The hippocampus is a heterogenous structure that exhibits functional segregation along its longitudinal axis. We recently showed that in male mice, microglia, the brain’s resident immune cells, differ between the dorsal (DH) and ventral (VH) hippocampus, impacting long-term potentiation (LTP) mainly through the CX3CL1-CX3CR1 signaling. Here, we assessed the specific features of the hippocampal poles in female mice, demonstrating a similar LTP amplitude in VH and DH in both control and Cx3cr1 knock-out mice. In addition, the expression levels of Cx3cr1 and Cx3cl1 mRNA do not differ between the two poles in control mice. These data support the critical role of the CX3CL1-CX3CR1 signaling in setting the physiological amount of plasticity, equally between poles in females. Although BDNF is higher in DH compared to VH, the expression levels of inflammatory markers involved in plasticity and of phagocytosis markers in microglia are comparable between the two poles. In accordance, microglia soma and arborization area/perimeter, and microglial ultrastructure are similar across regions, with the exception of microglial density, cells arborization solidity and circularity that are higher in DH. Understanding the molecular processes underlying microglial sex differences and their potential implications for plasticity in specific brain regions is of major importance in physiological and pathological conditions.
{"title":"Female mice exhibit similar long-term plasticity and microglial properties between the dorsal and ventral hippocampal poles","authors":"Eleonora De Felice , Bianca Caroline Bobotis , Giovanna Rigillo , Mohammadparsa Khakpour , Elisa Gonçalves de Andrade , Cristina Benatti , Antonietta Vilella , Fabio Tascedda , Cristina Limatola , Marie-Ève Tremblay , Silvia Alboni , Laura Maggi","doi":"10.1016/j.bbi.2024.11.034","DOIUrl":"10.1016/j.bbi.2024.11.034","url":null,"abstract":"<div><div>The hippocampus is a heterogenous structure that exhibits functional segregation along its longitudinal axis. We recently showed that in male mice, microglia, the brain’s resident immune cells, differ between the dorsal (DH) and ventral (VH) hippocampus, impacting long-term potentiation (LTP) mainly through the CX3CL1-CX3CR1 signaling. Here, we assessed the specific features of the hippocampal poles in female mice, demonstrating a similar LTP amplitude in VH and DH in both control and <em>Cx3cr1</em> knock-out mice. In addition, the expression levels of <em>Cx3cr1</em> and <em>Cx3cl1</em> mRNA do not differ between the two poles in control mice. These data support the critical role of the CX3CL1-CX3CR1 signaling in setting the physiological amount of plasticity, equally between poles in females. Although BDNF is higher in DH compared to VH, the expression levels of inflammatory markers involved in plasticity and of phagocytosis markers in microglia are comparable between the two poles. In accordance, microglia soma and arborization area/perimeter, and microglial ultrastructure are similar across regions, with the exception of microglial density, cells arborization solidity and circularity that are higher in DH. Understanding the molecular processes underlying microglial sex differences and their potential implications for plasticity in specific brain regions is of major importance in physiological and pathological conditions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 192-204"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.bbi.2024.12.023
Yanning Li , Yi Zhang , Dandan Lin , Xiaoliang Fu , Chenchen Jing
Psychological stress can lead to emotional disorders, such as anxiety and depression; however, the underlying mechanisms are complicated and remain unclear. In this study, we established a mouse psychological stress model using an improved communication box, in which the psychologically stressed mice received visual, auditory, and olfactory emotional stimuli from the mice receiving electric foot shock, thus avoiding physical stress interference. After the 14-day psychological stress paradigm, our mice exhibited a significant increase in depressive and anxious behaviors. We then performed proteomic liquid chromatography–tandem mass spectrometry for proteomic data analysis of the amygdala, and the results demonstrated that differentially expressed proteins were more enriched in myelin-related biological processes, cellular components, and molecular functions, indicating a correlation between psychological stress–induced emotional disorders and amygdala myelin damage. Molecular and morphological evidence further confirmed that psychological stress damages myelin ultrastructure, downregulated myelin basic protein and proteolipid protein expression, and reduced oligodendrocyte proliferation in the amygdala. Moreover, clemastine, an antimuscarinic and antihistaminic compound that has been shown to enhance oligodendrocyte differentiation and myelination, rescued depressive behaviors accompanied by increased oligodendrogenesis. In the amygdala, psychological stress was also noted to activate microglia and increase the levels of NOD-like receptor protein 3 (NLRP3) and the proinflammatory cytokines interleukin 1β and tumor necrosis factor α, as indicated by ELISA and Western blot analyses. Moreover, in stressed mice, the administration of Brilliant Blue G, a purinergic ligand-gated ion channel 7 receptor (P2X7R) antagonist, completely reversed the increases in NLRP3 and cleaved caspase-1 levels and partially prevented amygdala myelin damage. In conclusion, amygdala demyelination may mediate psychological stress–induced emotional disorders, and P2X7R/NLRP3 cascade activation partially contributes to amygdala myelin damage after psychological stress.
