Pub Date : 2025-12-24DOI: 10.1016/j.bbi.2025.106244
Mehwish Younas , Harry R. Deijnen , Ruth Stephens , Alison Harris , Thomas O. Williams , Sabrina Tamburrano , Ian E. Prise , Craig J. Smith , Stuart M. Allan , Laura McCulloch , John R. Grainger , Barry W. McColl
Distinct B cell populations are found in circulation, including those with innate-like properties, that have varied functions in pathogen protection, vaccination and immunoregulation. The effects of tissue injury on circulating B cell populations are poorly explored. Here we show that, following acute ischaemic stroke (AIS), a common cause of neurological disability associated with systemic immune dysfunction, the circulating B cell compartment has altered functionality, alongside marked reductions in marginal zone (MZ)-like B cells, an innate-like B cell subset. Of note, release of Immunoglobulin (Ig) M, a key innate-like B cell-derived factor important in anti-bacterial responses, and regulatory cytokines including IL-6 and IL-10, was impaired upon stimulation of sorted B cells from AIS patients. B cells express adrenergic receptors (ARs), in both control and AIS patients, and release of the β2-AR agonist noradrenaline (NA) is elevated acutely following stroke. In vitro exposure of B cells from healthy individuals to NA recapitulated some of the functional modulation observed in AIS patients. Moreover, increased cell death of MZ-like B cells was observed in response to NA. Secondary infection is a common post-stroke complication that could be responsible for altered B cell characteristics. However, in line with the impact of NA on B cell populations, alterations were largely driven by stroke rather than secondary infection. Taken together, these findings demonstrate that neuroimmune factors are an important signal that could rapidly modify defined B cell populations early after tissue injury and highlight altered innate-like B cell function as a previously unappreciated characteristic of the systemic immunological response to acute stroke.
{"title":"Acute ischaemic stroke alters the composition and function of circulating B cells","authors":"Mehwish Younas , Harry R. Deijnen , Ruth Stephens , Alison Harris , Thomas O. Williams , Sabrina Tamburrano , Ian E. Prise , Craig J. Smith , Stuart M. Allan , Laura McCulloch , John R. Grainger , Barry W. McColl","doi":"10.1016/j.bbi.2025.106244","DOIUrl":"10.1016/j.bbi.2025.106244","url":null,"abstract":"<div><div>Distinct B cell populations are found in circulation, including those with innate-like properties, that have varied functions in pathogen protection, vaccination and immunoregulation. The effects of tissue injury on circulating B cell populations are poorly explored. Here we show that, following acute ischaemic stroke (AIS), a common cause of neurological disability associated with systemic immune dysfunction, the circulating B cell compartment has altered functionality, alongside marked reductions in marginal zone (MZ)-like B cells, an innate-like B cell subset. Of note, release of Immunoglobulin (Ig) M, a key innate-like B cell-derived factor important in anti-bacterial responses, and regulatory cytokines including IL-6 and IL-10, was impaired upon stimulation of sorted B cells from AIS patients. B cells express adrenergic receptors (ARs), in both control and AIS patients, and release of the β2-AR agonist noradrenaline (NA) is elevated acutely following stroke. <em>In vitro</em> exposure of B cells from healthy individuals to NA recapitulated some of the functional modulation observed in AIS patients. Moreover, increased cell death of MZ-like B cells was observed in response to NA. Secondary infection is a common post-stroke complication that could be responsible for altered B cell characteristics. However, in line with the impact of NA on B cell populations, alterations were largely driven by stroke rather than secondary infection. Taken together, these findings demonstrate that neuroimmune factors are an important signal that could rapidly modify defined B cell populations early after tissue injury and highlight altered innate-like B cell function as a previously unappreciated characteristic of the systemic immunological response to acute stroke.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106244"},"PeriodicalIF":7.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843673","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 : 2025-12-22DOI: 10.1016/j.bbi.2025.106241
Yinxian Chen , Sarina Abrishamcar , Jasmine K. Aqua , Christian Dye , Linda C. Gallo , Maria M. Llabre , Frank J. Penedo , Carmen R. Isasi , Krista M. Perreira , Bharat Thyagarajan , Martha Daviglus , Amber Pirzada , Andrea Baccarelli , Karen N. Conneely , Rebecca Jones-Antwi , Shakira F. Suglia
Background
This study examined whether social factors, including social support, social networks, and familism, modify the longitudinal association between ACEs and epigenetic age acceleration (EAA).
Methods
We analyzed DNA methylation (DNAm) profile data from two visits (approximately six years apart) among 960 Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). GrimAge epigenetic age and DunedinPACE pace of aging were used. Linear mixed models examined effect modification of social support, social networks (network diversity and the number of embedded networks), and familism (family obligation, support, and as referents) on the association between high vs. low-to-moderate ACEs (i.e., ≥ 4 vs. < 4 ACEs) and repeatedly measured EAA. Models adjusted for age, sex, parental education, childhood economic hardship, nativity, and cell-type proportions. We also dichotomized the levels of social support and both subscales of social networks to low (≤ 75th percentile) and high (> 75th percentile), and assessed joint effect modification by social support and networks.
Results
The mean difference in GrimAge acceleration (AgeAccelGrim) between high and low-to-moderate ACEs was statistically significantly attenuated when social support levels were higher (β for interaction = -0.73 years; 95 % CI: −1.23, −0.24; p = 0.003). No evidence of effect modification was found for social networks or familism. Having only high social support (β for interaction = -1.40 years; 95 % CI: −2.79, −0.01; p = 0.049) or both high social support and network diversity (β for interaction = -1.57 years; 95 % CI: −2.72, −0.42; p = 0.008) significantly decreased the mean difference in AgeAccelGrim between high and low-to-moderate ACEs.
