Pub Date : 2025-12-18DOI: 10.1016/j.bbi.2025.106233
Michael R. Duggan , Zena K. Chatila , Lavinia A. Auber , Esther Silberberg , Juan R. Fernandez , Keenan A. Walker , Nikki M. Schultek
Investments in SARS-CoV-2 research provide a unique opportunity to explore how microbes may contribute to neurological conditions, an area of investigation that has been chronically underfunded. As exemplified by HIV/AIDS funding, crisis-driven research can yield broader biomedical advances, including spillover effects that address unanticipated and unmet medical needs. Leveraging newly established SARS-CoV-2 funding opportunities to study immune crosstalk and genetic predispositions could reveal therapeutic pathways and biomarkers for individuals who are vulnerable to infection-related dementia risk and neuropsychiatric symptoms. Despite the vast consequences of SARS-CoV-2, research investments following this pandemic may have long lasting benefits for other scientific endeavors, including insights for microbial contributions to neurodegenerative disease.
{"title":"Can the COVID-19 pandemic advance neuroinfectious research?","authors":"Michael R. Duggan , Zena K. Chatila , Lavinia A. Auber , Esther Silberberg , Juan R. Fernandez , Keenan A. Walker , Nikki M. Schultek","doi":"10.1016/j.bbi.2025.106233","DOIUrl":"10.1016/j.bbi.2025.106233","url":null,"abstract":"<div><div>Investments in SARS-CoV-2 research provide a unique opportunity to explore how microbes may contribute to neurological conditions, an area of investigation that has been chronically underfunded. As exemplified by HIV/AIDS funding, crisis-driven research can yield broader biomedical advances, including spillover effects that address unanticipated and unmet medical needs. Leveraging newly established SARS-CoV-2 funding opportunities to study immune crosstalk and genetic predispositions could reveal therapeutic pathways and biomarkers for individuals who are vulnerable to infection-related dementia risk and neuropsychiatric symptoms. Despite the vast consequences of SARS-CoV-2, research investments following this pandemic may have long lasting benefits for other scientific endeavors, including insights for microbial contributions to neurodegenerative disease.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106233"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797460","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 : 2025-12-18DOI: 10.1016/j.bbi.2025.106228
Sarah E. Fromme , Gara Arteaga-Henríquez , Bartholomeus C.M. Haarman , Annemarie Wijkhuijs , Raf Berghmans , Trine Munk-Olsen , Hemmo Drexhage , Bernhard T. Baune
<div><div>A proportion of patients diagnosed with major depressive disorder (MDD) exhibit signs of premature T cell aging, i.e. memory T cell inflation, characterized by elevated levels of memory CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Physical endurance training, including spinning therapy (ST), is known to counteract both T cell aging and depression.</div><div>The primary aim of this randomized, treatment-as-usual (TAU)-controlled study was to investigate whether signs of T cell aging (determined prior to ST) characterized remitters and responders to the intervention.</div><div>Patients aged 18–65 years with a diagnosis of MDD (Hamilton Depression Rating Scale (HDRS) ≥ 13) were included and randomized 1:1 to TAU or TAU + ST. The intervention consisted of moderate-intensity cycling sessions (30 min, three times per week), for eight consecutive weeks. A total of 72 patients (n = 35 TAU, n = 37 TAU + ST) with complete baseline immunophenotyping were included in the analyses (49 % females; mean age, 32 years).</div><div>We found that remitters to TAU + ST displayed significantly higher baseline levels of CD8<sup>+</sup> memory T cells, particularly T central memory (Tcm) cells and T effector memory cells re-expressing CD45RA (TEMRA) cells, compared to non-remitters. Correction for potential confounders and logistic regression analysis revealed that baseline levels of CD8<sup>+</sup> Tcm cells showed the strongest predictive value in the TAU + ST group (OR = 7.66, <em>P</em> = 0.03), suggesting that these cells may serve as treatment-specific predictors of remission to adjunctive ST. Post hoc stratification of patients based on the levels of CD8<sup>+</sup>Tcm cells identified a subgroup of n = 20 patients exhibiting several signs of T cell inflation in both the CD8<sup>+</sup> and CD4<sup>+</sup> T memory cell populations. This subgroup was older and showed a higher prevalence of cytomegalovirus seropositivity, suggesting a state of post-infectious T cell senescence. In addition, this subgroup was characterized by higher remission rates to TAU + ST compared to TAU alone, particularly in the long run (i.e., 75 % vs. 42 % at week 8, and 75 % vs. 17 % at the end of the follow-up phase at week 24, <em>P</em> = 0.03; note the small group sizes of n = 8 and n = 12 patients, respectively). Although no significant effects of add-on ST on CD8<sup>+</sup> memory T cells were found, adjunctive ST significantly increased naïve CD4<sup>+</sup> T cells and decreased effector memory CD4<sup>+</sup> T cells within the senescent subgroup. Add-on ST was not superior to TAU in the entire group of patients with MDD.</div><div>Taken together, our findings suggest that patients with MDD with a T memory cell inflation profile may be the one and only who would benefit from TAU + ST as an add-on treatment strategy. These results support the development of personalized psychiatry approaches guided by immunological profiling and challenge the conventional “one-size-fit”
