Brain, Behavior, and Immunity最新文献

{"title":"Microglial cGAS-STING-TBK1 activation in paraventricular thalamus mediates sleep and emotional disturbances in lupus mice","authors":"Hui Yuan ,&nbsp;Zijie Li ,&nbsp;Xueru Wang ,&nbsp;Siyuan Zeng ,&nbsp;Chenye Jin ,&nbsp;Jingyu Chen ,&nbsp;Xuejiao Wang ,&nbsp;Pingting Yang ,&nbsp;Ling Qin","doi":"10.1016/j.bbi.2025.06.042","DOIUrl":"10.1016/j.bbi.2025.06.042","url":null,"abstract":"<div><div>Sleep and emotional disturbances are prevalent in systemic lupus erythematosus (SLE) patients, yet the neuroinflammatory mechanisms remain unclear. Here, we investigated this issue using pristane-induced lupus (PIL) mice. We firstly confirmed that PIL mice exhibited progressive fragmentation of NREM sleep and decreased cumulative sleep time, correlating with blood–brain barrier (BBB) leakage and IgG deposition in the paraventricular thalamus (PVT). Concurrently, PVT neurons showed aberrant excitatory activity, including a high level of cFos expression, decreased amplitude and increased rate of Ca²⁺ transients during wakefulness. Bulk RNA sequencing and protein analyses demonstrated upregulation of the cyclic GMP-AMP synthase (cGAS) −stimulator of interferon genes (STING) −TANK-binding kinase 1 (TBK1) activation pathway in PVT microglia, with elevated phosphorylation of STING (pSTING) and TBK1 (pTBK1), promoting synthesis of pro-inflammatory cytokines. Selectively knockdown STING in microglia effectively normalized PVT neuronal excitability, restored sleep homeostasis, and ameliorated anxiety/depression-like behaviors. Notably, we identified selective expression of cannabinoid receptor type 2 (CB2R) in PVT microglia. Pharmacological CB2R activation could inhibit TBK1 phosphorylation, attenuate microglial inflammatory responses, and improve sleep and emotional disturbances. Our findings elucidate a novel neuroimmune axis in SLE-related neuropsychiatric symptoms, offering potential therapeutic avenues for mitigating neuroinflammation and associated behavioral comorbidities in lupus.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 634-648"},"PeriodicalIF":8.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535226","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":"Dependence of fasting-induced hypothalamic anti-inflammatory microglia mechanisms on adrenal glucocorticoid secretion","authors":"Balázs Juhász,&nbsp;Krisztina Horváth,&nbsp;Dániel Kuti,&nbsp;Szilamér Ferenczi,&nbsp;Zsuzsanna Winkler,&nbsp;Krisztina J. Kovács","doi":"10.1016/j.bbi.2025.06.038","DOIUrl":"10.1016/j.bbi.2025.06.038","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Fasting triggers complex physiological and neuroimmune adaptations, yet its impact on hypothalamic microglia and the underlying regulatory role of glucocorticoids remains incompletely understood. The present study focused on fasting-induced systemic changes and cellular adaptations seen in the hypothalamus where components of metabolic- hormonal- and immune regulations are integrated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Adult male microglia reporter (CX3CR1&lt;sup&gt;+/Gfp&lt;/sup&gt;) mice were subjected short term (18 h) overnight fasting. Metabolic changes were followed using indirect calorimetry. Hypothalamic expression of pro-and anti-inflammatory markers, hypothalamic neuropeptides and select genes involved in metabolic regulation was measured by qPCR. Number of microglia and their morphological characteristics was analysed by Sholl analysis. The dependence of these markers on fasting-induced corticosterone was studied in adrenalectomized (ADX) or metyrapone-treated mice. Plasma levels of corticosterone and ketone body, β-hydroxybutyrate was assayed by radioimmunassay and a colorimetric kit respectively.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Overnight fasting resulted in a decrease in energy expenditure and respiratory exchange ratio (RER) indicating conservation of energy and a metabolic shift towards utilization of fatty acids as alternative energy source. Fasting increased hypothalamic expression of orexigenic neuropeptides and mRNA levels of &lt;em&gt;Pdk4, Glut1&lt;/em&gt;, and &lt;em&gt;Mct2&lt;/em&gt; genes, in line with metabolic compensation. Upregulation of hypothalamic &lt;em&gt;Crh&lt;/em&gt; and increased plasma concentration of corticosterone indicated sustained activation of the HPA axis. Importantly, fasting promoted an anti-inflammatory milieu in the hypothalamus characterized by elevated &lt;em&gt;Il-4&lt;/em&gt;, &lt;em&gt;Il-10&lt;/em&gt; and &lt;em&gt;IkBα&lt;/em&gt; genes without significant activation of pro-inflammatory cytokines (e.g., &lt;em&gt;Il-1β, Il-6, Tnfα&lt;/em&gt;). Morphological analysis revealed region-specific changes in microglia number and branching complexity, particularly in hypothalamic regions