心理压力会导致情绪障碍，如焦虑和抑郁；然而，潜在的机制是复杂的，仍然不清楚。本研究采用改进的通讯箱建立小鼠心理应激模型，心理应激小鼠接受足电小鼠的视觉、听觉和嗅觉情绪刺激，避免物理应激干扰。经过14天的心理应激模式后，我们的小鼠表现出抑郁和焦虑行为的显著增加。然后，我们对杏仁核的蛋白质组学数据进行了蛋白质组学液相色谱-串联质谱分析，结果表明差异表达的蛋白质在髓磷脂相关的生物过程、细胞成分和分子功能中更丰富，表明心理应激诱导的情绪障碍与杏仁核髓磷脂损伤之间存在相关性。分子和形态学证据进一步证实，心理应激损伤髓鞘超微结构，下调髓鞘碱性蛋白和蛋白脂蛋白表达，减少杏仁核少突胶质细胞增殖。此外，clemastine，一种抗蛇毒碱和抗组胺化合物，已被证明可以促进少突胶质细胞分化和髓鞘形成，挽救伴随少突胶质形成增加的抑郁行为。ELISA和Western blot分析显示，在杏仁核中，心理应激也可以激活小胶质细胞，增加nod样受体蛋白3 （NLRP3）和促炎细胞因子白介素1β和肿瘤坏死因子α的水平。此外，在应激小鼠中，给予嘌呤能配体门控制离子通道7受体（P2X7R）拮抗剂Brilliant Blue G，完全逆转了NLRP3和caspase-1水平的升高，并部分预防了杏仁核髓磷脂损伤。综上所述，杏仁核脱髓鞘可能介导心理应激性情绪障碍，P2X7R/NLRP3级联激活在一定程度上参与了心理应激后杏仁核髓磷脂损伤。
{"title":"Demyelination of the amygdala mediates psychological stress-induced emotional disorders partially contributed by activation of P2X7R/NLRP3 cascade","authors":"Yanning Li , Yi Zhang , Dandan Lin , Xiaoliang Fu , Chenchen Jing","doi":"10.1016/j.bbi.2024.12.023","DOIUrl":"10.1016/j.bbi.2024.12.023","url":null,"abstract":"<div><div>Psychological stress can lead to emotional disorders, such as anxiety and depression; however, the underlying mechanisms are complicated and remain unclear. In this study, we established a mouse psychological stress model using an improved communication box, in which the psychologically stressed mice received visual, auditory, and olfactory emotional stimuli from the mice receiving electric foot shock, thus avoiding physical stress interference. After the 14-day psychological stress paradigm, our mice exhibited a significant increase in depressive and anxious behaviors. We then performed proteomic liquid chromatography–tandem mass spectrometry for proteomic data analysis of the amygdala, and the results demonstrated that differentially expressed proteins were more enriched in myelin-related biological processes, cellular components, and molecular functions, indicating a correlation between psychological stress–induced emotional disorders and amygdala myelin damage. Molecular and morphological evidence further confirmed that psychological stress damages myelin ultrastructure, downregulated myelin basic protein and proteolipid protein expression, and reduced oligodendrocyte proliferation in the amygdala. Moreover, clemastine, an antimuscarinic and antihistaminic compound that has been shown to enhance oligodendrocyte differentiation and myelination, rescued depressive behaviors accompanied by increased oligodendrogenesis. In the amygdala, psychological stress was also noted to activate microglia and increase the levels of NOD-like receptor protein 3 (NLRP3) and the proinflammatory cytokines interleukin 1β and tumor necrosis factor α, as indicated by ELISA and Western blot analyses. Moreover, in stressed mice, the administration of Brilliant Blue G, a purinergic ligand-gated ion channel 7 receptor (P2X7R) antagonist, completely reversed the increases in NLRP3 and cleaved caspase-1 levels and partially prevented amygdala myelin damage. In conclusion, amygdala demyelination may mediate psychological stress–induced emotional disorders, and P2X7R/NLRP3 cascade activation partially contributes to amygdala myelin damage after psychological stress.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 365-375"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845686","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 : 2025-02-01DOI: 10.1016/j.bbi.2024.12.006
Felipe Couto Amendola , Guilherme Roncete , Sophia Aguiar Monteiro Borges , Cristiana Castanho de Almeida Rocca , Antonio de Pádua Serafim , Gabriela Salim de Castro , Marilia Seelaender , Euripedes Constantino Miguel , Geraldo Busatto Filho , Orestes V. Forlenza , Rodolfo Furlan Damiano