{"title":"One treatment does not fit all: Indications that spinning therapy benefits only a subgroup of patients with depression characterized by a T memory cell inflation profile","authors":"Sarah E. Fromme , Gara Arteaga-Henríquez , Bartholomeus C.M. Haarman , Annemarie Wijkhuijs , Raf Berghmans , Trine Munk-Olsen , Hemmo Drexhage , Bernhard T. Baune","doi":"10.1016/j.bbi.2025.106228","DOIUrl":"10.1016/j.bbi.2025.106228","url":null,"abstract":"<div><div>A proportion of patients diagnosed with major depressive disorder (MDD) exhibit signs of premature T cell aging, i.e. memory T cell inflation, characterized by elevated levels of memory CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Physical endurance training, including spinning therapy (ST), is known to counteract both T cell aging and depression.</div><div>The primary aim of this randomized, treatment-as-usual (TAU)-controlled study was to investigate whether signs of T cell aging (determined prior to ST) characterized remitters and responders to the intervention.</div><div>Patients aged 18–65 years with a diagnosis of MDD (Hamilton Depression Rating Scale (HDRS) ≥ 13) were included and randomized 1:1 to TAU or TAU + ST. The intervention consisted of moderate-intensity cycling sessions (30 min, three times per week), for eight consecutive weeks. A total of 72 patients (n = 35 TAU, n = 37 TAU + ST) with complete baseline immunophenotyping were included in the analyses (49 % females; mean age, 32 years).</div><div>We found that remitters to TAU + ST displayed significantly higher baseline levels of CD8<sup>+</sup> memory T cells, particularly T central memory (Tcm) cells and T effector memory cells re-expressing CD45RA (TEMRA) cells, compared to non-remitters. Correction for potential confounders and logistic regression analysis revealed that baseline levels of CD8<sup>+</sup> Tcm cells showed the strongest predictive value in the TAU + ST group (OR = 7.66, <em>P</em> = 0.03), suggesting that these cells may serve as treatment-specific predictors of remission to adjunctive ST. Post hoc stratification of patients based on the levels of CD8<sup>+</sup>Tcm cells identified a subgroup of n = 20 patients exhibiting several signs of T cell inflation in both the CD8<sup>+</sup> and CD4<sup>+</sup> T memory cell populations. This subgroup was older and showed a higher prevalence of cytomegalovirus seropositivity, suggesting a state of post-infectious T cell senescence. In addition, this subgroup was characterized by higher remission rates to TAU + ST compared to TAU alone, particularly in the long run (i.e., 75 % vs. 42 % at week 8, and 75 % vs. 17 % at the end of the follow-up phase at week 24, <em>P</em> = 0.03; note the small group sizes of n = 8 and n = 12 patients, respectively). Although no significant effects of add-on ST on CD8<sup>+</sup> memory T cells were found, adjunctive ST significantly increased naïve CD4<sup>+</sup> T cells and decreased effector memory CD4<sup>+</sup> T cells within the senescent subgroup. Add-on ST was not superior to TAU in the entire group of patients with MDD.</div><div>Taken together, our findings suggest that patients with MDD with a T memory cell inflation profile may be the one and only who would benefit from TAU + ST as an add-on treatment strategy. These results support the development of personalized psychiatry approaches guided by immunological profiling and challenge the conventional “one-size-fit”","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106228"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800330","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 : 2025-12-18DOI: 10.1016/j.bbi.2025.106229
Florencia Peña , Claudio Rodríguez-Camejo , Ana Hernández , Mayda Rivas , Anderson Saravia , Diego Serantes , Juan Pedro Castro , Pablo Torterolo , Teresa Freire , Luciana Benedetto
Background
sleep disturbances can trigger a wide range of physiological consequences, affecting hormonal regulation, metabolism, cognitive function, and immune responses. Human mothers worldwide frequently experience sleep restriction and fragmentation, a pattern also observed in other mammalian mothers, such as rats. These alterations may add to sleep disturbances unrelated to motherhood. Considering this, we wondered about the impact of sleep restriction in postpartum mother rats on their immunological status. Furthermore, given that early-life experiences can shape the immune system and that even subtle parental changes can influence offspring development, we hypothesized that maternal sleep loss might also exert detrimental effects on the pups. In this study, we investigated the effects of acute and chronic maternal sleep restriction during the postpartum period on immune parameters in both mother rats and their offspring by analyzing antibody titers and systemic inflammation.