Conclusion
Social support may independently buffer the adverse impact of ACEs on biological age acceleration among Hispanic/Latino adults, and the buffering effect may be stronger when accompanied by diverse social networks.
背景：本研究探讨了社会支持、社会网络和家族主义等社会因素是否改变了ace与表观遗传年龄加速（EAA）之间的纵向关联。方法：我们分析了西班牙裔社区健康研究/拉丁裔研究（HCHS/SOL）中960名西班牙裔/拉丁裔成年人两次访问（间隔约6年）的DNA甲基化（DNAm）数据。采用GrimAge表观遗传年龄和DunedinPACE衰老速度。线性混合模型检验了社会支持、社会网络（网络多样性和嵌入网络的数量）和家庭主义（家庭义务、支持和作为参考）对高与低至中度ace（即≥4 vs 第75百分位）之间关联的效应修正，并评估了社会支持和网络的联合效应修正。结果：当社会支持水平较高时，高、低中度ace之间的平均grage加速（AgeAccelGrim）差异有统计学意义（β交互作用 = -0.73 年；95 % CI: -1.23, -0.24; p = 0.003）。没有证据表明社会网络或家庭主义的影响会改变。只有高社会支持(β互动 = -1.40 年;95年 % CI: -2.79, -0.01; p = 0.049)或高社会支持和网络多样性(β互动 = -1.57 年;95年 % CI: -2.72, -0.42; p = 0.008)显著下降的平均差AgeAccelGrim高和中度ace之间。结论：社会支持可以独立地缓冲ace对西班牙/拉丁裔成人生理年龄加速的不利影响，并且当社会网络多样化时，缓冲作用可能更强。
{"title":"Social factors as buffers for the adverse impact of adverse childhood experiences on biological age acceleration among adults in Hispanic Community Health Study / Study of Latinos","authors":"Yinxian Chen , Sarina Abrishamcar , Jasmine K. Aqua , Christian Dye , Linda C. Gallo , Maria M. Llabre , Frank J. Penedo , Carmen R. Isasi , Krista M. Perreira , Bharat Thyagarajan , Martha Daviglus , Amber Pirzada , Andrea Baccarelli , Karen N. Conneely , Rebecca Jones-Antwi , Shakira F. Suglia","doi":"10.1016/j.bbi.2025.106241","DOIUrl":"10.1016/j.bbi.2025.106241","url":null,"abstract":"<div><h3>Background</h3><div>This study examined whether social factors, including social support, social networks, and familism, modify the longitudinal association between ACEs and epigenetic age acceleration (EAA).</div></div><div><h3>Methods</h3><div>We analyzed DNA methylation (DNAm) profile data from two visits (approximately six years apart) among 960 Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). GrimAge epigenetic age and DunedinPACE pace of aging were used. Linear mixed models examined effect modification of social support, social networks (network diversity and the number of embedded networks), and familism (family obligation, support, and as referents) on the association between high vs. low-to-moderate ACEs (i.e., ≥ 4 vs. < 4 ACEs) and repeatedly measured EAA. Models adjusted for age, sex, parental education, childhood economic hardship, nativity, and cell-type proportions. We also dichotomized the levels of social support and both subscales of social networks to low (≤ 75th percentile) and high (> 75th percentile), and assessed joint effect modification by social support and networks.</div></div><div><h3>Results</h3><div>The mean difference in GrimAge acceleration (AgeAccelGrim) between high and low-to-moderate ACEs was statistically significantly attenuated when social support levels were higher (β for interaction = -0.73 years; 95 % CI: −1.23, −0.24; p = 0.003). No evidence of effect modification was found for social networks or familism. Having only high social support (β for interaction = -1.40 years; 95 % CI: −2.79, −0.01; p = 0.049) or both high social support and network diversity (β for interaction = -1.57 years; 95 % CI: −2.72, −0.42; p = 0.008) significantly decreased the mean difference in AgeAccelGrim between high and low-to-moderate ACEs.</div></div><div><h3>Conclusion</h3><div>Social support may independently buffer the adverse impact of ACEs on biological age acceleration among Hispanic/Latino adults, and the buffering effect may be stronger when accompanied by diverse social networks.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106241"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826918","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 : 2025-12-22DOI: 10.1016/j.bbi.2025.106240
J.C. Zwiep , F. Lamers , C.H. Vinkers , N.J.A. van der Wee , B.W.J.H. Penninx , L. Nawijn , Y. Milaneschi
Introduction
Depression manifests heterogenous bio-clinical profiles. Anhedonia has been previously linked to inflammation. Other research has associated inflammation and metabolic dysregulations with atypical, energy-related depressive symptoms (AES). In the present study, we examined the associations of inflammation and metabolic dysregulations with anhedonia and compared these associations with those of inflammation and metabolic dysregulations with AES, and with a negative control symptom profile, previously shown unrelated to inflammation and metabolic dysregulation.
Methods
Data was from 2,981 persons of the Netherlands Study of Depression and Anxiety (NESDA). Inflammatory markers included C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and glycoprotein acetyls. Metabolic markers were body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Anhedonia, AES and negative control symptom profiles were based on sum scores from different items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR). The results were internally replicated in NESDA’s 6-year follow-up (N = 2,256).