directly exposed to blood-borne signals. Functional profiling showed increased microglial expression of IkBα and decreased pIkBα, indicating suppressed NFkB signaling. Adrenalectomy (1 week) and acute pharmacological inhibition of corticosterone synthesis (methyrapone) revealed that fasting-induced anti-inflammatory and metabolic gene expression, as well as microglial plasticity were largely glucocorticoid dependent. Hypothalamic expression of fasting-related neuropeptides (&lt;em&gt;Npy&lt;/em&gt;, &lt;em&gt;Agrp&lt;/em&gt;) and genes, related to the metabolic shift (&lt;em&gt;Pdk4, Glut-1, Mct2, Angptl4&lt;/em&gt;) as well as some immune-related genes (&lt;em&gt;Il10, Iba1&lt;/em&gt;) was dependent on presence of the adrenal gland or fasting-induced elevation of corticosterone.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;These findings highlight short term fasting as a potent modulator of hypothalamic immune-metabolic cr","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 557-572"},"PeriodicalIF":8.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522966","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":"Evidence of postnatal neglect-dependent resiliency in thymic, gut, and behavioral outcomes in a mouse model of early life stress","authors":"Jamie Y. Choe ,&nbsp;Michael Donkor ,&nbsp;Yan Zhang ,&nbsp;Isabelle K. Gorham ,&nbsp;Jessica L. Bradshaw ,&nbsp;Philip H. Vann ,&nbsp;Nathalie Sumien ,&nbsp;Rebecca L. Cunningham ,&nbsp;Michael S. Allen ,&nbsp;Byron Quinn ,&nbsp;Nicole R. Phillips ,&nbsp;Harlan P. Jones","doi":"10.1016/j.bbi.2025.06.036","DOIUrl":"10.1016/j.bbi.2025.06.036","url":null,"abstract":"<div><h3>Background</h3><div>Early life is an impressionable period often regarded as the window of opportunity. Environmental exposures, such as stress, in the early postnatal period can influence developmental trajectory and long-term health. The brain and immune systems continue to develop after birth and are shaped by postnatal exposures. While chronic traumatic stress is understood to adversely affect individuals by overwhelming coping abilities, there is evidence for stress exposure to be beneficial by promoting resilience. Early life stress (ELS) is a significant postnatal exposure, which encompasses childhood maltreatment and trauma. Neglect is the most common form of maltreatment in children and takes many forms, including physical and nutritional.</div></div><div><h3>Methods</h3><div>Here, we describe a novel mouse model of neglect-related ELS based on maternal separation with early weaning (MSEW) with a distinct early weaning (EW) stress group to study how an environment of neglect impacts the developing microbiome, thymocytes, and stress-related behavior. Neglect-related stress was emulated based on scheduled dam-pup separation (physical neglect) and a high carbohydrate early-wean diet (malnutrition). C57BL/6J mice were bred in-house and ELS pups were subjected to: (1) daily dam-pup separation on postnatal days (PD) 2–13 and/or (2) early weaning to a high carbohydrate diet on PD14-21.</div></div><div><h3>Results</h3><div>The present study focused on a defined early life window (PD0-21) and revealed that MSEW versus EW exposures generate distinguishable and distinct effects on behavior and thymic T cells, leading to phenotypes of stress resilience versus vulnerability. Although impacts of the two ELS groups were indistinguishable on lower gastrointestinal tract microbiome composition, the effects on ELS groups were significant compared to controls.</div></div><div><h3>Conclusions</h3><div>Our findings provide evidence for circumstances where prior stress can induce resilience and emphasizes the nuanced approach required for studies to begin parsing out toxic versus beneficial stress.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 595-608"},"PeriodicalIF":8.8,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522820","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":"Targeted activation of Nrf2 at sites of oxidative stress reverses doxorubicin-induced cognitive impairments in mice","authors":"Anand K. Singh ,&nbsp;David Ruiz ,&nbsp;Vipul K. Pandey ,&nbsp;Mohd Sami Ur Rasheed ,&nbsp;Dion J.L. Turner ,&nbsp;Thomas D. Avery ,&nbsp;Andrew D. Abell ,&nbsp;Peter M. Grace","doi":"10.1016/j.bbi.2025.06.037","DOIUrl":"10.1016/j.bbi.2025.06.037","url":null,"abstract":"<div><div>While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, and processing speed, known as chemotherapy-induced cognitive impairment or “chemobrain”. Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) using compound <strong>1c</strong> or diroximel fumarate (DRF) would restore cognitive function after doxorubicin treatment. Compound <strong>1c</strong> is a prodrug which locally releases the Nrf2 activator monomethyl fumarate (MMF) specifically at sites of oxidative stress, while DRF systemically releases MMF. Compound <strong>1c</strong> and DRF both reversed doxorubicin-induced deficits in executive function, and spatial and working memory, across male and female mice. Nrf2 activators decreased malonaldehyde and protein carbonyl levels induced by doxorubicin in the hippocampus. Consistently, <strong>1c</strong> increased nuclear translocation (activation) of Nrf2 in the hippocampus after doxorubicin treatment, whereas DRF indiscriminately activated Nrf2 in the hippocampus of vehicle-treated mice as well. Therapeutic actions of compound <strong>1c</strong> and DRF were lost in Nrf2 knockout mice, confirming Nrf2 as the therapeutic target. Nrf2 activators reversed doxorubicin-induced loss of synaptic protein PSD95 and restored microglial morphology in the hippocampus while there was no significant effect of the drug treatment on adult neurogenesis. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, and associated structural, phenotypic, and molecular changes in the hippocampus. The localized release of MMF by <strong>1c</strong> at sites of oxidative stress has the potential to diminish unwanted effects of fumarates while reversing CICI induced by doxorubicin.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 547-556"},"PeriodicalIF":8.8,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517371","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":"Il-6 knockout reduces doxorubicin-induced toxicity in the developing mouse brain","authors":"Jonas Yeung ,&nbsp;Henry Quach ,&nbsp;Amy P. Wong ,&nbsp;Anne L. Wheeler ,&nbsp;Rosanna Weksberg ,&nbsp;Sharon L. Guger ,&nbsp;Russell J. Schachar ,&nbsp;Shinya Ito ,&nbsp;Johann Hitzler ,&nbsp;Brian J. Nieman","doi":"10.1016/j.bbi.2025.06.034","DOIUrl":"10.1016/j.bbi.2025.06.034","url":null,"abstract":"<div><h3>Purpose</h3><div>Doxorubicin (DXR) treatment is linked to cognitive impairments in cancer patients, including pediatric survivors. However, since DXR does not readily cross the blood–brain barrier, systemic mechanisms such as DXR-induced elevations of pro-inflammatory cytokines may be key in mediating neurotoxicity. Using a mouse model of pediatric cancer treatment, we investigated cytokine levels following DXR treatment and evaluated its effects on brain toxicity through genetic knockout.</div></div><div><h3>Experimental design</h3><div>Mice were treated with DXR at a childhood-equivalent age (P17 and P19) and sacrificed at P20 to measure cytokine levels in plasma and brain tissue. IL-6 was significantly elevated in both after DXR treatment. We assessed brain volume alterations using longitudinal in vivo MRI (from P14 to P98) and performed histological analysis to further explore DXR impact on the brain in wildtype and <em>Il-6</em> knockout mice.</div></div><div><h3>Results</h3><div>DXR treatment caused widespread brain volume reductions. The volume reductions were partially rescued in <em>Il-6</em> knockout mice treated with DXR, which showed progressive brain volume improvements over time. Additionally, histological analysis revealed an increase in the pro-inflammatory microglial marker CD68 in wildtype mice treated with DXR, a response that was mitigated in <em>Il-6</em> knockout mice.</div></div><div><h3>Conclusions</h3><div>Our results indicate that IL-6 plays a role in DXR-induced brain toxicity, offering a potential mechanism by which DXR affects the brain despite its limited penetration of the blood–brain barrier. This study also provides evidence that targeting IL-6 may alleviate side effects of chemotherapy associated with structural brain changes, such as cognitive deficits in cancer survivors treated with DXR.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 609-619"},"PeriodicalIF":8.8,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522833","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":"Peripheral leptin receptor gene network modulates the impact of childhood adversity on mental health disorders","authors":"Randriely Merscher Sobreira de Lima ,&nbsp;Barbara Barth ,&nbsp;Danusa Mar Arcego ,&nbsp;Euclides José de Mendonça Filho ,&nbsp;Sachin Patel ,&nbsp;Zihan Wang ,&nbsp;Guillaume Elgbeili ,&nbsp;Irina Pokhvisneva ,&nbsp;Carine Parent ,&nbsp;Robert D. Levitan ,&nbsp;Michael S. Kobor ,&nbsp;Carla Dalmaz ,&nbsp;Patrícia Pelufo Silveira","doi":"10.1016/j.bbi.2025.06.035","DOIUrl":"10.1016/j.bbi.2025.06.035","url":null,"abstract":"<div><div>Psychiatric disorders are highly prevalent and often co-morbid with metabolic syndrome. Exposure to adversity in early life is a risk factor for both metabolic and behavioral problems, modifying leptin metabolism and signaling. Leptin is not only an energy-balance regulator, being also associated with the development of affective disorders. Our objective was to