Methods
mother rats were surgically implanted with electrodes for polysomnographic recordings and for sleep deprivation (deep electrodes targeting the mesopontine wake-promoting area). From postpartum day 5 to day 9, lactating dams were randomly assigned to one of three groups: chronic sleep restriction (CSR; 6 h of sleep deprivation per day for five consecutive days), acute sleep restriction (ASR; 6 h of sleep deprivation only on postpartum day 9), or control (undisturbed). On postpartum day 9, mothers were milked, and blood samples from both mothers and pups were subsequently collected. ELISA assays quantified IL-17A, IL-6, IgG, and IgG2a in maternal serum; IgG and IgG2a in milk; and IgG in pup serum. Hematological parameters, including leukocyte profiles, were also assessed in peripheral blood of dams and pups.
Results
maternal immune parameters analyzed remained unaffected by sleep restriction. IgG levels were lower in male pups from mothers subjected to ASR (5560 ± 734 µg/mL) compared with the control group (8666 ± 463 µg/mL; p = 0.025), whereas female pups showed no significant changes. Additionally, both female (4.10 ± 0.58) and male (3.81 ± 0.42) pups from dams subjected to CSR exhibited higher absolute lymphocytes counts relative to the control group (females: 2.28 ± 0.25, p = 0.004; males: 2.44 ± 0.25; p = 0.029).
Conclusions
Chronic and acute maternal sleep restriction had distinct impacts on offspring immunity, altering serum antibody and leukocyte profiles, while leaving maternal parameters unaffected. These results indicate that maternal sleep loss can influence the offspring even in the absence of detectable maternal immune alterations, with certain effects observed only in male pups.
{"title":"Differential effects of postpartum sleep restriction on maternal and offspring immunity in the rat","authors":"Florencia Peña , Claudio Rodríguez-Camejo , Ana Hernández , Mayda Rivas , Anderson Saravia , Diego Serantes , Juan Pedro Castro , Pablo Torterolo , Teresa Freire , Luciana Benedetto","doi":"10.1016/j.bbi.2025.106229","DOIUrl":"10.1016/j.bbi.2025.106229","url":null,"abstract":"<div><h3>Background</h3><div>sleep disturbances can trigger a wide range of physiological consequences, affecting hormonal regulation, metabolism, cognitive function, and immune responses. Human mothers worldwide frequently experience sleep restriction and fragmentation, a pattern also observed in other mammalian mothers, such as rats. These alterations may add to sleep disturbances unrelated to motherhood. Considering this, we wondered about the impact of sleep restriction in postpartum mother rats on their immunological status. Furthermore, given that early-life experiences can shape the immune system and that even subtle parental changes can influence offspring development, we hypothesized that maternal sleep loss might also exert detrimental effects on the pups. In this study, we investigated the effects of acute and chronic maternal sleep restriction during the postpartum period on immune parameters in both mother rats and their offspring by analyzing antibody titers and systemic inflammation.</div></div><div><h3>Methods</h3><div>mother rats were surgically implanted with electrodes for polysomnographic recordings and for sleep deprivation (deep electrodes targeting the mesopontine wake-promoting area). From postpartum day 5 to day 9, lactating dams were randomly assigned to one of three groups: chronic sleep restriction (CSR; 6 h of sleep deprivation per day for five consecutive days), acute sleep restriction (ASR; 6 h of sleep deprivation only on postpartum day 9), or control (undisturbed). On postpartum day 9, mothers were milked, and blood samples from both mothers and pups were subsequently collected. ELISA assays quantified IL-17A, IL-6, IgG, and IgG2a in maternal serum; IgG and IgG2a in milk; and IgG in pup serum. Hematological parameters, including leukocyte profiles, were also assessed in peripheral blood of dams and pups.</div></div><div><h3>Results</h3><div>maternal immune parameters analyzed remained unaffected by sleep restriction. IgG levels were lower in male pups from mothers subjected to ASR (5560 ± 734 µg/mL) compared with the control group (8666 ± 463 µg/mL; p = 0.025), whereas female pups showed no significant changes. Additionally, both female (4.10 ± 0.58) and male (3.81 ± 0.42) pups from dams subjected to CSR exhibited higher absolute lymphocytes counts relative to the control group (females: 2.28 ± 0.25, p = 0.004; males: 2.44 ± 0.25; p = 0.029).</div></div><div><h3>Conclusions</h3><div>Chronic and acute maternal sleep restriction had distinct impacts on offspring immunity, altering serum antibody and leukocyte profiles, while leaving maternal parameters unaffected. These results indicate that maternal sleep loss can influence the offspring even in the absence of detectable maternal immune alterations, with certain effects observed only in male pups.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106229"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800408","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 : 2025-12-18DOI: 10.1016/j.bbi.2025.106227