Results
Anhedonia was positively associated with IL-6, glycoprotein acetyls, BMI, waist circumference, triglycerides, glucose, and leptin (β ranging from 0.063 to 0.122) and negatively associated with HDL cholesterol (β = -0.063). Associations were only partially explained by major lifestyle and health-related factors and confirmed at 6-year follow-up (r = 0.939 correlation between estimates at baseline and follow-up). AES showed highly consistent associations with the markers, with relatively larger effects as compared to anhedonia, while the negative control symptoms were linked only to higher glycoprotein acetyls.
Conclusion
Our results indicate consistent associations between several markers of inflammation and metabolic dysregulation with anhedonia and AES. Full characterization of depression profiles and their complex interrelations should be leveraged in future clinical research to select specific subgroup of depressed patients and develop more targeted treatment approaches.
{"title":"Inflammation, metabolic dysregulation, and depression profiles related to anhedonia and atypical, energy-related symptoms","authors":"J.C. Zwiep , F. Lamers , C.H. Vinkers , N.J.A. van der Wee , B.W.J.H. Penninx , L. Nawijn , Y. Milaneschi","doi":"10.1016/j.bbi.2025.106240","DOIUrl":"10.1016/j.bbi.2025.106240","url":null,"abstract":"<div><h3>Introduction</h3><div>Depression manifests heterogenous bio-clinical profiles. Anhedonia has been previously linked to inflammation. Other research has associated inflammation and metabolic dysregulations with atypical, energy-related depressive symptoms (AES). In the present study, we examined the associations of inflammation and metabolic dysregulations with anhedonia and compared these associations with those of inflammation and metabolic dysregulations with AES, and with a negative control symptom profile, previously shown unrelated to inflammation and metabolic dysregulation.</div></div><div><h3>Methods</h3><div>Data was from 2,981 persons of the Netherlands Study of Depression and Anxiety (NESDA). Inflammatory markers included C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and glycoprotein acetyls. Metabolic markers were body mass index (BMI), waist circumference, triglycerides, high-density-lipoprotein cholesterol (HDL cholesterol), glucose and leptin. Anhedonia, AES and negative control symptom profiles were based on sum scores from different items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR). The results were internally replicated in NESDA’s 6-year follow-up (N = 2,256).</div></div><div><h3>Results</h3><div>Anhedonia was positively associated with IL-6, glycoprotein acetyls, BMI, waist circumference, triglycerides, glucose, and leptin (β ranging from 0.063 to 0.122) and negatively associated with HDL cholesterol (β = -0.063). Associations were only partially explained by major lifestyle and health-related factors and confirmed at 6-year follow-up (<em>r</em> = 0.939 correlation between estimates at baseline and follow-up). AES showed highly consistent associations with the markers, with relatively larger effects as compared to anhedonia, while the negative control symptoms were linked only to higher glycoprotein acetyls.</div></div><div><h3>Conclusion</h3><div>Our results indicate consistent associations between several markers of inflammation and metabolic dysregulation with anhedonia and AES. Full characterization of depression profiles and their complex interrelations should be leveraged in future clinical research to select specific subgroup of depressed patients and develop more targeted treatment approaches.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106240"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826954","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 : 2025-12-22DOI: 10.1016/j.bbi.2025.106239
Hatice Satilmis , Adrien Denis , Karin Vanderkerken , Elke De Bruyne , Eline Menu , Erica K Sloan , Kim De Veirman
The role of the sympathetic nervous system (SNS) in cancer biology has gained increasing attention, and its ability to affect immunotherapy is starting to become clearer. Extensive evidence shows that neuro-onco-immune interactions significantly influence tumor progression and the effectiveness of cancer treatments. Blocking SNS signaling, primarily through β-adrenergic receptors, enhances immune cell functions, by increasing CD8+ T-cell activation and cytokine production, while reducing immunosuppressive cell populations.
This review explores the relationship between SNS signaling and cancer immunotherapy, emphasizing how SNS activation affects the efficacy of various immunotherapies, including immune modulators, immune checkpoint inhibitors, oncolytic virus therapy, therapeutic vaccines, and CAR-T cell therapies. We summarize retrospective studies investigating the use of β-blockers during immunotherapy, suggesting potential benefits for treatment outcomes of blocking SNS signaling in the tumor microenvironment. We examine ongoing clinical trials that evaluate the use of beta-blockers with immune checkpoint inhibitors, which aim to improve patient outcomes. While translational and preclinical studies provide ample evidence for targeting SNS signaling in cancer immunotherapy, clinical studies are only beginning to emerge. Ultimately, this review underscores the need for further research to better understand how SNS signaling can be targeted to optimize immunotherapy, paving the way for more effective treatment strategies.