investigate if individual variations in peripheral leptin receptor (LepR) gene network function moderate the effect of childhood adversity on psychopathology. We created expression-based polygenic scores (ePRS) reflecting genetic variations that affect expression of the liver LepR gene network. We investigated the interaction between the LepR-ePRS and early adversity on mental health outcomes, namely anxiety and depression, in childhood (MAVAN) and adolescence (ALSPAC). In both cohorts, there were interaction effects between early adversity exposure and the liver-based LepR-ePRS, in which adversity was associated with depression only in individuals from the high ePRS group. Our findings suggest that exposure to early adversity is associated with mental health problems in children and adolescents. The liver leptin receptor gene network is an important moderator of these effects, and this may be due to individual differences within metabolic and inflammatory pathways represented by this gene network.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 585-594"},"PeriodicalIF":8.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522818","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":"Executive function and soluble urokinase-type plasminogen activator receptor (suPAR): a longitudinal study of midlife adults","authors":"Abigail Shell ,&nbsp;Colin Vize ,&nbsp;Peter Gianaros ,&nbsp;Line Jee Hartmann Rasmussen ,&nbsp;Anna L. Marsland","doi":"10.1016/j.bbi.2025.06.030","DOIUrl":"10.1016/j.bbi.2025.06.030","url":null,"abstract":"<div><div>Executive function (EF) declines with age. Declines in EF are associated with adverse outcomes, but there is substantial inter-individual variability in rate and magnitude of decline. Evidence suggests that systemic inflammation may contribute to declines in EF. Extant studies are largely cross-sectional and examine markers of inflammation that are not specific to the immune system and influenced by acute contemporaneous factors. We examined a newer marker of chronic inflammation, soluble urokinase Plasminogen Activator Receptor (suPAR) alongside more traditional markers, IL-6 and CRP. We hypothesized that higher baseline and greater increases in suPAR across an 8–19 (median 17) year period of midlife would associate with larger age-related declines in EF. Data were drawn from the Adult Health and Behavior (AHAB) study (n=599). Participants (55.5% female, 86.2% white, mean age 45 years at W1 and 60 years at W2) completed a neuropsychological battery and blood draw at both waves. EF was comprised of the Trail Making Test, the STROOP Test, and Matrix Reasoning. Univariate and Bivariate Latent change score models (LCSM) examined whether baseline and change in circulating levels of inflammatory mediators were associated with change in EF from W1 to W2. Baseline inflammation was not associated with change in EF. Increases in suPAR were significantly related to concomitant declines in EF (= −0.315; p &lt;.05). No similar effects were observed for IL6 or CRP. Further research should examine suPAR as potential marker of chronic systemic inflammation and its relationship to cognitive aging.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 537-546"},"PeriodicalIF":8.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511583","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":"Microglia-mediated neurogenesis is linked to cognitive deficits in a two-hit model of maternal immune activation and juvenile stress","authors":"Qiuying Zhao,&nbsp;Jiutai Wang,&nbsp;Yue Han,&nbsp;Wan Yan,&nbsp;Shuo Yan,&nbsp;Lei Xie,&nbsp;Zili You","doi":"10.1016/j.bbi.2025.06.032","DOIUrl":"10.1016/j.bbi.2025.06.032","url":null,"abstract":"<div><div>Maternal immune activation (MIA), combined with exposure to a second environmental stressor, contributes to neurodevelopmental disorders in offspring. Immune-challenged microglial cells play a crucial role in the pathogenesis of these disorders. However, the mechanisms through which microglia mediate cognitive impairments in individuals exposed to dual stresses remain poorly understood. In this research, pregnant rat dams were subjected to viral mimetic, poly(I:C), and their young male offspring were either exposed to a second stressor or not during juvenile age. The results showed that a pathological microglial phenotype was accompanied by impairments in hippocampal neurogenesis and deficits in hippocampus-dependent spatial learning and memory in the MIA offspring exposed to the second stressor during juvenile age. Minocycline shifts pathological microglial cells to a neuroprotective state, alleviating neurogenesis impairments and spatial learning and memory deficits in these “two-hit” animals. However, the cognitive improvements induced by minocycline were blocked by temozolomide treatment, as evidenced by the inhibition of neurogenesis. Our findings highlight the important role of hippocampal neurogenesis in inflammatory-mediated cognitive abnormalities and provide insights into the roles of microglia underlying neurodevelopmental disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 649-661"},"PeriodicalIF":8.