This study investigates the relationship between clinical, sociodemographic, and neuropsychological symptoms and serum cytokine concentrations with long-term cognitive and psychiatric outcomes in long-COVID-19 patients. We reassessed 108 adults who survived moderate to severe COVID-19 at two intervals post-discharge (T1, mean 6.9 months; T2, mean 23.5 months). Baseline sociodemographic and clinical data were collected from hospital records, while cognitive and mental health assessments included psychometric tests such as the Hospital Anxiety and Depression Scale (HADS) and Immediate and Delayed Recall Tests from the CERAD Battery. Serum cytokine levels were measured at T1. Generalized Additive Models (GAMs), Elastic Net Regression (NET), and Psychological Network Analysis (PNA) were used to analyze the data. The GAM analysis revealed significant associations between acute COVID-19 severity and Epworth Sleepiness Score with persistent anxiety symptoms at T2. For depression, both WHO severity class and Eotaxin levels were significant predictors. The Anti-inflammatory Index showed a marginally significant relationship with immediate recall, while age was marginally associated with delayed recall performance. In NET, only anxiety was significantly associated with Epworth Sleepiness Score, WHO severity class, and Proinflammatory Index. PNA did not reveal direct connections between cytokines and neuropsychological outcomes in the graphical model. However, centrality measures indicated that the Proinflammatory Index and VEGF were more central within the network, suggesting they might be important components of the overall system. This study provides insights into the complex role of cytokines and inflammation in long-COVID-19 outcomes, potentially aiding in the identification of biomarkers for diagnosis and prognosis.
{"title":"A Two-Year cohort study examining the impact of cytokines and chemokines on cognitive and psychiatric outcomes in Long-COVID-19 patients","authors":"Felipe Couto Amendola , Guilherme Roncete , Sophia Aguiar Monteiro Borges , Cristiana Castanho de Almeida Rocca , Antonio de Pádua Serafim , Gabriela Salim de Castro , Marilia Seelaender , Euripedes Constantino Miguel , Geraldo Busatto Filho , Orestes V. Forlenza , Rodolfo Furlan Damiano","doi":"10.1016/j.bbi.2024.12.006","DOIUrl":"10.1016/j.bbi.2024.12.006","url":null,"abstract":"<div><div>This study investigates the relationship between clinical, sociodemographic, and neuropsychological symptoms and serum cytokine concentrations with long-term cognitive and psychiatric outcomes in long-COVID-19 patients. We reassessed 108 adults who survived moderate to severe COVID-19 at two intervals post-discharge (T1, mean 6.9 months; T2, mean 23.5 months). Baseline sociodemographic and clinical data were collected from hospital records, while cognitive and mental health assessments included psychometric tests such as the Hospital Anxiety and Depression Scale (HADS) and Immediate and Delayed Recall Tests from the CERAD Battery. Serum cytokine levels were measured at T1. Generalized Additive Models (GAMs), Elastic Net Regression (NET), and Psychological Network Analysis (PNA) were used to analyze the data. The GAM analysis revealed significant associations between acute COVID-19 severity and Epworth Sleepiness Score with persistent anxiety symptoms at T2. For depression, both WHO severity class and Eotaxin levels were significant predictors. The Anti-inflammatory Index showed a marginally significant relationship with immediate recall, while age was marginally associated with delayed recall performance. In NET, only anxiety was significantly associated with Epworth Sleepiness Score, WHO severity class, and Proinflammatory Index. PNA did not reveal direct connections between cytokines and neuropsychological outcomes in the graphical model. However, centrality measures indicated that the Proinflammatory Index and VEGF were more central within the network, suggesting they might be important components of the overall system. This study provides insights into the complex role of cytokines and inflammation in long-COVID-19 outcomes, potentially aiding in the identification of biomarkers for diagnosis and prognosis.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 218-225"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817134","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 : 2025-02-01DOI: 10.1016/j.bbi.2024.11.036
Yoshiyasu Takefuji