{"title":"Neural control of Immunotherapy: how Tumor-innervation shapes Anti-Tumor immune responses","authors":"Hatice Satilmis , Adrien Denis , Karin Vanderkerken , Elke De Bruyne , Eline Menu , Erica K Sloan , Kim De Veirman","doi":"10.1016/j.bbi.2025.106239","DOIUrl":"10.1016/j.bbi.2025.106239","url":null,"abstract":"<div><div>The role of the sympathetic nervous system (SNS) in cancer biology has gained increasing attention, and its ability to affect immunotherapy is starting to become clearer. Extensive evidence shows that neuro-onco-immune interactions significantly influence tumor progression and the effectiveness of cancer treatments. Blocking SNS signaling, primarily through β-adrenergic receptors, enhances immune cell functions, by increasing CD8<sup>+</sup> T-cell activation and cytokine production, while reducing immunosuppressive cell populations.</div><div>This review explores the relationship between SNS signaling and cancer immunotherapy, emphasizing how SNS activation affects the efficacy of various immunotherapies, including immune modulators, immune checkpoint inhibitors, oncolytic virus therapy, therapeutic vaccines, and CAR-T cell therapies. We summarize retrospective studies investigating the use of β-blockers during immunotherapy, suggesting potential benefits for treatment outcomes of blocking SNS signaling in the tumor microenvironment. We examine ongoing clinical trials that evaluate the use of beta-blockers with immune checkpoint inhibitors, which aim to improve patient outcomes. While translational and preclinical studies provide ample evidence for targeting SNS signaling in cancer immunotherapy, clinical studies are only beginning to emerge. Ultimately, this review underscores the need for further research to better understand how SNS signaling can be targeted to optimize immunotherapy, paving the way for more effective treatment strategies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106239"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826889","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 : 2025-12-22DOI: 10.1016/j.bbi.2025.106242
Natalie M. Antenucci , Mallory J. Feldman , Tatum A. Jolink , Taylor N. West , Megan N. Cardenas , Gabriella M. Alvarez , Keely A. Muscatell
While social group divisions occur naturally, inauspicious contexts like pathogen threat may exacerbate divides, driving in-group favoritism and out-group derogation. Minimal work has examined biological underpinnings of intergroup dynamics, particularly immune changes likely to accompany pathogen threat. To address this, we administered the influenza vaccine to 44 young adult participants. Before and after receiving the vaccine, participants completed a modified affect misattribution procedure, wherein they rated the trustworthiness of racial in-group and out-group faces. Participants also provided pre- and post-vaccine blood samples which were assayed for the inflammatory cytokine interleukin-6 (IL-6). Results showed a negative association between inflammatory reactivity and ratings of out-group faces: those who experienced greater increases in IL-6 rated racial out-group faces as less trustworthy than those with less IL-6 reactivity. This work begins exploring the role of inflammation in intergroup processes and findings, while preliminary, suggest a novel biological process that is associated with intergroup perception.
{"title":"Increases in inflammation are associated with decreased trust of racial out-group members","authors":"Natalie M. Antenucci , Mallory J. Feldman , Tatum A. Jolink , Taylor N. West , Megan N. Cardenas , Gabriella M. Alvarez , Keely A. Muscatell","doi":"10.1016/j.bbi.2025.106242","DOIUrl":"10.1016/j.bbi.2025.106242","url":null,"abstract":"<div><div>While social group divisions occur naturally, inauspicious contexts like pathogen threat may exacerbate divides, driving in-group favoritism and out-group derogation. Minimal work has examined biological underpinnings of intergroup dynamics, particularly immune changes likely to accompany pathogen threat. To address this, we administered the influenza vaccine to 44 young adult participants. Before and after receiving the vaccine, participants completed a modified affect misattribution procedure, wherein they rated the trustworthiness of racial in-group and out-group faces. Participants also provided pre- and post-vaccine blood samples which were assayed for the inflammatory cytokine interleukin-6 (IL-6). Results showed a negative association between inflammatory reactivity and ratings of out-group faces: those who experienced greater increases in IL-6 rated racial out-group faces as less trustworthy than those with less IL-6 reactivity. This work begins exploring the role of inflammation in intergroup processes and findings, while preliminary, suggest a novel biological process that is associated with intergroup perception.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106242"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826965","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 : 2025-12-22DOI: 10.1016/j.bbi.2025.106243
Jay O’Shields , Helisha Soni , Orion Mowbray
Objective
Major depression is often difficult to treat, particularly among individuals exposed to psychosocial risks like childhood maltreatment, loneliness, and recent stress. These experiences may lead to biological dysregulation consistent with allostatic load theory. This study explored whether distinct biological profiles among adults with depression are associated with specific psychosocial and health-related factors.
Method
Data were drawn from the Midlife in the United States study (MIDUS), including 367 participants with clinically significant depressive symptoms (CES-D ≥ 16). Latent profile analysis identified biological profiles based on 23 biomarkers across seven systems: inflammation, glucose, sympathetic and parasympathetic nervous systems, HPA-axis, cardiovascular, and lipids. Multinomial regression models examined associations between profile membership and psychosocial (childhood maltreatment, loneliness, recent stress), health (alcohol use, smoking, exercise), and demographic variables (sex, race/ethnicity, age, education).
Results
A five-profile solution best fit the data: High Inflammation & Glucose (n = 74), Low PNS (n = 83), High PNS (n = 73), Healthy Depression (n = 67), and High HPA-Axis (n = 70). Childhood maltreatment significantly predicted membership in the High Inflammation & Glucose and Low PNS profiles compared to the Healthy Depression group, even after controlling for health behaviors and demographics. Loneliness and recent stress were not significant predictors.
Conclusion
Childhood maltreatment is a predictor of biological dysregulation in depression, differentially predicting profiles characterized by inflammatory and metabolic vs parasympathetic functioning. These may represent different vulnerability pathways from social experiences to depressive illness. Incorporating measurement strategies specific to these pathways may aide in selecting treatment options for people who have depression and a history of childhood maltreatment.