Michal Bajo , Pauravi Gandhi , Suzanne S. Fei , Yun Yu , Lina Gao , Rupak Khadka , Madison B. Blanton , Ilhem Messaoudi , Anna S. Warden , R. Dayne Mayfield , Verginia C. Cuzon Carlson , Kathleen A. Grant , Marisa Roberto
The implications of the neuroimmune system in the pathogenesis of alcohol use disorders (AUD) have been undeniable. Understanding how chronic alcohol dysregulates inflammatory pathways in the brain leading to altered neuronal functions could provide insight into specific mechanisms and neuroadaptations that may contribute to drinking behaviors. For example, the neuroadaptations at inhibitory GABAergic synapses in the central nucleus of the amygdala (CeA) of rodents and macaques involve the recruitment of neuroimmune pathways. This study tested the hypothesis that chronic alcohol consumption dysregulates the pro-inflammatory cytokine, interleukin 6 (IL-6) in the CeA of rhesus macaques. Male and female rhesus macaques were provided continuous choice to drink either 4 % (w/v) ethanol or water for 22 h/day, every day, for more than one year. We assessed the impact of chronic ethanol drinking on the cytokine abundance, including IL-6, in the blood, and adaptive changes in the CeA GABAergic transmission and transcriptome. We observed a main effect of sex on the IL-6 circulating plasma levels at necropsy, with higher IL-6 plasma levels in females, but no main effect of ethanol nor an interaction between sex and ethanol drinking. IL-6 decreased CeA GABA release (sIPSC frequency) in both control and alcohol drinkers, however chronic ethanol drinking significantly potentiated the IL-6 effects in both sexes. While, IL-6 had no effects on the sIPSC amplitudes in the control group, we observed a main effect of ethanol drinking on IL-6-induced decrease of sIPSC amplitude in both male and female drinkers. IL-6 also significantly prolonged the kinetics (decay times) of sIPSCs in male controls and drinkers, but not in the females, regardless of drinking. These data suggest that IL-6 modulation of GABAergic transmission within the CeA via a presynaptic reduction in GABA release independent of sex, whereas postsynaptic GABA receptor mediated functions (sIPSC amplitude and decay time) show sex- and ethanol specific effects. Lastly, transcriptomic analysis of the IL-6-immune-related genes in the CeA between high and low ethanol drinkers identified several DEGs (differentially expressed genes) implicating the neural and glial processes, and extracellular matrix as a generalized inflammatory response to ethanol in the high drinkers.
{"title":"Chronic alcohol consumption sex-dependently affects IL-6 modulation of GABAergic synapses in the central amygdala of rhesus macaques","authors":"Michal Bajo , Pauravi Gandhi , Suzanne S. Fei , Yun Yu , Lina Gao , Rupak Khadka , Madison B. Blanton , Ilhem Messaoudi , Anna S. Warden , R. Dayne Mayfield , Verginia C. Cuzon Carlson , Kathleen A. Grant , Marisa Roberto","doi":"10.1016/j.bbi.2025.106227","DOIUrl":"10.1016/j.bbi.2025.106227","url":null,"abstract":"<div><div>The implications of the neuroimmune system in the pathogenesis of alcohol use disorders (AUD) have been undeniable. Understanding how chronic alcohol dysregulates inflammatory pathways in the brain leading to altered neuronal functions could provide insight into specific mechanisms and neuroadaptations that may contribute to drinking behaviors. For example, the neuroadaptations at inhibitory GABAergic synapses in the central nucleus of the amygdala (CeA) of rodents and macaques involve the recruitment of neuroimmune pathways. This study tested the hypothesis that chronic alcohol consumption dysregulates the pro-inflammatory cytokine, interleukin 6 (IL-6) in the CeA of rhesus macaques. Male and female rhesus macaques were provided continuous choice to drink either 4 % (w/v) ethanol or water for 22 h/day, every day, for more than one year. We assessed the impact of chronic ethanol drinking on the cytokine abundance, including IL-6, in the blood, and adaptive changes in the CeA GABAergic transmission and transcriptome. We observed a main effect of sex on the IL-6 circulating plasma levels at necropsy, with higher IL-6 plasma levels in females, but no main effect of ethanol nor an interaction between sex and ethanol drinking. IL-6 decreased CeA GABA release (sIPSC frequency) in both control and alcohol drinkers, however chronic ethanol drinking significantly potentiated the IL-6 effects in both sexes. While, IL-6 had no effects on the sIPSC amplitudes in the control group, we observed a main effect of ethanol drinking on IL-6-induced decrease of sIPSC amplitude in both male and female drinkers. IL-6 also significantly prolonged the kinetics (decay times) of sIPSCs in male controls and drinkers, but not in the females, regardless of drinking. These data suggest that IL-6 modulation of GABAergic transmission within the CeA via a presynaptic reduction in GABA release independent of sex, whereas postsynaptic GABA receptor mediated functions (sIPSC amplitude and decay time) show sex- and ethanol specific effects. Lastly, transcriptomic analysis of the IL-6-immune-related genes in the CeA between high and low ethanol drinkers identified several DEGs (differentially expressed genes) implicating the neural and glial processes, and extracellular matrix as a generalized inflammatory response to ethanol in the high drinkers.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106227"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800259","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 : 2025-12-18DOI: 10.1016/j.bbi.2025.106223