Skorobogatov et al. developed supervised machine learning models to predict diagnoses and illness states in schizophrenia and bipolar disorder. However, their reliance on bootstrap forests and generalized regressions introduces significant biases in feature importance assessments. This paper highlights the critical distinction between feature importances generated by machine learning and actual associations, which are often model-specific and context-dependent. We underscore the limitations of biased feature importances and advocate for the use of robust statistical methods, such as Chi-squared tests and Spearman’s correlation, to reveal true associations. Reassessing findings with these methods will enable more accurate interpretations and reinforce the importance of understanding the limitations inherent in machine learning methodologies.
{"title":"Reevaluating feature importances in machine learning models for schizophrenia and bipolar disorder: The need for true associations","authors":"Yoshiyasu Takefuji","doi":"10.1016/j.bbi.2024.11.036","DOIUrl":"10.1016/j.bbi.2024.11.036","url":null,"abstract":"<div><div>Skorobogatov et al. developed supervised machine learning models to predict diagnoses and illness states in schizophrenia and bipolar disorder. However, their reliance on bootstrap forests and generalized regressions introduces significant biases in feature importance assessments. This paper highlights the critical distinction between feature importances generated by machine learning and actual associations, which are often model-specific and context-dependent. We underscore the limitations of biased feature importances and advocate for the use of robust statistical methods, such as Chi-squared tests and Spearman’s correlation, to reveal true associations. Reassessing findings with these methods will enable more accurate interpretations and reinforce the importance of understanding the limitations inherent in machine learning methodologies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 123-124"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766338","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 : 2025-02-01DOI: 10.1016/j.bbi.2025.01.021
Danielle Antoine, Junyi Tao, Salma Singh, Praveen Kumar Singh, Barbara G Marin, Sabita Roy
Opioids, such as morphine, are used in the Neonatal Intensive Care Unit (NICU) for pain relief in neonates. However, the available evidence concerning the benefits and harms of opioid therapy in neonates remains limited. While previous studies have reported that neonatal morphine exposure (NME) results in long-term heightened pain sensitivity, the underlying mechanisms are not well understood. This study proposes that dysbiosis of the gut microbiome contributes to pain hypersensitivity following NME. Using an adolescent female murine model, pain sensitivity was evaluated using tail flick and hot plate assays for thermal pain and the Von Frey assay for mechanical pain. Gut microbiome composition was assessed using 16 s rRNA sequencing, while transcriptomic changes in midbrain samples were investigated using bulk RNA-sequencing. NME induced prolonged hypersensitivity to thermal and mechanical pain in adolescence, accompanied by persistent gut microbial dysbiosis and sustained systemic inflammation, characterized by elevated circulating cytokine levels (e.g., IL-1α, IL-12p70, IFN-γ, IL-10). Transplantation of the microbiome from NME adolescents recapitulated pain hypersensitivity in naïve adolescent mice, while neonatal probiotic intervention with Bifidobacterium infantis (B. infantis) reversed the hypersensitivity by preventing gut dysbiosis and associated systemic inflammation. Furthermore, transcriptomic analysis of the midbrain tissues revealed that NME upregulated several genes and key signaling pathways, including those related to immune activation and excitatory signaling, which were notably mitigated by neonatal B. infantis administration. Together, these findings highlight the critical role of the gut-brain axis in modulating pain sensitivity and suggest that targeting the gut microbiome offers a promising therapeutic strategy for managing neurobiological disorders following early opioid exposure.