目的：重度抑郁症通常很难治疗，特别是那些暴露于心理社会风险的个体，如童年虐待、孤独和最近的压力。这些经历可能导致与适应负荷理论一致的生物失调。这项研究探讨了成人抑郁症患者的不同生物学特征是否与特定的社会心理和健康相关因素有关。方法：数据来自Midlife in the United States研究（MIDUS），包括367名具有临床显著抑郁症状（CES-D ≥ 16）的参与者。潜在特征分析确定了基于七个系统的23个生物标志物的生物特征：炎症、葡萄糖、交感和副交感神经系统、hpa轴、心血管和脂质。多项回归模型检验了档案成员与社会心理（童年虐待、孤独、最近的压力）、健康（饮酒、吸烟、锻炼）和人口统计变量（性别、种族/民族、年龄、教育）之间的关联。结果:five-profile解决方案最适合的数据:高炎症和葡萄糖(n = 74),低pn (n = 83),高pn (n = 73),健康的抑郁症(n = 67),和高hpa轴(n = 70)。与健康抑郁组相比，童年虐待显著预测了高炎症、高血糖和低PNS特征的成员，即使在控制了健康行为和人口统计学之后也是如此。孤独和最近的压力并不是显著的预测因子。结论：童年虐待是抑郁症生物学失调的预测因子，预测炎症和代谢与副交感神经功能的差异。这些可能代表了从社会经历到抑郁症的不同脆弱性途径。结合特定于这些途径的测量策略可能有助于为患有抑郁症和童年虐待史的人选择治疗方案。
{"title":"Using social risk factors to predict allostatic biotypes of depression: A latent profile and multinomial regression analysis","authors":"Jay O’Shields , Helisha Soni , Orion Mowbray","doi":"10.1016/j.bbi.2025.106243","DOIUrl":"10.1016/j.bbi.2025.106243","url":null,"abstract":"<div><h3>Objective</h3><div>Major depression is often difficult to treat, particularly among individuals exposed to psychosocial risks like childhood maltreatment, loneliness, and recent stress. These experiences may lead to biological dysregulation consistent with allostatic load theory. This study explored whether distinct biological profiles among adults with depression are associated with specific psychosocial and health-related factors.</div></div><div><h3>Method</h3><div>Data were drawn from the Midlife in the United States study (MIDUS), including 367 participants with clinically significant depressive symptoms (CES-D ≥ 16). Latent profile analysis identified biological profiles based on 23 biomarkers across seven systems: inflammation, glucose, sympathetic and parasympathetic nervous systems, HPA-axis, cardiovascular, and lipids. Multinomial regression models examined associations between profile membership and psychosocial (childhood maltreatment, loneliness, recent stress), health (alcohol use, smoking, exercise), and demographic variables (sex, race/ethnicity, age, education).</div></div><div><h3>Results</h3><div>A five-profile solution best fit the data: High Inflammation & Glucose (<em>n</em> = 74), Low PNS (<em>n</em> = 83), High PNS (<em>n</em> = 73), Healthy Depression (<em>n</em> = 67), and High HPA-Axis (<em>n</em> = 70). Childhood maltreatment significantly predicted membership in the High Inflammation & Glucose and Low PNS profiles compared to the Healthy Depression group, even after controlling for health behaviors and demographics. Loneliness and recent stress were not significant predictors.</div></div><div><h3>Conclusion</h3><div>Childhood maltreatment is a predictor of biological dysregulation in depression, differentially predicting profiles characterized by inflammatory and metabolic vs parasympathetic functioning. These may represent different vulnerability pathways from social experiences to depressive illness. Incorporating measurement strategies specific to these pathways may aide in selecting treatment options for people who have depression and a history of childhood maltreatment.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106243"},"PeriodicalIF":7.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826944","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 : 2025-12-20DOI: 10.1016/j.bbi.2025.106235
Yan Li , Guangfa Wang , Xinyu Fang , Yuru Ling , Chao Zhou , Jin Fang , Renliang Cai , Yunshan Hu , Chaoran Wu , Shaotong Zhang , Ayesha Zafar Iqbal , Yu Wang , Kuan-Pin Su , Xiangrong Zhang
Background
Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.
Methods
We conducted untargeted metabolomics analyses (GC–MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.
Results
Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.
Conclusions
This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT’s therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.
{"title":"Metabolomic signatures of electroconvulsive therapy in schizophrenia: Mitochondrial energy metabolism and inflammation as therapeutic targets","authors":"Yan Li , Guangfa Wang , Xinyu Fang , Yuru Ling , Chao Zhou , Jin Fang , Renliang Cai , Yunshan Hu , Chaoran Wu , Shaotong Zhang , Ayesha Zafar Iqbal , Yu Wang , Kuan-Pin Su , Xiangrong Zhang","doi":"10.1016/j.bbi.2025.106235","DOIUrl":"10.1016/j.bbi.2025.106235","url":null,"abstract":"<div><h3>Background</h3><div>Electroconvulsive therapy (ECT) demonstrates efficacy in treatment-resistant schizophrenia, yet the underlying metabolic mechanisms remain poorly understood. This study employed comprehensive metabolomics to elucidate the therapeutic mechanisms of ECT and identify predictive biomarkers.</div></div><div><h3>Methods</h3><div>We conducted untargeted metabolomics analyses (GC–MS/LC-MS) on plasma samples from 78 schizophrenia patients (pre- and post-ECT) and 76 healthy controls, followed by targeted metabolomics validation in an independent schizophrenia cohort (n = 66). Advanced bioinformatics, including WGCNA and SVM-RFE, identified treatment-responsive metabolites.</div></div><div><h3>Results</h3><div>Schizophrenia patients exhibited 542 differentially expressed metabolites compared to controls (420 downregulated, 122 upregulated), predominantly lipids involved in energy metabolism pathways. Post-ECT, 200 metabolites changed significantly (153 upregulated, 47 downregulated), primarily affecting glycolysis, ketone body metabolism, and inflammatory pathways. WGCNA revealed metabolites in the turquoise module (n = 1329) strongly correlated with symptom severity. SVM-RFE identified 10 baseline metabolites distinguishing ECT responders from non-responders (AUC = 0.724). Targeted validation confirmed 6 metabolites, with 4 showing consistent elevation in responders: N-phenylanthranilic acid, Hydroxy-alpha-sanshool and Linoelaidic acid, and Piperine. Crucially, only responders demonstrated significant post-ECT increases in Hydroxy-alpha-sanshool and Piperine, both TRPV1/TRPA1 channel agonists implicated in neuroprotection and inflammation modulation.