Shivangi Jain , Patricio Solis-Urra , Alina Lesnovskaya , Lu Wan , Cristina Molina-Hidalgo , Audrey Collins , Haiqing Huang , Kelsey R. Sewell , Rebecca Reed , Renee J. Rogers , Anna L. Marsland , George Grove , Lauren E. Oberlin , Chaeryon Kang , John M. Jakicic , Lauren Raine , Joseph Mettenburg , Lauren M. Sparks , Arthur F. Kramer , Charles Hillman , Kirk I. Erickson
White matter hyperintensities or lesions (WMLs) increase the risk for cognitive impairment and dementia. Cardiometabolic factors (e.g., excess adiposity) and markers of systemic inflammation relate to greater WML volume, but few studies have examined whether specific compartments of adipose tissue (e.g., visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT)) relative to total body adiposity (TBA) differentially relate to WML volume or whether these patterns could be statistically mediated by inflammation. We examined associations between markers of low-grade systemic inflammation and compartments of adipose tissue relative to total body adiposity (rVAT or rASAT respectively), measured by dual-energy x-ray absorptiometry (DXA), and WML volume. We hypothesized that higher rVAT and not rASAT would be associated with greater WML volume, and that this association would be statistically mediated by concentrations of inflammatory cytokines. We used baseline data (n = 648) from the multisite study “Investigating Gains in Neurocognition in an Intervention Trial of Exercise” (IGNITE; mean age = 69.9 ± 3.8 years, 70.5 % females). IL-6, IL-1RA, and TNF-α were included as markers of systemic inflammation and age, sex, years of education, hypertension status, and study site were included as covariates. Our hypotheses were partially supported such that the relationship between rVAT and WMLs, as well as between rASAT and WMLs, were statistically mediated by IL-6 and TNF-α. These findings suggest that both higher rVAT and rASAT, are associated with higher WML burden through an elevated inflammatory state. These results set a testable mechanistic pathway for future longitudinal and intervention studies examining whether managing low-grade systemic inflammation and intentional weight loss would be beneficial for supporting brain health in older adults.
{"title":"Associations between white matter lesions, adiposity, and systemic inflammation in late adulthood: Results from the IGNITE study","authors":"Shivangi Jain , Patricio Solis-Urra , Alina Lesnovskaya , Lu Wan , Cristina Molina-Hidalgo , Audrey Collins , Haiqing Huang , Kelsey R. Sewell , Rebecca Reed , Renee J. Rogers , Anna L. Marsland , George Grove , Lauren E. Oberlin , Chaeryon Kang , John M. Jakicic , Lauren Raine , Joseph Mettenburg , Lauren M. Sparks , Arthur F. Kramer , Charles Hillman , Kirk I. Erickson","doi":"10.1016/j.bbi.2025.106223","DOIUrl":"10.1016/j.bbi.2025.106223","url":null,"abstract":"<div><div>White matter hyperintensities or lesions (WMLs) increase the risk for cognitive impairment and dementia. Cardiometabolic factors (e.g., excess adiposity) and markers of systemic inflammation relate to greater WML volume, but few studies have examined whether specific compartments of adipose tissue (e.g., visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT)) relative to total body adiposity (TBA) differentially relate to WML volume or whether these patterns could be statistically mediated by inflammation. We examined associations between markers of low-grade systemic inflammation and compartments of adipose tissue relative to total body adiposity (rVAT or rASAT respectively), measured by dual-energy x-ray absorptiometry (DXA), and WML volume. We hypothesized that higher rVAT and not rASAT would be associated with greater WML volume, and that this association would be statistically mediated by concentrations of inflammatory cytokines. We used baseline data (n = 648) from the multisite study “Investigating Gains in Neurocognition in an Intervention Trial of Exercise” (IGNITE; mean age = 69.9 ± 3.8 years, 70.5 % females). IL-6, IL-1RA, and TNF-α were included as markers of systemic inflammation and age, sex, years of education, hypertension status, and study site were included as covariates. Our hypotheses were partially supported such that the relationship between rVAT and WMLs, as well as between rASAT and WMLs, were statistically mediated by IL-6 and TNF-α. These findings suggest that both higher rVAT and rASAT, are associated with higher WML burden through an elevated inflammatory state. These results set a testable mechanistic pathway for future longitudinal and intervention studies examining whether managing low-grade systemic inflammation and intentional weight loss would be beneficial for supporting brain health in older adults.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106223"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800257","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 : 2025-12-18DOI: 10.1016/j.bbi.2025.106226
