Brain, Behavior, and Immunity最新文献

{"title":"The effects of P2Y12 loss on microglial gene expression, dynamics, and injury response in the cerebellum and cerebral cortex","authors":"Mark B. Stoessel ,&nbsp;Rianne D. Stowell ,&nbsp;Rebecca L. Lowery ,&nbsp;Linh H.D. Le ,&nbsp;Andy N. Vu ,&nbsp;Brendan S. Whitelaw ,&nbsp;Ania K. Majewska","doi":"10.1016/j.bbi.2025.03.036","DOIUrl":"10.1016/j.bbi.2025.03.036","url":null,"abstract":"<div><div><ul><li><span></span><span><div>Despite the emerging consensus that microglia are critical to physiological and pathological brain function, it is unclear how microglial roles, and their underlying mechanisms differ between brain regions. Microglia throughout the brain express common markers, such as the purinergic receptor P2Y12, that delineate them from monocytes and brain macrophages. P2Y12 is a critical sensor of injury but also contributes to the sensing of neuronal activity and remodeling of synapses, with microglial loss of P2Y12 resulting in behavioral deficits. P2Y12 has largely been studied in cortical microglia, despite the fact that a growing body of evidence suggests that microglia exhibit a high degree of regional specialization. Cerebellar microglia, in particular, exhibit transcriptional, epigenetic, and functional profiles that set them apart from their better studied cortical and hippocampal counterparts. Here, we demonstrate that P2Y12 is required for a full microglial response to focal injury in the cortex but not in the cerebellum, suggesting that cerebellar and cortical microglia utilize P2Y12 signaling differently. We therefore investigated the effects of P2Y12 deficiency on cerebellar microglial physiology and function, and overall contributions to synaptic plasticity. We found that P2Y12 deficiency does little to disturb the distinct transcriptomic profiles of cortical and cerebellar microglia and does not alter the morphology, distribution, or homeostatic dynamics of microglia in the cerebellum. However, we show that P2Y12 deficiency impairs cerebellar learning in a delay eyeblink conditioning task, a common test of cerebellar plasticity and circuit function. Overall, our findings suggest not only region-specific roles of microglial P2Y12 signaling in the focal injury response, but also indicate a conserved role for P2Y12 in microglial modulation of plasticity across regions.</div></span></li></ul></div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 99-120"},"PeriodicalIF":8.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCL25 in the cerebrospinal fluid is negatively correlated with fatigue in chronic pain patients","authors":"Alexander H.C. Rosenström ,&nbsp;Aisha Siddiqah Ahmed ,&nbsp;Alex Bersellini Farinotti ,&nbsp;Kim Kultima ,&nbsp;Svante Berg ,&nbsp;Martin F. Bjurström ,&nbsp;Camilla I. Svensson ,&nbsp;Eva Kosek","doi":"10.1016/j.bbi.2025.03.030","DOIUrl":"10.1016/j.bbi.2025.03.030","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and aim&lt;/h3&gt;&lt;div&gt;Chronic pain is often accompanied by other symptoms such as fatigue and sleep disturbance, and these symptoms all correlate with neuroimmune activation. However, their relation to one another on a neuroimmune axis remains elusive. Based on a recent review, cytokines in the cerebrospinal fluid (CSF) seem to be generally upregulated in patients with chronic pain compared to controls, disregarding pain type. Some of these have the possilibity of altering blood–brain barrier (BBB) permeability. Therefore, cytokine levels in serum and CSF, as well as BBB permeability, were measured in a cohort of patients suffering from either degenerative disc disease (DDD), lumbar disc herniation (LDH) or osteoarthritis (OA). In this exploratory study, we were interested in whether cytokines in the serum or CSF are associated with sleep disturbance or fatigue, with special consideration of the effect of BBB permeability, and whether functional clusters can be found among these cytokines.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Method&lt;/h3&gt;&lt;div&gt;One-hundred-twenty patients with DDD/LDH/OA, all awaiting surgery, were included. Blood and CSF were collected on the day of surgery. Pain was measured with a visual analog scale 0–100 mm, sleep disturbance was assessed using Pittsburgh Sleep Quality Index (PSQI), and fatigue was measured using the Multidimensional Fatigue Inventory (MFI). A 92-protein multiplex panel (OLINK, Sweden) was used to analyze cytokine expression in serum and CSF, respectively. CSF-serum albumin quotient was measured using ELISA. Non-parametric statistics were used for univariate analyses, and a false discovery rate (FDR) &lt; 0.10 was considered statistically significant. Bonferroni correction was applied to all multivariable protein analyses to obtain conservative effect estimates.