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum kynurenine metabolites and cytokine levels: diagnostic and predictive implications in acute manic episodes of bipolar disorder","authors":"Wei Li ,&nbsp;Zhaofan Liu ,&nbsp;Jue Wang ,&nbsp;Xiaoying Wang ,&nbsp;Wenjin Chen ,&nbsp;Na Li ,&nbsp;Junchao Huang ,&nbsp;Mengzhuang Gou ,&nbsp;Ping Zhang ,&nbsp;Ran Liu ,&nbsp;Hu Deng ,&nbsp;Kebing Yang ,&nbsp;Song Chen ,&nbsp;Ting Xie ,&nbsp;Li Tian ,&nbsp;Fude Yang ,&nbsp;Baopeng Tian ,&nbsp;Chiang-Shan R. Li ,&nbsp;Yanli Li ,&nbsp;Yunlong Tan","doi":"10.1016/j.bbi.2025.06.033","DOIUrl":"10.1016/j.bbi.2025.06.033","url":null,"abstract":"<div><div>In this study, we aimed to integrate serum cytokine and kynurenine metabolite levels to identify key biomarkers for diagnosing and predicting treatment outcomes in bipolar disorder during manic episodes (BDM). A total of 52 patients with BDM and 49 healthy controls (HCs) were recruited. Serum levels of cytokines and kynurenine metabolites were measured at baseline. Manic symptom severity was assessed using the Young Mania Rating Scale (YMRS) at baseline and after 8 weeks of treatment. Correlations between cytokines and kynurenine metabolites were analysed. Support Vector Machine (SVM) classifiers and Partial Least Squares (PLS) regression were employed to differentiate individuals with BDM from HCs and to predict treatment outcomes based on these profiles. Key findings included: (1) significant differences in kynurenine metabolites between individuals with BDM and HCs, whereas cytokine levels did not differ significantly; (2) weaker correlations between cytokines and kynurenine metabolites in individuals with BDM compared to HCs; (3) integrated models of kynurenine and cytokine systems achieved 89 % cross-validated accuracy in classifying individuals with BDM and HCs, outperforming models based on either system alone; and (4) interleukin (IL)-10, IL-8, kynurenine, IL-4, and tryptophan were key predictors of treatment outcomes, with IL-10 correlating significantly with 8-week treatment response. This study highlights the potential of integrating these systems to improve diagnostic accuracy and predict treatment outcomes in individuals with BDM, offering insights into novel therapeutic targets.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 485-493"},"PeriodicalIF":8.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144491332","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":"Sex-specific spatial memory deficits associated with region-specific neuroinflammatory changes in the dorsal hippocampus of rats exposed to neonatal repeated maternal separation","authors":"Hannah Illouz ,&nbsp;Yannick Menger ,&nbsp;Ophélie Schaack ,&nbsp;Vincent Lelievre ,&nbsp;Pierrick Poisbeau","doi":"10.1016/j.bbi.2025.06.031","DOIUrl":"10.1016/j.bbi.2025.06.031","url":null,"abstract":"<div><div>The hippocampus is an essential brain structure for memory and emotional regulation and is particularly vulnerable to early life stress, which disrupts its development and increases the risk of neuropsychiatric disorders. Using the neonatal maternal separation model of early life stress, we explored sex-specific behavioral and molecular alterations, focusing on hippocampal function, neuroinflammation, and associated signaling pathways.</div><div>Our results show that neonatal maternal separation induces mechanical and thermal hypersensitivity, as well as anxiety-like behaviors in both male and female rats, but spatial memory deficits were observed exclusively in males. These male-specific cognitive impairments are associated with a pro-inflammatory response in the dorsal CA1 subregion of the hippocampus. Molecular analyses also showed sex- and region-specific changes in oxytocinergic signaling and chloride cotransporters, suggesting plastic mechanisms affecting local neuronal inhibition.</div><div>These findings highlight the pronounced sex differences in hippocampal vulnerability to early adversity, with males displaying an intense neuroinflammatory signature in dorsal CA1 associated with spatial memory deficits. This work highlights that the cognitive component of pain needs to be studied more systematically to better understand sex differences that are not necessarily easy to observe in the sensory and emotional components.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 388-398"},"PeriodicalIF":8.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335983","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}