Adil El Mesaoudi , Abdelmoumen Kassoussi , Amina Zahaf , Maysoun Ayadi , Sara Naglieri , Corentine Marie , Ferechte Razavi , Pierre Bobé , Jelena Martinovic , Carlos Parras , Elisabeth Traiffort
The brain resident macrophages, or microglia, display essential functions ranging from contributing to brain development to triggering innate immune responses. The different ways microglia operate reflect their varying context-dependent states. However, the mechanisms that control these states remain largely unknown. Here, we identified a small population of microglia that express Smoothened (Smo), the well-known key component of the Hedgehog signaling pathway. Our experiments involving both loss and gain of function, demonstrate that the intrinsic activity of microglial Smo is mostly associated with the effective initiation of appropriate innate immune responses to pathogens and the control of microglia phagocytic activities. Microglial Smo activity is also involved in the appearance of amoeboid microglia that transiently arise in the developing white matter during the perinatal period. Moreover, the exogenous and Hedgehog signaling-independent activation of microglial Smo counteracts the molecular cascades occurring in microglia under inflammatory conditions. All these data indicate previously unrecognized roles for the Smo receptor and could lead to further research to discover a new category of non-canonical Smo agonists that might specifically regulate microglial states.
{"title":"Smoothened-mediated signaling contributes to immune and non-immune functions of microglia","authors":"Adil El Mesaoudi , Abdelmoumen Kassoussi , Amina Zahaf , Maysoun Ayadi , Sara Naglieri , Corentine Marie , Ferechte Razavi , Pierre Bobé , Jelena Martinovic , Carlos Parras , Elisabeth Traiffort","doi":"10.1016/j.bbi.2025.106226","DOIUrl":"10.1016/j.bbi.2025.106226","url":null,"abstract":"<div><div>The brain resident macrophages, or microglia, display essential functions ranging from contributing to brain development to triggering innate immune responses. The different ways microglia operate reflect their varying context-dependent states. However, the mechanisms that control these states remain largely unknown. Here, we identified a small population of microglia that express Smoothened (Smo), the well-known key component of the Hedgehog signaling pathway. Our experiments involving both loss and gain of function, demonstrate that the intrinsic activity of microglial Smo is mostly associated with the effective initiation of appropriate innate immune responses to pathogens and the control of microglia phagocytic activities. Microglial Smo activity is also involved in the appearance of amoeboid microglia that transiently arise in the developing white matter during the perinatal period. Moreover, the exogenous and Hedgehog signaling-independent activation of microglial Smo counteracts the molecular cascades occurring in microglia under inflammatory conditions. All these data indicate previously unrecognized roles for the Smo receptor and could lead to further research to discover a new category of non-canonical Smo agonists that might specifically regulate microglial states.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106226"},"PeriodicalIF":7.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800356","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 : 2025-12-17DOI: 10.1016/j.bbi.2025.106222
Maria Elisa Caetano-Silva , Miranda E. Hilt , Ivan Valishev , Casey Lim , Mikaela Kasperek , Akriti Shrestha , Helen Fu , Eleanor Eck , Robert McCusker , Heather Armstrong , Brett Loman , Michael T. Bailey , Jacob M. Allen
Psychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including α2-/β-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre-treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either Citrobacter rodentium infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitors and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (Duox2), Dual oxidase maturation factor 2 (Duoxa2), and inducible nitric oxide synthase 2 (Nos2) in IECs (2- to 8-fold, p < 0.0001), effects reversed by β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α −diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (C. rodentium) and chemically induced (DSS) colitis, amplifying colonic expression of Duox2, Nos2, and Ccl2, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase–driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.