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Main results&lt;/h3&gt;&lt;div&gt;There was an association between BBB permeability and serum-CSF dynamics: thirty-one cytokines showed significant CSF-serum correlation, and BBB permeability was significantly correlated to the quotients of 35 cytokines and to the CSF levels of 11 cytokines. Several cytokines were negatively correlated to both pain at rest and general fatigue. No correlations were found between sleep disturbance and cytokines. Network analyses of serum and CSF cytokines that were correlated with fatigue revealed functional clusters in both compartments. Anxiety, depression, and pain during rest were important regressors for sleep disturbance with an R&lt;sup&gt;2&lt;/sup&gt; = 0.41. In addition to depression and pain during rest, CSF levels of CCL25 was a significant regressor regarding general fatigue, with an R&lt;sup&gt;2&lt;/sup&gt; = 0.47.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Discussion and conclusion&lt;/h3&gt;&lt;div&gt;In this exploratory study of immune profiles in chronic pain cohorts awaiting surgery, the importance of BBB dynamics on serum-CSF cytokine dynamics, and to a lesser extent on central levels of cytokines, is highlighted. Surprisingly, there were no association","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 54-64"},"PeriodicalIF":8.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751218","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}

{"title":"Elevated neuroinflammation, autoimmunity, and altered IgG glycosylation profile in the cerebral spinal fluid of severe COVID-19 patients","authors":"Tanner Shull ,&nbsp;Pavan Bhimalli ,&nbsp;Samantha Welninski ,&nbsp;Byoung-Kyu Cho ,&nbsp;Basil Mattamana ,&nbsp;Jaison Arivalagan ,&nbsp;Imad Tarhoni ,&nbsp;Young Ah Goo ,&nbsp;Julie A. Schneider ,&nbsp;Sonal Agrawal ,&nbsp;David A Bennett ,&nbsp;Sue Leurgans ,&nbsp;Mayur B. Patel ,&nbsp;E.Wesley Ely ,&nbsp;Neil L. Kelleher ,&nbsp;Jeffrey A. Borgia ,&nbsp;Jeffrey R. Schneider ,&nbsp;Lena Al-Harthi","doi":"10.1016/j.bbi.2025.03.031","DOIUrl":"10.1016/j.bbi.2025.03.031","url":null,"abstract":"<div><h3>Background and Objectives</h3><div>A spectrum of neurologic complications associated with COVID-19 are well documented. While neuroinflammation in the brain of COVID-19 patients likely contributes to these complications, the mechanisms of neuroinflammation and correlates of neurologic complications remain elusive, especially since the etiologic pathogen of COVID-19, SARS-CoV-2, minimally invades the CNS. This study aimed to evaluate markers of neuroinflammation, IgG glycosylation patterns indicative of pro- or anti-inflammatory state, and prevalence of brain auto-reactive antibodies in the CSF of COVID-19 patients and their relationship to brain neuropathology.</div></div><div><h3>Methods</h3><div>We evaluated the CSF of 11 deceased unvaccinated COVID-19 donors and 13 matched non-COVID-19 controls. Markers of neuroinflammation, IgG glycosylation patterns, and brain auto-reactive antibodies were assessed, along with their correlation to brain neuropathology. Statistical analyses were performed to compare groups and assess relationships between variables, using non-parametric tests and bootstrap analysis.</div></div><div><h3>Results</h3><div>COVID-19 CSF showed higher levels of neopterin and ANNA-1, markers of neuroinflammation and autoimmunity, respectively, and lower IFN response compared to non-COVID-19 donors. In brain regions of high microglial activation, IL4 and RANTES were significantly increased. SARS-CoV-2 was undetectable in the CSF and brain of COVID-19 donors, yet anti-SARS-CoV-2 CSF antibodies were detected. Fucosylated IgG were associated with Spike IgG, CSF protein, and soluble CD14, whereas afucosylated bisecting IgG were inversely correlated with Spike IgG. Sialic acid containing IgG were positively correlated with IL1β and TNFα. These associations were not found in non-COVID-19 donors. Inflammatory agalactosylated fucosylated IgG (G0F) were associated with infiltrating CD4 + T cells in the brains of COVID-19 donors. COVID-19 donor CSF displayed higher levels of auto-reactive antibodies to human brain antigens compared to non-COVID-19 donors and donors with positive autoantibodies showed higher levels of neopterin.