{"title":"Neonatal exposure to morphine results in prolonged pain hypersensitivity during adolescence, driven by gut microbial dysbiosis and gut-brain axis-mediated inflammation.","authors":"Danielle Antoine, Junyi Tao, Salma Singh, Praveen Kumar Singh, Barbara G Marin, Sabita Roy","doi":"10.1016/j.bbi.2025.01.021","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.01.021","url":null,"abstract":"<p><p>Opioids, such as morphine, are used in the Neonatal Intensive Care Unit (NICU) for pain relief in neonates. However, the available evidence concerning the benefits and harms of opioid therapy in neonates remains limited. While previous studies have reported that neonatal morphine exposure (NME) results in long-term heightened pain sensitivity, the underlying mechanisms are not well understood. This study proposes that dysbiosis of the gut microbiome contributes to pain hypersensitivity following NME. Using an adolescent female murine model, pain sensitivity was evaluated using tail flick and hot plate assays for thermal pain and the Von Frey assay for mechanical pain. Gut microbiome composition was assessed using 16 s rRNA sequencing, while transcriptomic changes in midbrain samples were investigated using bulk RNA-sequencing. NME induced prolonged hypersensitivity to thermal and mechanical pain in adolescence, accompanied by persistent gut microbial dysbiosis and sustained systemic inflammation, characterized by elevated circulating cytokine levels (e.g., IL-1α, IL-12p70, IFN-γ, IL-10). Transplantation of the microbiome from NME adolescents recapitulated pain hypersensitivity in naïve adolescent mice, while neonatal probiotic intervention with Bifidobacterium infantis (B. infantis) reversed the hypersensitivity by preventing gut dysbiosis and associated systemic inflammation. Furthermore, transcriptomic analysis of the midbrain tissues revealed that NME upregulated several genes and key signaling pathways, including those related to immune activation and excitatory signaling, which were notably mitigated by neonatal B. infantis administration. Together, these findings highlight the critical role of the gut-brain axis in modulating pain sensitivity and suggest that targeting the gut microbiome offers a promising therapeutic strategy for managing neurobiological disorders following early opioid exposure.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122211","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 : 2025-02-01DOI: 10.1016/j.bbi.2024.12.010
Germana Cocozza , Ludovica Maria Busdraghi , Giuseppina Chece , Antonio Menini , Marco Ceccanti , Laura Libonati , Chiara Cambieri , Francesco Fiorentino , Dante Rotili , Ferdinando Scavizzi , Marcello Raspa , Eleonora Aronica , Maurizio Inghilleri , Stefano Garofalo , Cristina Limatola
Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.
{"title":"GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis","authors":"Germana Cocozza , Ludovica Maria Busdraghi , Giuseppina Chece , Antonio Menini , Marco Ceccanti , Laura Libonati , Chiara Cambieri , Francesco Fiorentino , Dante Rotili , Ferdinando Scavizzi , Marcello Raspa , Eleonora Aronica , Maurizio Inghilleri , Stefano Garofalo , Cristina Limatola","doi":"10.1016/j.bbi.2024.12.010","DOIUrl":"10.1016/j.bbi.2024.12.010","url":null,"abstract":"<div><div>Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1<sup>G93A</sup> mouse model and that GFRAL is upregulated in the brainstem of hSOD1<sup>G93A</sup> mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1<sup>G93A</sup> mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 280-293"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.bbi.2024.12.014
Liqi Li
{"title":"Preventive application of probiotics in ischemic stroke therapy through the gut-spleen-brain axis","authors":"Liqi Li","doi":"10.1016/j.bbi.2024.12.014","DOIUrl":"10.1016/j.bbi.2024.12.014","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Page 294"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823742","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 : 2025-02-01DOI: 10.1016/j.bbi.2024.11.022
Lingmin Chen , Jiao Jiao , Fan Lei , Bin Zhou , Hong Li , Ping Liao , Xin Li , Yi Kang , Jin Liu , Ruotian Jiang
Astrocytes, which actively participate in cognitive processes, have a complex spongiform morphology, highlighted by extensive ramified fine processes that closely enwrap the pre- and post-synaptic compartments, forming tripartite synapses. However, the role of astrocyte morphology in cognitive processes remains incompletely understood and even controversial. The actin-binding protein Ezrin is highly expressed in astrocytes and is a key structural determinant of astrocyte morphology. Here, we found that Ezrin expression and astrocyte fine process volume in the hippocampus of male mice increased after learning but decreased after lipopolysaccharide injection and in a mouse model of postoperative cognitive dysfunction, both of which involved models with impaired cognitive function. Additionally, astrocytic Ezrin knock-out led to significantly decreased astrocytic fine process volumes, decreased astrocyte-neuron proximity, and induced anxiety-like behaviors and cognitive dysfunction. Astrocytic