</div></div><div><h3>Conclusions</h3><div>This first comprehensive metabolomic investigation of ECT in schizophrenia reveals energy metabolism dysregulation as a core pathophysiological mechanism. ECT’s therapeutic effects involve metabolic reprogramming and inflammation resolution, with Hydroxy-alpha-sanshool and Piperine emerging as potential predictive and therapeutic candidates. These findings advance precision psychiatry approaches and provide mechanistic insights for developing novel schizophrenia treatments targeting mitochondrial-inflammatory networks.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106235"},"PeriodicalIF":7.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.bbi.2025.106232
Ellen Jopling , Avril Metcalfe-Roach , Stuart E. Turvey , Piushkumar Mandhane , the CHILD Study investigators , B. Brett Finlay , Joelle LeMoult
Elevated stress during the prenatal period is associated with increased psychiatric risk among children. However, less is known about the mechanisms through which this intergenerational transmission of risk occurs. The early life microbiome is one candidate mechanism through which maternal stress during the prenatal period could impact offspring mental health, with a growing body of literature highlighting the importance of the early life microbiome in mental health across the lifespan. This study leverages Canada’s largest deeply phenotyped birth cohort to elucidate the mechanistic associations between maternal prenatal stress, dynamic changes in the microbiome across the first year of life, and child internalizing symptoms. Analytic sample size with use of full information maximum likelihood methodology was 2,985. Analyses indicated that early diversification of the early life microbiome significantly mediated the relation between higher maternal perceived stress during pregnancy and increased internalizing symptoms among offspring at 5 years of age. Crucially, microbial taxa impacted by early diversification of the microbiome implicated the immune system. This work supports maturational dynamics of the microbiome as one mechanism through which prenatal stress is biologically embedded to impact offspring’s later mental health. By linking several burgeoning areas of research, this study lays the groundwork for future multidisciplinary work examining the intergenerational transmission of psychiatric risk through the microbiome.
{"title":"The infant gut microbiome and the intergenerational transmission of psychiatric risk","authors":"Ellen Jopling , Avril Metcalfe-Roach , Stuart E. Turvey , Piushkumar Mandhane , the CHILD Study investigators , B. Brett Finlay , Joelle LeMoult","doi":"10.1016/j.bbi.2025.106232","DOIUrl":"10.1016/j.bbi.2025.106232","url":null,"abstract":"<div><div>Elevated stress during the prenatal period is associated with increased psychiatric risk among children. However, less is known about the mechanisms through which this intergenerational transmission of risk occurs. The early life microbiome is one candidate mechanism through which maternal stress during the prenatal period could impact offspring mental health, with a growing body of literature highlighting the importance of the early life microbiome in mental health across the lifespan. This study leverages Canada’s largest deeply phenotyped birth cohort to elucidate the mechanistic associations between maternal prenatal stress, dynamic changes in the microbiome across the first year of life, and child internalizing symptoms. Analytic sample size with use of full information maximum likelihood methodology was 2,985. Analyses indicated that early diversification of the early life microbiome significantly mediated the relation between higher maternal perceived stress during pregnancy and increased internalizing symptoms among offspring at 5 years of age. Crucially, microbial taxa impacted by early diversification of the microbiome implicated the immune system. This work supports maturational dynamics of the microbiome as one mechanism through which prenatal stress is biologically embedded to impact offspring’s later mental health. By linking several burgeoning areas of research, this study lays the groundwork for future multidisciplinary work examining the intergenerational transmission of psychiatric risk through the microbiome.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106232"},"PeriodicalIF":7.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809642","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 : 2025-12-20DOI: 10.1016/j.bbi.2025.106237
Vera Korenblik , Natalia K.M. Schilder , Ilke G.S. de Lange , Joost G. Daams , Claudi L.H. Bockting , Stanley Brul , Max Nieuwdorp , Anja Lok , Aniko Korosi