</div></div><div><h3>Discussion</h3><div>These data describe increased neuroinflammation and autoreactive antibody markers in the CSF of COVID-19 donors and suggest that IgG glycosylation and autoimmunity may contribute to COVID-19 pathology, highlighting potential mechanisms underlying the neurologic complications associated with COVID-19.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 289-302"},"PeriodicalIF":8.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of TrkB-BDNF positive feedback loop attenuates intervertebral disc degeneration and low back pain in a composite mouse model","authors":"Xiang Ao ,&nbsp;Kun Li ,&nbsp;Yujie Chen ,&nbsp;Weiyi Lai ,&nbsp;Zhengnan Lian ,&nbsp;Zhengnong Wei ,&nbsp;Liang Wang ,&nbsp;Zhongmin Zhang ,&nbsp;Minjun Huang","doi":"10.1016/j.bbi.2025.03.029","DOIUrl":"10.1016/j.bbi.2025.03.029","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain (LBP); however, the specific mechanisms involved remain unclear. Herein, a novel LBP mouse model was developed by integrating a bipedal standing model with a lumbar spine instability model (BS + LSI). This model effectively reproduced the behavioral characteristics of LBP and the pathological features of IVDD. Notably, a higher degree of degeneration and innervation in the endplates were observed in the BS + LSI mice. Transcriptome analysis revealed a significant upregulation of Ntrk2, the gene encoding TrkB, in the intervertebral discs of BS + LSI mice. Immunohistochemical staining further confirmed elevated expression of TrkB and its ligand BDNF in the endplates of these mice. Moreover, cyclic tensile strain (CTS) (20 %, 0.1 Hz, 24 h) upregulated TrkB expression and activated NF-κB signaling pathway to promote inflammatory responses in endplate chondrocytes. siBDNF transfection or treatment with the TrkB inhibitor ANA-12 effectively inhibited these pathological changes. Mechanistically, TrkB promoted BDNF expression by enhancing CREB phosphorylation, thereby establishing a TrkB-CREB-BDNF positive feedback loop. In vivo injection of ANA-12 significantly alleviated endplate inflammation and LBP-related behaviors in BS + LSI mice. Thus, an effective and replicable mouse model of LBP was established to identify TrkB as both the receptor for and an upstream regulator of BDNF, making it a crucial target for interventions to alleviate CEP inflammation and LBP.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 37-53"},"PeriodicalIF":8.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of Nuclear Factor-kappa B in the nucleus accumbens core is necessary for chronic stress-induced glutamate and neuro-immune alterations that facilitate cocaine self-administration","authors":"Bethania Mongi-Bragato ,&nbsp;Marianela Adela Sánchez ,&nbsp;María Paula Avalos ,&nbsp;María Julieta Boezio ,&nbsp;Andrea Susana Guzman ,&nbsp;Diana Rigoni ,&nbsp;Eduardo Marcelo Perassi ,&nbsp;Carlos Ruben Mas ,&nbsp;Mariano Bisbal ,&nbsp;Flavia Andrea Bollati ,&nbsp;Liliana Marina Cancela","doi":"10.1016/j.bbi.2025.03.028","DOIUrl":"10.1016/j.bbi.2025.03.028","url":null,"abstract":"<div><div>Stressful events are associated with impaired glutamate signaling and neuroimmune adaptations that may increase the vulnerability of individuals to cocaine addiction. We previously demonstrated that chronic stress induced reactive microglia and increased TNF-α expression in the nucleus accumbens core (NAcore), both alterations strongly linked with impaired glutamate homeostasis and the facilitation of cocaine self-administration. The nuclear factor kappa-B (NF-κB) is a critical regulator of many immune- and addiction-related genes, such as the gene coding for glutamate transporter (GLT-1), and it is considered a master regulator of inflammation, reported to be a key driver of microglia activation in psychiatric diseases. However, no studies have examined the role of NF-κB signaling within the NAcore in the neuroimmune and glutamate mechanism, underpinning stress-induced vulnerability to cocaine self-administration. Here we investigate whether viral dominant negative inhibition of I kappa B kinase (IKKdn), a signaling molecule responsible for NF-κB activation, would prevent stress-induced facilitation to cocaine self-administration and associated changes in accumbal GLT-1 and TNF-α expression. We also explore N-myc proto-oncogene protein (N-myc) levels as a link between NF-κB and stress-induced GLT-1 downregulation. For seven days (days 1–7), adult male rats were restrained for 2 h/day. Animals were administered an intra-NAcore with IKKdn or empty lentiviruses on day 14 after the first restraint stress session. Marked activation of NF-κB was detected in the NAcore of stressed subjects, along with increased NF-κB expression in astrocytes. Consistently, viral NF-κB inhibition prevented stress-induced facilitation of cocaine self-administration. Moreover, NF-κB blockade results in the restoration of stress-induced reduction in GLT-1 levels and was effective in suppressing stress-induced TNF-α within the NAcore. These findings suggest that accumbal NF-κB signaling exerts a central control over stress-altered downstream neuroimmune and glutamate function underlying vulnerability to cocaine use disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 1-15"},"PeriodicalIF":8.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-tyrosine alleviates autism-like behavior in mice by remodeling the gut microbiota","authors":"Jingjing Fang ,&nbsp;Jingya Guo ,&nbsp;Yujie Lao ,&nbsp;Seong-Gook Kang ,&nbsp;Kunlun Huang ,&nbsp;Tao Tong","doi":"10.1016/j.bbi.2025.03.025","DOIUrl":"10.1016/j.bbi.2025.03.025","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is characterized by impaired social interaction and repetitive stereotyped behavior, and effective interventions for the core autistic symptoms are currently limited. This study examines the protective role of L-tyrosine in alleviating ASD-like behavioral disorders in a valproic acid (VPA)-induced ASD mouse model and explores the underlying mechanisms via integrated multi-omics. We first investigated the potential of dietary L-tyrosine in mitigating autistic behavior. Subsequently, 16S rRNA sequencing, hippocampal transcriptomics, and neurotransmitter metabolome were employed to elucidate the underlying mechanism. Further, we conducted transplantation of the L-tyrosine-regulated microbiota in VPA-induced ASD mice. The results showed that L-tyrosine supplementation significantly mitigates ASD-like behavioral disorders, alleviates social communication deficits, and reduces repetitive behavior in autistic mice. L-tyrosine also attenuates the neuronal loss caused by VPA treatment in the DG and CA1 hippocampal regions in mice. The hippocampi of the L-tyrosine-treated mouse model for ASD displays modified gene expression profiles and different neurotransmitter levels. L-tyrosine also mitigates colonic barrier damage and amends the gut microbial composition and function. The integrative transcriptomic, metabolomic, and microbiome analysis shows strong connections between the hippocampal genes, neurotransmitters, and gut microbiota affected by L-tyrosine. The transplantation of microbiota from L-tyrosine-treated mice to VPA-induced ASD mice recipients recapitulated the preventive and protective effects of L-tyrosine on autistic behavior disorders. These findings suggest that dietary L-tyrosine may represent a viable, effective treatment option for managing the physiological and behavioral deficits associated with ASD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"127 ","pages":"Pages 358-374"},"PeriodicalIF":8.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropsychiatric sequelae in an experimental model of post-COVID syndrome in mice","authors":"Jordane Clarisse Pimenta ,&nbsp;Vinícius Amorim Beltrami ,&nbsp;Bruna da Silva Oliveira ,&nbsp;Celso Martins Queiroz-Junior ,&nbsp;Jéssica Barsalini ,&nbsp;Danielle Cunha Teixeira ,&nbsp;Luiz Pedro de Souza-Costa ,&nbsp;Anna Luiza Diniz Lima ,&nbsp;Caroline Amaral Machado ,&nbsp;Bárbara Zuccolotto Schneider Guimarães Parreira ,&nbsp;Felipe Rocha da Silva Santos ,&nbsp;Pedro Augusto Carvalho Costa ,&nbsp;Larisse de Souza Barbosa Lacerda ,&nbsp;Matheus Rodrigues Gonçalves ,&nbsp;Ian de Meira Chaves ,&nbsp;Manoela Gonzaga Gontijo Couto ,&nbsp;Victor Rodrigues de Melo Costa ,&nbsp;Natália Ribeiro Cabacinha Nóbrega ,&nbsp;Bárbara Luísa Silva ,&nbsp;Talita Fonseca ,&nbsp;Vivian Vasconcelos Costa","doi":"10.1016/j.bbi.2025.03.022","DOIUrl":"10.1016/j.bbi.2025.03.022","url":null,"abstract":"<div><div>The global impact of the COVID-19 pandemic has been unprecedented, and presently, the world is facing a new challenge known as post-COVID syndrome (PCS). Current estimates suggest that more than 100 million people are grappling with PCS, encompassing several manifestations, including pulmonary, musculoskeletal, metabolic, and neuropsychiatric sequelae (cognitive and behavioral). The mechanisms underlying PCS