Ezrin deficiency in the hippocampus was achieved by using a microRNA silencing technique delivered by adeno-associated viruses. Down-regulation of Ezrin in hippocampal astrocytes led to disrupted astrocyte-synapse interactions and impaired synaptic functions, including synaptic transmission and synaptic plasticity, which could be rescued by exogenous administration of D-serine. Remarkably, decreased Ezrin expression and reduced astrocyte fine processes volumes were also observed in aged mice with decreased cognitive function. Moreover, overexpression of astrocytic Ezrin increased astrocyte fine process volumes and improved cognitive function in aged mice. Overall, our results indicate Ezrin-mediated astrocyte fine processes integrity shapes astrocyte-synapse signaling contributing to cognitive function.
{"title":"Ezrin-mediated astrocyte-synapse signaling regulates cognitive function via astrocyte morphological changes in fine processes in male mice","authors":"Lingmin Chen , Jiao Jiao , Fan Lei , Bin Zhou , Hong Li , Ping Liao , Xin Li , Yi Kang , Jin Liu , Ruotian Jiang","doi":"10.1016/j.bbi.2024.11.022","DOIUrl":"10.1016/j.bbi.2024.11.022","url":null,"abstract":"<div><div>Astrocytes, which actively participate in cognitive processes, have a complex spongiform morphology, highlighted by extensive ramified fine processes that closely enwrap the pre- and post-synaptic compartments, forming tripartite synapses. However, the role of astrocyte morphology in cognitive processes remains incompletely understood and even controversial. The actin-binding protein Ezrin is highly expressed in astrocytes and is a key structural determinant of astrocyte morphology. Here, we found that Ezrin expression and astrocyte fine process volume in the hippocampus of male mice increased after learning but decreased after lipopolysaccharide injection and in a mouse model of postoperative cognitive dysfunction, both of which involved models with impaired cognitive function. Additionally, astrocytic Ezrin knock-out led to significantly decreased astrocytic fine process volumes, decreased astrocyte-neuron proximity, and induced anxiety-like behaviors and cognitive dysfunction. Astrocytic Ezrin deficiency in the hippocampus was achieved by using a microRNA silencing technique delivered by adeno-associated viruses. Down-regulation of Ezrin in hippocampal astrocytes led to disrupted astrocyte-synapse interactions and impaired synaptic functions, including synaptic transmission and synaptic plasticity, which could be rescued by exogenous administration of D-serine. Remarkably, decreased Ezrin expression and reduced astrocyte fine processes volumes were also observed in aged mice with decreased cognitive function. Moreover, overexpression of astrocytic Ezrin increased astrocyte fine process volumes and improved cognitive function in aged mice. Overall, our results indicate Ezrin-mediated astrocyte fine processes integrity shapes astrocyte-synapse signaling contributing to cognitive function.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 177-191"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695089","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 : 2025-02-01DOI: 10.1016/j.bbi.2024.11.028
Vera Flasbeck , Fabian T. Ramseyer , Manfred Schedlowski , Harald Engler , Martin Brüne
Interpersonal connectedness is a central feature of human interaction that can be compromised during illness. Nonverbal signals play a crucial role in this context, and humans, like other animals, have evolved a behavioral immune system that enables individuals to detect subtle cues of sickness in others. Conversely, sick individuals often tend to avoid social interaction, a key component of sickness behavior. The coordination of body movements between two individuals (movement synchrony) is a measure of the quality of relationships that could provide insights into an interlocutor’s sickness state. In the present study, we explored the effect of lipopolysaccharide (LPS) administration, a naturalistic stimulus for inflammation-induced sickness, on movement synchrony in healthy volunteers randomly assigned to a double-blind interview with a non-treated interviewer conducted 2.5 h after intravenous injection of either LPS (N = 26) or placebo (N = 25). Movement synchrony was assessed by automated video analysis of subject’s and interviewer’s head movements. Lagged cross-correlations were used to objectively quantify coordination in dyads and to assess patterns of temporal movement synchronization. Data analysis revealed that dyads with subjects under placebo displayed a pattern of movement coordination comparable to that seen in previous studies. However, dyads with subjects under LPS showed a loss of simultaneous movement (i.e. moving at the same time) with the interview partner, which is normally the temporal domain providing the highest level of synchrony. Together, the findings suggest that immediate social interaction is attenuated when one interlocutor is exposed to systemic inflammation, while the other is unaffected. This effect can be attributed to both sickness behavior on one hand and correlates of the behavioral immune system on the other hand.