{"title":"Social stress worsens colitis through β-adrenergic–driven oxidative stress in intestinal mucosal compartments","authors":"Maria Elisa Caetano-Silva , Miranda E. Hilt , Ivan Valishev , Casey Lim , Mikaela Kasperek , Akriti Shrestha , Helen Fu , Eleanor Eck , Robert McCusker , Heather Armstrong , Brett Loman , Michael T. Bailey , Jacob M. Allen","doi":"10.1016/j.bbi.2025.106222","DOIUrl":"10.1016/j.bbi.2025.106222","url":null,"abstract":"<div><div>Psychological stress is a known risk factor for inflammatory bowel disease (IBD), but the mechanisms linking stress to worsened disease remain unclear. Because distinct stress paradigms activate different neuroimmune circuits, it is critical to investigate model-specific effects. We examined how social stress primes the gut for heightened inflammation and whether this is mediated by specific neuroendocrine pathways, including α2-/β-adrenergic (sympathetic) or glucocorticoid/ corticotropin-releasing hormone receptor (CRHR1) (HPA axis) signaling. Mice were exposed to social disruption (SDR) stress and pre-treated with pharmacological antagonists targeting α2-adrenergic receptors (idazoxan), β-adrenergic receptor (β-AR) (propranolol), glucocorticoid receptor (mifepristone), or CRHR1 (antalarmin). Intestinal epithelial cell (IEC) gene expression and microbiota composition were assessed following SDR. To determine disease impact, SDR was combined with either <em>Citrobacter rodentium</em> infection or dextran sulfate sodium (DSS)-induced colitis, with interventions including the β-AR inhibitors and the NADPH oxidase inhibitor apocynin. SDR significantly upregulated expression of Dual oxidase 2 (<em>Duox2</em>), Dual oxidase maturation factor 2 (<em>Duoxa2</em>), and inducible nitric oxide synthase 2 (<em>Nos2</em>) in IECs (2- to 8-fold, <em>p</em> < 0.0001), effects reversed by β-AR blockade but not α2-adrenergic, CRH, or glucocorticoid inhibition. SDR also induced microbial dysbiosis, characterized by reduced α −diversity and compositional shifts, which was rescued by propranolol. Stress exacerbated disease severity in both infectious (<em>C. rodentium</em>) and chemically induced (DSS) colitis, amplifying colonic expression of <em>Duox2</em>, <em>Nos2</em>, and <em>Ccl2</em>, especially. Apocynin mitigated stress-induced ROS/RNS production and body weight loss even prior to colitis onset, reduced colonic expression of key oxidative enzymes, especially DUOX2, and alleviated both chemically and infectious colitis severity. These findings provide strong evidence that social stress sensitizes the gut to inflammation through β-adrenergic and NADPH oxidase–driven oxidative stress, highlighting potential therapeutic targets for mitigating stress-exacerbated IBD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106222"},"PeriodicalIF":7.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793402","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}
Excessive fructose intake is a growing public health concern, yet many individuals have a limited capacity to absorb typical dietary levels, leading to chronic fructose malabsorption and intestinal spillover. In animal models, this spillover disrupts the gut microbiota, but its impact in humans remains unexplored. We hypothesized that fructose malabsorption–induced dysbiosis contributes to peripheral inflammation, which, together with neuroinflammation, plays a role in mood disorders. This study investigates the link between fructose malabsorption, gut microbiota, and mood disorders in a human cohort, and explores their association with neuroinflammation in a Glut5 knockout (GLUT5_KO) mouse model of fructose-malabsorption.
In a human cohort of male healthy volunteers, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS), IL8 and TNFα levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, GLUT5_KO male mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed.
Sixty percent of volunteers exhibited fructose malabsorption, along with elevated plasma LPS, IL8 and TNFα levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, GLUT5_KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes.
These findings highlight the complex interplay between dietary fructose, gut microbiota, low grade inflammation and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions.
{"title":"Fructose malabsorption induces dysbiosis and increases anxiety in male human and animal models","authors":"Adeline Coursan , Delphine Polve , Anne-Marie Leroi , Magali Monnoye , Lea Roussin , Clara Benatar , Marie-Pierre Tavolacci , Muriel Quillard Muraine , Mathilde Maccarone , Olivia Guérin , Estelle Houivet , Charlène Guérin , Valery Brunel , Jérôme Bellenger , Jean-Paul Pais de Barros , Guillaume Gourcerol , Laurent Naudon , Sophie Layé , Charlotte Madore , Xavier Fioramonti , Véronique Douard","doi":"10.1016/j.bbi.2025.106221","DOIUrl":"10.1016/j.bbi.2025.106221","url":null,"abstract":"<div><div>Excessive fructose intake is a growing public health concern, yet many individuals have a limited capacity to absorb typical dietary levels, leading to chronic fructose malabsorption and intestinal spillover. In animal models, this spillover disrupts the gut microbiota, but its impact in humans remains unexplored. We hypothesized that fructose malabsorption–induced dysbiosis contributes to peripheral inflammation, which, together with neuroinflammation, plays a role in mood disorders. This study investigates the link between fructose malabsorption, gut microbiota, and mood disorders in a human cohort, and explores their association with neuroinflammation in a <em>Glut5</em> knockout (GLUT5_KO) mouse model of fructose-malabsorption.</div><div>In a human cohort of male healthy volunteers, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS), IL8 and TNFα levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, GLUT5_KO male mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed.</div><div>Sixty percent of volunteers exhibited fructose malabsorption, along with elevated plasma LPS, IL8 and TNFα levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, GLUT5_KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes.</div><div>These findings highlight the complex interplay between dietary fructose, gut microbiota, low grade inflammation and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"133 ","pages":"Article 106221"},"PeriodicalIF":7.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793369","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 : 2025-12-11DOI: 10.1016/j.bbi.2025.106217
Viacheslav A. Petrov , Sebastian Schade , Cedric C. Laczny , Jenny Hällqvist , Patrick May , Christian Jäger , Velma T.E. Aho , Oskar Hickl , Rashi Halder , Elisabeth Lang , Jordan Caussin , Laura A. Lebrun , Janine Schulz , Marcus Michael Unger , Kevin Mills , Brit Mollenhauer , Paul Wilmes
Alterations in the gut microbiome and a “leaky” gut are associated with Parkinson’s disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet.