remain unclear. The present study aimed to: (i) comprehensively characterize the acute effects of pulmonary inoculation of the betacoronavirus MHV-A59 in immunocompetent mice at clinical, cellular, and molecular levels; (ii) examine potential acute and long-term pulmonary, musculoskeletal, and neuropsychiatric sequelae induced by the betacoronavirus MHV-A59; and to (iii) assess sex-specific differences. Male and female C57Bl/6 mice were initially inoculated with varying viral titers (3x10³ to 3x10⁵ PFU/30 μL) of the betacoronavirus MHV-A59 via the intranasal route to define the highest inoculum capable of inducing disease without causing mortality. Further experiments were conducted with the 3x10⁴ PFU inoculum. Mice exhibited an altered neutrophil/lymphocyte ratio in the blood in the 2nd and 5th day post-infection (dpi). Marked lung lesions were characterized by hyperplasia of the alveolar walls, infiltration of polymorphonuclear leukocytes (PMN) and mononuclear leukocytes, hemorrhage, increased concentrations of CCL2, CCL3, CCL5, and CXCL1 chemokines, as well as high viral titers until the 5th dpi. While these lung inflammatory signs resolved, other manifestations were observed up to the 60 dpi, including mild brain lesions with gliosis and hyperemic blood vessels, neuromuscular dysfunctions, anhedonic-like behavior, deficits in spatial working memory, and short-term aversive memory. These musculoskeletal and neuropsychiatric complications were exclusive to female mice and prevented after ovariectomy. In summary, our study describes for the first time a novel sex-dependent model of PCS focused on neuropsychiatric and musculoskeletal disorders. This model provides a unique platform for future investigations regarding the effects of acute therapeutic interventions on the long-term sequelae unleashed by betacoronavirus infection.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 16-36"},"PeriodicalIF":8.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation and psychomotor retardation in depression: The moderating role of glymphatic system","authors":"Qunjun Liang ,&nbsp;Bo Peng ,&nbsp;Shengli Chen ,&nbsp;Hongyue Wei ,&nbsp;Shiwei Lin ,&nbsp;Xiaoshan Lin ,&nbsp;Ying Li ,&nbsp;Yingli Zhang ,&nbsp;Zhifeng Zhou ,&nbsp;Ziyun Xu ,&nbsp;Gangqiang Hou ,&nbsp;Yingwei Qiu","doi":"10.1016/j.bbi.2025.03.024","DOIUrl":"10.1016/j.bbi.2025.03.024","url":null,"abstract":"<div><h3>Background</h3><div>Psychomotor retardation (PMR) is a predominant symptom in patients with major depressive disorder (MDD). The relationship between inflammation and PMR is the subject of ongoing debate. The glymphatic system (GS) is a waste clearance system in the brain that interacts with the immune system. Herein, we hypothesized that GS function moderates the association between inflammation and PMR.</div></div><div><h3>Methods</h3><div>A total of 67 patients with MDD and 67 healthy controls (HCs) were recruited and underwent MRI scanning. PMR and inflammation, which were evaluated by measuring high-sensitivity C-reactive protein (hsCRP) levels in peripheral blood, were assessed in all patients. Diffusion tensor imaging analysis along the perivascular space was used to assess GS function. Functional connectivity (FC) and morphology within the motor circuit were also assessed. Moderation models were constructed to estimate the effect of GS function as a moderator of the relationships between hsCRP level and PMR and between hsCRP level and motor cortex FC and morphology.</div></div><div><h3>Results</h3><div>GS function in patients was impaired compared with that in HCs (<em>t</em> = –2.635, <em>p</em> = 0.009). Moderation models showed that hsCRP level significantly aggravated PMR severity at low levels of GS function, whereas this effect was negligible in patients with optimal GS function (<em>F</em> = 6.725, <em>p</em> = 0.021). GS function also exhibited a moderation effect on inflammation-related alterations in morphology (<em>F</em> = 13.86, <em>p</em> = 0.047) and FC (<em>F</em> = 13.765, <em>p</em> &lt; 0.001) in the motor circuit.</div></div><div><h3>Conclusion</h3><div>A well-functioning GS mitigates inflammation-induced PMR and protects neurons from inflammatory damage. Given its moderating effect, GS function may play a crucial role in MDD psychopathology, and targeting GS function may have therapeutic value as an MDD treatment strategy.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"127 ","pages":"Pages 387-395"},"PeriodicalIF":8.