<div><h3>Introduction</h3><div>Despite available therapies for depression, many patients do not achieve adequate improvement, illustrating the need for innovative treatment strategies. Nutritional psychiatry is an emerging area, with increasing evidence that microbially derived butyrate contributes to the beneficial effects of dietary, pre-, pro- and synbiotics interventions − raising the exciting possibility that direct butyrate administration might alleviate depressive symptoms. The main objective was to systematically review the effects of butyrate on depressive symptoms in humans and depressive-like behavior in animals (PROSPERO; CRD42023g0739).</div></div><div><h3>Methods</h3><div>A search was conducted in MEDLINE, Embase, PsycINFO, and Web of Science, ICTPR and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> up to October 2025. Studies were included if they examined depressive symptoms in humans or relevant behaviors in animal models of depression/anxiety, involved treatment with butyrate formulations, included a control or pre-post comparison, and reported behavioral or clinical outcomes. Eligible designs included case-control, cohort, (randomized) controlled trials, experimental, or in vivo studies published in English or Dutch. Studies were excluded if depression was not the primary focus or if butyrate was combined with another treatment. Risk of bias was assessed with SYRCLE for animal studies and RoB 2 for the human studies.</div></div><div><h3>Results</h3><div>Of the two randomized controlled trials, one found no measurable effect of 1-week oral butyrate in healthy males, whereas the other found reductions in depressive and anxiety symptoms in patients with ulcerative colitis after 12-weeks oral butyrate. Thirty-two animal studies showed that butyrate generally modulated depressive- and anxiety-like phenotypes in rodents, potentially via anti-inflammatory, neuroplastic, epigenetic and gut-mediated mechanisms.</div></div><div><h3>Discussion</h3><div>Preclinical findings support the therapeutic promise of butyrate as a novel intervention for depression, warranting further clinical investigation.</div><div>Abbreviations: BDNF, Brain-derived neurotrophic factor; CRS, Chronic restraint stress; CSD, Chronic social defeat; CUMS, Chronic unpredictable mild stress; DASS, Depression, anxiety, Stress Scales; EPM, Elevated plus maze; FMT, Fecal microbiota transplant; FST, Forced swim test; HDAC, Histone deacetylase; HFD, High-fat diet; HPA, Hypothalamic–pituitary–adrenal; ICTRP International Clinical Trials Registry Platform; IL, Interleukin; LDB, Light-dark box; LEIDS-R, Leiden Index of Depression Severity-Revised; LPS, Lipopolysaccharide; MD, Maternal deprivation; MDD, Major depressive disorder; MGBA, Microbiota-gut-brain axis; NORT, Novel object recognition test; OFT, Open field test; PFC, Prefrontal cortex; PRISMA Preferred reporting items for systematic reviews and meta-analyses; SCFA, Short-chain fatty acid; SPT, Sucro
导言：尽管有治疗抑郁症的方法，但许多患者并没有得到充分的改善，这说明需要创新的治疗策略。营养精神病学是一个新兴的领域，越来越多的证据表明，微生物衍生的丁酸盐有助于饮食、前、前和合成干预的有益效果，这增加了直接给药丁酸盐可能减轻抑郁症状的令人兴奋的可能性。主要目的是系统地回顾丁酸盐对人类抑郁症状和动物抑郁样行为的影响（PROSPERO; CRD42023g0739）。方法：检索截至2025年10月的MEDLINE、Embase、PsycINFO、Web of Science、ICTPR和ClinicalTrials.gov。如果研究检查了人类的抑郁症状或抑郁/焦虑动物模型的相关行为，涉及丁酸盐制剂治疗，包括对照或前后比较，并报告了行为或临床结果，则纳入研究。符合条件的设计包括以英语或荷兰语发表的病例对照、队列、（随机）对照试验、实验或体内研究。如果抑郁症不是主要焦点，或者丁酸盐单独与其他治疗联合使用，则排除研究。对动物研究的偏倚风险进行了cycle评估，对人类研究的偏倚风险进行了RoB 2评估。结果：在两项随机对照试验中，一项发现健康男性口服1周丁酸盐没有可测量的效果，而另一项发现溃疡性结肠炎患者口服12周丁酸盐后抑郁和焦虑症状减轻。32项动物研究表明，丁酸盐可能通过抗炎、神经可塑性、表观遗传和肠道介导的机制，普遍调节啮齿动物的抑郁和焦虑样表型。讨论：临床前研究结果支持丁酸盐作为一种新的抑郁症干预手段的治疗前景，值得进一步的临床研究。缩写：BDNF，脑源性神经营养因子；慢性约束应激；慢性社会失败；慢性不可预测的轻度应激；抑郁，焦虑，压力量表；EPM，高架+迷宫；FMT，粪便微生物群移植；FST：力游试验；组蛋白去乙酰化酶；HFD，高脂肪饮食；HPA -肾上腺;ICTRP国际临床试验注册平台；IL,白介素;LDB，明暗箱；LEIDS-R抑郁严重程度Leiden指数修订有限合伙人,脂多糖;MD，孕产妇剥夺；重度抑郁障碍；MGBA，微生物-肠-脑轴；NORT，新目标识别测试；OFT，开场测试；前额叶皮层；用于系统评价和荟萃分析的首选报告项目；短链脂肪酸；蔗糖偏好试验；sycle，实验动物实验系统审查中心；TCA，三羧酸；肿瘤坏死因子；TST，尾悬架试验；ZO-1 Zonulin-1。
{"title":"From gut to glee: Is butyrate a promising antidepressant? A systematic review and mechanistic insights","authors":"Vera Korenblik , Natalia K.M. Schilder , Ilke G.S. de Lange , Joost G. Daams , Claudi L.H. Bockting , Stanley Brul , Max Nieuwdorp , Anja Lok , Aniko Korosi","doi":"10.1016/j.bbi.2025.106237","DOIUrl":"10.1016/j.bbi.2025.106237","url":null,"abstract":"<div><h3>Introduction</h3><div>Despite available therapies for depression, many patients do not achieve adequate improvement, illustrating the need for innovative treatment strategies. Nutritional psychiatry is an emerging area, with increasing evidence that microbially derived butyrate contributes to the beneficial effects of dietary, pre-, pro- and synbiotics interventions − raising the exciting possibility that direct butyrate administration might alleviate depressive symptoms. The main objective was to systematically review the effects of butyrate on depressive symptoms in humans and depressive-like behavior in animals (PROSPERO; CRD42023g0739).</div></div><div><h3>Methods</h3><div>A search was conducted in MEDLINE, Embase, PsycINFO, and Web of Science, ICTPR and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> up to October 2025. Studies were included if they examined depressive symptoms in humans or relevant behaviors in animal models of depression/anxiety, involved treatment with butyrate formulations, included a control or pre-post comparison, and reported behavioral or clinical outcomes. Eligible designs included case-control, cohort, (randomized) controlled trials, experimental, or in vivo studies published in English or Dutch. Studies were excluded if depression was not the primary focus or if butyrate was combined with another treatment. Risk of bias was assessed with SYRCLE for animal studies and RoB 2 for the human studies.