Our findings reveal associations between dietary patterns and changes in the gut microbiome’s taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in Faecalibacterium species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD.
Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients.
{"title":"Resistant starch improves Parkinson’s disease symptoms through restructuring of the gut microbiome and modulating inflammation","authors":"Viacheslav A. Petrov , Sebastian Schade , Cedric C. Laczny , Jenny Hällqvist , Patrick May , Christian Jäger , Velma T.E. Aho , Oskar Hickl , Rashi Halder , Elisabeth Lang , Jordan Caussin , Laura A. Lebrun , Janine Schulz , Marcus Michael Unger , Kevin Mills , Brit Mollenhauer , Paul Wilmes","doi":"10.1016/j.bbi.2025.106217","DOIUrl":"10.1016/j.bbi.2025.106217","url":null,"abstract":"<div><div>Alterations in the gut microbiome and a “leaky” gut are associated with Parkinson’s disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet.</div><div>Our findings reveal associations between dietary patterns and changes in the gut microbiome’s taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in <em>Faecalibacterium</em> species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD.</div><div>Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106217"},"PeriodicalIF":7.6,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751664","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 : 2025-12-10DOI: 10.1016/j.bbi.2025.106219
Junli Zhao , Runda Li , Yuqing Wang , Sharat Chandra , Vivian Zhang , Haichen Wang , Ru-Rong Ji
Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., Fkbp5). The antinociceptive effects of NPD1 were abolished in Gpr37−/− mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not Gpr37−/− mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.
{"title":"NPD1/GPR37 signaling protects against painful traumatic brain injury and comorbidities by regulating demyelination, glial responses, and neuroinflammation in the mouse brain","authors":"Junli Zhao , Runda Li , Yuqing Wang , Sharat Chandra , Vivian Zhang , Haichen Wang , Ru-Rong Ji","doi":"10.1016/j.bbi.2025.106219","DOIUrl":"10.1016/j.bbi.2025.106219","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) often leads to neuropathic pain and a range of comorbidities, including post-traumatic stress disorder (PTSD), cognitive decline and depression. Neuroprotectin D1 (NPD1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA), exhibits neuroprotective properties; however, the distinct roles of NPD1 and DHA in mitigating TBI-induced deficits remain unclear. In a mouse model of closed-head TBI, transient neuropathic pain lasting less than two weeks was observed, characterized by periorbital and cutaneous mechanical allodynia/hyperalgesia, motor deficits, and cognitive impairment. Peri-surgical administration of NPD1 (500 ng/mouse), but not DHA (500 µg/mouse), effectively prevented mechanical hypersensitivity, motor deficits, and cognitive impairment. NPD1 treatment also attenuated TBI-induced microgliosis, astrogliosis, and demyelination in the sensory cortex and hippocampus. RNA sequencing revealed that NPD1 suppressed neuroinflammatory responses and normalized the alteration of PTSD-related genes (e.g., <em>Fkbp5</em>). The antinociceptive effects of NPD1 were abolished in <em>Gpr37<sup>−</sup>/<sup>−</sup></em> mice. Moreover, swimming-induced stress prolonged TBI-evoked pain, and NPD1 prevented this transition from acute to chronic pain in wild-type but not <em>Gpr37<sup>−</sup></em>/<em><sup>−</sup></em> mice. Chronic pain was accompanied by depression- and anxiety-like behaviors, both of which were mitigated by NPD1 via GPR37. In addition, NPD1 post-treatment attenuated stress/TBI-induced chronic pain and comorbidities. Together, these findings identify the NPD1/GPR37 signaling axis as a key protective mechanism that modulates glial responses, demyelination, and neuroinflammation, offering a promising therapeutic target for TBI-associated pain and neuropsychiatric comorbidities.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"132 ","pages":"Article 106219"},"PeriodicalIF":7.6,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741102","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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