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into the neuroprotective effects of low-intensity transcranial ultrasound stimulation in post-cardiac arrest brain injury: Modulation of the Piezo1-Dkk3/PI3K-Akt pathway","authors":"Shuang Xu ,&nbsp;Lulu Gu ,&nbsp;Banghe Bao ,&nbsp;Qian Liu ,&nbsp;Qiaofeng Jin ,&nbsp;Yannan Ma ,&nbsp;Siyi Zhou ,&nbsp;Beibei Li ,&nbsp;Li Xu ,&nbsp;Guangqi Guo ,&nbsp;Jinpiao Zhu ,&nbsp;Kuan-Pin Su ,&nbsp;Peng Sun","doi":"10.1016/j.bbi.2025.03.027","DOIUrl":"10.1016/j.bbi.2025.03.027","url":null,"abstract":"<div><div>Post-cardiac arrest brain injury (PCABI) remains a significant challenge, marked by high mortality and disability rates due to persistent neuroinflammation. This study explored the neuroprotective potential of low-intensity transcranial ultrasound stimulation (LITUS) in mitigating brain damage after cardiopulmonary resuscitation (CPR) using a murine model and in vitro assays. LITUS treatment improved 24-h survival rates and neurological recovery in cardiac arrest (CA) mice, as evidenced by behavioral assessments and reduced neurological deficit scores. Proteomic analyses revealed modulation of Piezo1-Dkk3/PI3K-Akt signaling pathway, characterized by decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Mechanistic studies demonstrated that LITUS enhanced Piezo1 and Dkk3 activation, promoting calcium influx and anti-inflammatory responses. The Piezo1 antagonist GsMTx4 abrogated these effects, underscoring Piezo1’s specific role. Additionally, in vitro experiments using oxygen/glucose deprivation and reoxygenation (OGD/R)-treated BV2 microglial cells confirmed that LITUS reduced inflammatory responses and enhanced cellular recovery via the Piezo1-Dkk3 axis. These findings highlight LITUS as a promising non-invasive therapeutic strategy to ameliorate PCABI by modulating neuroinflammation through the Piezo1-Dkk3/PI3K-Akt pathway. This work provides a basis for translational research and potential clinical applications in improving outcomes for CPR survivors.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"127 ","pages":"Pages 341-357"},"PeriodicalIF":8.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale effects of prenatal inflammation and early life circadian disruption in mice: Implications for neurodevelopmental disorders","authors":"Tara C. Delorme ,&nbsp;Danusa M. Arcego ,&nbsp;Danae Penichet ,&nbsp;Nicholas O’Toole ,&nbsp;Nikki Huebener ,&nbsp;Patrícia P. Silveira ,&nbsp;Lalit K. Srivastava ,&nbsp;Nicolas Cermakian","doi":"10.1016/j.bbi.2025.03.023","DOIUrl":"10.1016/j.bbi.2025.03.023","url":null,"abstract":"<div><div>Around 80 % of individuals with neurodevelopmental disorders such as schizophrenia and autism spectrum disorders experience disruptions in sleep/circadian rhythms. We explored whether environmental circadian disruption interacts with prenatal infection, a risk factor for neurodevelopmental disorders, to induce sex-specific deficits in mice. A maternal immune activation (MIA) protocol was used by injecting pregnant mice with viral mimic poly IC or saline at E9.5. Juvenile/adolescent male and female offspring (3–7 weeks old) were then subjected to a standard light:dark cycle (12:12LD) or to constant light (LL). Significant interactions between treatment (MIA, control) and lighting (12:12LD, LL) were evident in behaviors related to cognition, anxiety, and sociability. This pattern persisted in our RNA sequencing analysis of the dorsal hippocampus, where poly IC exposure resulted in numerous differentially expressed genes (DEGs) in males, while exposure to both poly IC and LL led to a marked reduction in DEGs. Through WGCNA analysis, many significant gene modules were found to be positively associated with poly IC (vs. saline) and LL (vs. LD) in males (fewer in females). Many of the identified hub-bottleneck genes were homologous to human genes associated with sleep/circadian rhythms and neurodevelopmental disorders as revealed by GWA studies. The MIA- and LL-associated modules were enriched in microglia gene signatures, which was paralleled by trends of effects of each of the factors on microglia morphology. In conclusion, in a mouse model of prenatal infection, circadian disruption induced by LL during adolescence acts as a modulator of the effects of MIA at behavioral, cellular, and molecular levels.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"127 ","pages":"Pages 409-422"},"PeriodicalIF":8.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673248","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}