spies","doi":"10.1016/j.bbi.2026.106283","DOIUrl":"10.1016/j.bbi.2026.106283","url":null,"abstract":"<div><div>Postoperative delirium is a severe complication associated with poor overall and especially neurocognitive prognosis after anesthesia and surgery. As a systemic phenomenon, peripheral immune response to surgical trauma may play a central role. Although analysis of differential gene expression in peripheral immune cells could provide insights into immune dysregulation in postoperative delirium (POD), no sufficiently powered prospective cohort study has yet been conducted.</div><div>We performed gene expression analysis in N = 599 cognitively healthy male and female patients ≥65 years who provided blood samples for microarray-based gene-expression data before major elective surgery and on the first postoperative day. Patients were followed up for delirium until the seventh postoperative day. We identified differentially expressed genes in POD using a multivariable linear regression framework adjusted for sex, age, body mass index, preoperative physical status, duration of anesthesia and operative procedure.</div><div>Preoperative gene expression did not differ significantly in patients who were later diagnosed with POD. However, we identified a total of 1,063 unique significantly associated genes which differed in baseline-corrected mRNA abundance among POD patients after surgery (n = 394 upregulated, n = 681 downregulated). This set was significantly enriched for genes related to cellular and humoral immune response, RNA metabolism and platelet function.</div><div>Post-, but not preoperative gene expression in peripheral immune cells has been found to be altered in patients with POD. Whereas most enriched pathways were related to immune response and acute phase reaction, few molecular alterations were found, which may reflect nervous system alterations and warrant further investigation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106283"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988364","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":"Chronic constriction of the sciatic nerve does not induce mood-related comorbidities in female mice","authors":"Marion Gaborit ,&nbsp;Quentin Leboulleux ,&nbsp;Noemie Willem ,&nbsp;Coline Sagot ,&nbsp;Stephane Doridot ,&nbsp;Karin Herbeaux ,&nbsp;Melanie Kremer ,&nbsp;Amandine Bery ,&nbsp;Katia Befort ,&nbsp;Dominique Massotte","doi":"10.1016/j.bbi.2026.106286","DOIUrl":"10.1016/j.bbi.2026.106286","url":null,"abstract":"<div><h3>Background</h3><div>Neuropathic pain affects around 7–8% of the population and is associated with a high level of lifetime anxio-depressive comorbidities. Despite the higher incidence of the pathology in women, preclinical studies using rodents almost exclusively focused on males so far.</div></div><div><h3>Methods</h3><div>Sciatic nerve cuffing is a well-characterized model of neuropathy in which anxio-depressive comorbidities develop over time in male mice. In order to examine potential sex-differences in this model, we compared the alterations in the mechanical sensitivity using von Frey testing and used three ethologically relevant tests to explore their well-being (nest building), social behaviour (dyadic social interaction), and depression-like state (splash test) seven weeks after surgery. We also examined sex-related differences in neuroinflammation by quantifying changes in cytokine expression in the brainstem, a region critically involved in descending pain modulation.</div></div><div><h3>Results/conclusion</h3><div>Both male and female mice developed mechanical hypersensitivity following cuff surgery. However, no alteration in nest building ability, social dyadic interaction or grooming activity was observed in female mice seven weeks after surgery. Our data therefore suggest sex differences in the development of comorbidities associated with mechanical hypersensitivity. In addition, we evidenced in the brainstem sex-related differences in the expression of cytokines relevant to human neuropathy. Altogether, these results emphasize the need for additional comparisons between males and females to better grasp the role of neuroinflammation in pain sensitization and associated comorbidities.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106286"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988410","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":"Activation of GLP-1R ameliorates microglial pyroptosis after spinal cord injury by restoring FANCC expression","authors":"Guangshen Li ,&nbsp;Yang Luo ,&nbsp;Tianyu Zhu ,&nbsp;Chunmao Chen ,&nbsp;Zhanyang Qian ,&nbsp;Haijun Li","doi":"10.1016/j.bbi.2026.106295","DOIUrl":"10.1016/j.bbi.2026.106295","url":null,"abstract":"<div><div>Secondary spinal cord injury (SCI) involves neuroinflammatory mechanisms such as microglial pyroptosis, which aggravates neural impairment via NLRP3 inflammasome activation. Although liraglutide (Lr) is commonly used for managing blood glucose, it also exhibits