</div></div><div><h3>Results</h3><div>Of the two randomized controlled trials, one found no measurable effect of 1-week oral butyrate in healthy males, whereas the other found reductions in depressive and anxiety symptoms in patients with ulcerative colitis after 12-weeks oral butyrate. Thirty-two animal studies showed that butyrate generally modulated depressive- and anxiety-like phenotypes in rodents, potentially via anti-inflammatory, neuroplastic, epigenetic and gut-mediated mechanisms.</div></div><div><h3>Discussion</h3><div>Preclinical findings support the therapeutic promise of butyrate as a novel intervention for depression, warranting further clinical investigation.</div><div>Abbreviations: BDNF, Brain-derived neurotrophic factor; CRS, Chronic restraint stress; CSD, Chronic social defeat; CUMS, Chronic unpredictable mild stress; DASS, Depression, anxiety, Stress Scales; EPM, Elevated plus maze; FMT, Fecal microbiota transplant; FST, Forced swim test; HDAC, Histone deacetylase; HFD, High-fat diet; HPA, Hypothalamic–pituitary–adrenal; ICTRP International Clinical Trials Registry Platform; IL, Interleukin; LDB, Light-dark box; LEIDS-R, Leiden Index of Depression Severity-Revised; LPS, Lipopolysaccharide; MD, Maternal deprivation; MDD, Major depressive disorder; MGBA, Microbiota-gut-brain axis; NORT, Novel object recognition test; OFT, Open field test; PFC, Prefrontal cortex; PRISMA Preferred reporting items for systematic reviews and meta-analyses; SCFA, Short-chain fatty acid; SPT, Sucro","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106237"},"PeriodicalIF":7.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809617","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 : 2025-12-20DOI: 10.1016/j.bbi.2025.106231
Rui Jiang , Ye Zhao , Lizhe Liu , Xueyong Yin , Jingxuan Yang , Zimo Tian , Xinran Hu , Yunxiang Ge , Yinuo Xin , Zicheng Wang , Zexi Zhen , Mengqi Han , Yun Shi , Xiaohui Xian , Yuan Gao , Haishui Shi
Sleep loss has been reported to induce alteration of immune homeostasis and brain dysfunction. The long-term consequences of early life sleep fragmentation (SF) on brain function and the underlying mechanisms are still poorly understood. The present study investigates the effects of postweaning SF on social behavior in adult mice, with a particular focus on ultrastructural and functional alterations in the ventral hippocampus and the potential therapeutic efficacy of oleoylethanolamide (OEA). Our findings demonstrate that postweaning SF induces significant behavioral deficits in adult social interactions. These behavioral changes were accompanied by ultrastructural damage to hippocampal neurons and synapses, as well as increased synaptic elimination mediated by microglia, which collectively contributed to long-term potentiation (LTP) impairment. Additionally, a pronounced reduction in hippocampal OEA levels was observed, indicative of disrupted metabolic homeostasis associated with SF. Notably, OEA administration effectively reversed SF-induced behavioral deficits, companied with restored LTP deficits, enhanced synaptic plasticity, and attenuated synaptic elimination. These results highlight the enduring impact of early-life SF on adult social behavior and hippocampal integrity, suggesting that OEA represents a promising therapeutic strategy for mitigating sleep-induced neuronal dysfunction and improving cognitive outcomes.
{"title":"Oleoylethanolamide supplement attenuates postweaning sleep fragmentation-induced social behavioral deficits via inhibiting hippocampal microglial reactivity in adult mice","authors":"Rui Jiang , Ye Zhao , Lizhe Liu , Xueyong Yin , Jingxuan Yang , Zimo Tian , Xinran Hu , Yunxiang Ge , Yinuo Xin , Zicheng Wang , Zexi Zhen , Mengqi Han , Yun Shi , Xiaohui Xian , Yuan Gao , Haishui Shi","doi":"10.1016/j.bbi.2025.106231","DOIUrl":"10.1016/j.bbi.2025.106231","url":null,"abstract":"<div><div>Sleep loss has been reported to induce alteration of immune homeostasis and brain dysfunction. The long-term consequences of early life sleep fragmentation (SF) on brain function and the underlying mechanisms are still poorly understood. The present study investigates the effects of postweaning SF on social behavior in adult mice, with a particular focus on ultrastructural and functional alterations in the ventral hippocampus and the potential therapeutic efficacy of oleoylethanolamide (OEA). Our findings demonstrate that postweaning SF induces significant behavioral deficits in adult social interactions. These behavioral changes were accompanied by ultrastructural damage to hippocampal neurons and synapses, as well as increased synaptic elimination mediated by microglia, which collectively contributed to long-term potentiation (LTP) impairment. Additionally, a pronounced reduction in hippocampal OEA levels was observed, indicative of disrupted metabolic homeostasis associated with SF. Notably, OEA administration effectively reversed SF-induced behavioral deficits, companied with restored LTP deficits, enhanced synaptic plasticity, and attenuated synaptic elimination. These results highlight the enduring impact of early-life SF on adult social behavior and hippocampal integrity, suggesting that OEA represents a promising therapeutic strategy for mitigating sleep-induced neuronal dysfunction and improving cognitive outcomes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106231"},"PeriodicalIF":7.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809666","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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