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Pub Date : 2025-02-01DOI: 10.1016/j.bbi.2024.11.035
Lorenzo Ghelfi , David Mongan , Subash Raj Susai , Melanie Föcking , David R. Cotter , Mary Cannon
Background
Converging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs’ functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood–brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC).
Methods
The present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink® Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking.
Results
There was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06–1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22–1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19–1.72). There was no evidence for an association between MMPs and psychotic disorders.
Conclusions
The study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.
背景：越来越多的证据支持基质金属蛋白酶（MMPs）在精神疾病中的作用。MMPs最初被认为是细胞外基质（ECM）的调节因子，其功能跨越多个过程，包括炎症、突触可塑性、神经元迁移和血脑屏障维持。金属蛋白酶组织抑制剂（TIMPs）是金属蛋白酶的主要调节因子。在本研究中，我们在雅芳父母和儿童纵向研究（ALSPAC）中检查了血浆MMPs和TIMPs与24 岁年轻人精神障碍的关系。方法：本研究是雅芳父母与儿童纵向研究中的一项巢式病例对照研究，包括374名符合精神障碍标准的参与者（35人符合精神障碍标准，201人符合轻度/中度抑郁症标准，266人符合广泛性焦虑症标准）和401名对照组。所有病例和对照组都是从4019名参与者中挑选出来的，这些参与者在24岁 岁时参加了研究，完成了精神评估并提供了血浆样本。MMP2、MMP3、MMP9和TIMP-4的血浆浓度采用Olink®Cardiovascular Panel III上提供的接近扩展测定法进行定量。Logistic回归分析比较了病例和对照组的标准化MMPs和TIMPs水平。模型根据性别、体重指数和吸烟情况进行了调整。结果：有证据表明MMP3与抑郁症之间存在关联（优势比[OR] 1.35, 95 %可信区间[CI] 1.06-1.73）。有证据表明TIMP4与抑郁症（OR 1.51, 95 % CI 1.22-1.88）和广泛性焦虑症（OR 1.43, 95 % CI 1.19-1.72）之间存在关联。没有证据表明MMPs和精神障碍之间存在关联。结论：研究显示，与对照组相比，24岁的抑郁症和焦虑症患者血浆中TIMP-4浓度升高。有证据表明MMP3和抑郁症之间存在关联。这些发现进一步支持金属蛋白酶作为生物标志物参与成年早期精神障碍的病理生理。
{"title":"Plasma levels of matrix metalloproteinases in early psychosis, anxiety and depression: Evidence from the ALSPAC cohort","authors":"Lorenzo Ghelfi , David Mongan , Subash Raj Susai , Melanie Föcking , David R. Cotter , Mary Cannon","doi":"10.1016/j.bbi.2024.11.035","DOIUrl":"10.1016/j.bbi.2024.11.035","url":null,"abstract":"<div><h3>Background</h3><div>Converging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs’ functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood–brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC).</div></div><div><h3>Methods</h3><div>The present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink® Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking.</div></div><div><h3>Results</h3><div>There was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06–1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22–1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19–1.72). There was no evidence for an association between MMPs and psychotic disorders.</div></div><div><h3>Conclusions</h3><div>The study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"124 ","pages":"Pages 137-143"},"PeriodicalIF":8.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766329","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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