anti-inflammatory effects. Previous studies from our group have shown that glucagon-like peptide-1 receptor (GLP-1R) activation in microglia attenuates neuroinflammation and promotes functional recovery after SCI, the precise mechanism linking GLP-1R to the inhibition of pyroptosis remained unclear. Here, we report that high-dose Lr (independent of its metabolic effects) significantly improves functional and histological outcomes in a murine SCI model, and these benefits are abolished in GLP-1R^−/− mice. In vitro, RNA sequencing, combined with pharmacological and genetic approaches, revealed that Lr, via the PI3K/Akt/transcription factor EB (TFEB) axis, by upregulates Fanconi anemia complementation group C (FANCC) to suppress pyroptosis. Crucially, FANCC knockdown both elevated p38 phosphorylation and blocked the anti-pyroptotic effect of Lr, thereby establishing FANCC as an essential downstream mediator. This signaling cascade culminates in the inhibition of p38-dependent NLRP3 inflammasome activation. Collectively, our work defines a novel GLP-1R/PI3K/Akt/TFEB/FANCC/p38 pathway through which Lr alleviates secondary SCI, identifying FANCC as a pivotal neuroprotective node and supporting the translational potential of GLP-1R modulation in SCI.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106295"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043882","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":"Diagnosis-independent contribution of low-grade inflammation to cortical atrophy across psychiatric disorders.","authors":"Moritz Rau, Luise Claaß, Lavinia Steinmann, Julian Herpertz, Maike Richter, Ramona Leenings, Janik Goltermann, Susanne Meinert, Nico Melzer, Sven Meuth, Luisa Klotz, Albrecht Stroh, Dominik Grotegerd, Elisabeth J Leehr, Tim Hahn, Kira Flinkenflügel, Tiana Borgers, Frederike Stein, Florian Thomas-Odenthal, Paula Usemann, Lea Teutenberg, Igor Nenadić, Benjamin Straube, Nina Alexander, Hamidreza Jamalabadi, Andreas Jansen, Harald Renz, Carsten Denkert, Tilo Kircher, Udo Dannlowski, Nils Opel","doi":"10.1016/j.bbi.2026.106792","DOIUrl":"https://doi.org/10.1016/j.bbi.2026.106792","url":null,"abstract":"<p><strong>Background: </strong>Peripheral low-grade inflammation has been implicated in the pathophysiology of various psychiatric disorders and has been associated with cortical brain structural alterations. However, it remains unclear whether inflammation-related cortical atrophy is disorder-specific or reflects shared, diagnosis-independent vulnerability across psychiatric conditions.</p><p><strong>Methods: </strong>We investigated cross-sectional and longitudinal associations between baseline high-sensitivity C-reactive protein (hs-CRP) and cortical thickness in participants from the Marburg Affective Disorders Cohort Study (MACS). The baseline sample comprised 683 patients (524 with major depressive disorder [MDD], 82 with bipolar disorder [BD], 77 with schizophrenia [SCZ]) and 620 healthy controls (HC) (59.9% female). After two years, follow-up data were available for 163 patients (125 MDD, 18 BD, 20 SCZ) and 184 HC (57.3% female). Serum hs-CRP levels were measured in all participants, and cortical thickness was assessed using structural MRI with FreeSurfer parcellation. Models were adjusted for age, sex, BMI, site, and diagnosis, with multiple comparisons corrected using the false discovery rate.</p><p><strong>Results: </strong>Higher baseline hs-CRP was significantly associated with reduced cortical thickness in the left paracentral lobule at baseline (β = -0.029; p _FDR = 0.017) and with cortical thinning over time in the left fusiform gyrus (β = -0.014; p _FDR = 0.038) in longitudinal analyses. No significant interaction effects were found for age, sex, diagnosis, or smoking status.</p><p><strong>Conclusions and relevance: </strong>Peripheral low-grade inflammation was associated with progressive cortical thinning across diagnostic groups, supporting a diagnosis-independent neurobiological mechanism, that is not specific to any psychiatric disorder, highlighting peripheral inflammation as potential target for preventive and therapeutic strategies in psychiatric care.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":"106792"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810880","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":"Modulation of HMGB1-mediated neuroinflammation and synaptic plasticity by ethyl pyruvate reduces methamphetamine reward and motivation in male rats","authors":"Huizhen Liu ,&nbsp;Fangmin Wang ,&nbsp;Zhongyu Zhang ,&nbsp;Xiaolei Huang ,&nbsp;Shanshan Chen ,&nbsp;Yuting Wang ,&nbsp;Yiying Zhou ,&nbsp;Tingting Wu ,&nbsp;Manqing Wu ,&nbsp;Baobao Shi ,&nbsp;Miaojun Lai ,&nbsp;Huifen Liu ,&nbsp;Wenhua Zhou","doi":"10.1016/j.bbi.2026.106481","DOIUrl":"10.1016/j.bbi.2026.106481","url":null,"abstract":"<div><h3>Background</h3><div>Methamphetamine (METH) addiction involves neuroinflammatory cascades and maladaptive synaptic plasticity in reward circuits. While high-mobility group box 1 (HMGB1) and its downstream neuroinflammatory pathways contribute to neuropsychiatric disorders, their therapeutic potential in METH addiction remains unexplored. This study investigated whether ethyl pyruvate (EP, an HMGB1 inhibitor) attenuates METH reinforcement and associated neurotoxicity in the rat infralimbic cortex (IL).</div></div><div><h3>Methods</h3><div>Male rats self-administering METH received systemic EP (0, 50, or 80 mg/kg, i.p.). Reinforcement, motivation, and reinforcing efficacy were assessed using fixed-ratio 1 (FR1), progressive ratio (PR), and dose–response paradigms. Western blotting quantified HMGB1-TLR4/MyD88/PI3K/Akt/NF-κB signaling, pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and synaptic proteins in the IL. Neuronal TLR4 and HMGB1 expression, apoptosis (TUNEL, cleaved caspase-3), and pyroptosis (cleaved caspase-1) were assessed by immunofluorescence staining. In vivo calcium dynamics in IL CaMKIIα⁺ neurons were recorded via fiber photometry, and synaptic transmission was assessed via patch-clamp recordings of spontaneous excitatory postsynaptic currents (sEPSCs). Region-specific effects were confirmed by local microinjections of EP.</div></div><div><h3>Results</h3><div>Systemic EP treatment reduced METH intake and motivation and downshifted the dose–response curve without affecting natural reward. EP reversed METH-induced HMGB1 nuclear-to-cytoplasmic translocation and neuronal TLR4 expression, and suppressed downstream neuroinflammatory signaling and cytokine release. Furthermore, EP also reduced METH-associated neuronal apoptosis and pyroptosis in the IL. It also restored calcium homeostasis in IL CaMKIIα⁺ neurons, normalized expression of key synaptic proteins (e.g., NR2A/B, GluA2, PSD95, SNAP25), and reversed METH-induced hyperexcitability (increased sEPSC frequency/amplitude) in IL pyramidal neurons. Critically, local IL microinjection of EP replicated these systemic effects, confirming the IL as a key site of action.</div></div><div><h3>Conclusion</h3><div>The HMGB1 inhibitor EP attenuated METH reinforcement and motivation by targeting the IL to disrupt a neuroinflammatory cascade, prevent apoptosis and pyroptosis, and restore synaptic homeostasis. These findings identify HMGB1 inhibitors as a novel therapeutic target for mitigating the neuropathology and motivational drive underlying METH addiction.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106481"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177735","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":"An extraverted behavior intervention improves immune gene expression","authors":"Ramona L. Martinez ,&nbsp;Sonja Lyubomirsky ,&nbsp;Steve W. Cole","doi":"10.1016/j.bbi.2026.106299","DOIUrl":"10.1016/j.bbi.2026.106299","url":null,"abstract":"<div><h3>Background</h3><div>Social connection is critical to both psychological well-being and optimal immune function. The present study tested whether a behavioral intervention to increase social connection (promoting extraverted behavior) might reduce a threat-related immunoregulatory gene expression program known as the Conserved Transcriptional Response to Adversity (CTRA). The CTRA is characterized by elevated inflammatory gene expression and reduced innate antiviral gene expression in response to beta adrenergic signaling and has been associated with adverse social conditions such as loneliness and ostracism.</div></div><div><h3>Methods</h3><div>In an 8-week intervention (with 6-week behavior change protocol), participants from a campus community (<em>N</em> = 119; 87 % undergraduate; 9 % graduate; 4 % staff) were randomized to act more extraverted (sociable; Extraversion condition) or track routine daily activities (Control condition). Participants reported on psychological outcomes and provided dried blood spots for RNA sampling at pre-test (Week 0), post-test (Week 8), and 1-month follow-up (Week 12). Multilevel models tested condition differences in CTRA expression over time and examined mediation via psychological outcomes.</div></div><div><h3>Results</h3><div>Pre-registered analyses of pre-specified CTRA indicator genes showed no significant effects. Secondary genome-wide bioinformatic analyses of NF-κB, IRF, and CREB transcription control pathways found significantly greater reductions in CTRA-characteristic gene regulation among the Extraversion group relative to controls. These effects were partially mediated by reductions in loneliness. However, the intervention effect on CTRA gene regulation was not sustained at 1-month follow-up.</div></div><div><h3>Implications</h3><div>Extraverted behavior may improve immune regulation by enhancing perceived social connection. Further research should replicate these findings and enhance the durability of effects.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"134 ","pages":"Article 106299"},"PeriodicalIF":7.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028391","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}