Bethania Mongi-Bragato , Marianela Adela Sánchez , María Paula Avalos , María Julieta Boezio , Andrea Susana Guzman , Diana Rigoni , Eduardo Marcelo Perassi , Carlos Ruben Mas , Mariano Bisbal , Flavia Andrea Bollati , Liliana Marina Cancela
{"title":"伏隔核核心核因子κ B的激活对于慢性应激诱导的谷氨酸和神经免疫改变是必要的,从而促进可卡因的自我给药。","authors":"Bethania Mongi-Bragato , Marianela Adela Sánchez , María Paula Avalos , María Julieta Boezio , Andrea Susana Guzman , Diana Rigoni , Eduardo Marcelo Perassi , Carlos Ruben Mas , Mariano Bisbal , Flavia Andrea Bollati , Liliana Marina Cancela","doi":"10.1016/j.bbi.2025.03.028","DOIUrl":null,"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":8.8000,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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 , Marianela Adela Sánchez , María Paula Avalos , María Julieta Boezio , Andrea Susana Guzman , Diana Rigoni , Eduardo Marcelo Perassi , Carlos Ruben Mas , Mariano Bisbal , Flavia Andrea Bollati , Liliana Marina Cancela\",\"doi\":\"10.1016/j.bbi.2025.03.028\",\"DOIUrl\":null,\"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\":8.8000,\"publicationDate\":\"2025-03-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain, Behavior, and Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0889159125001138\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain, Behavior, and Immunity","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0889159125001138","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
压力事件与受损的谷氨酸信号和神经免疫适应有关,这可能增加个体对可卡因成瘾的脆弱性。我们之前证明,慢性应激诱导反应性小胶质细胞和增加伏隔核(NAcore)中TNF-α的表达,这两种变化与谷氨酸稳态受损和可卡因自我给药的促进密切相关。核因子κ b (NF-κ b)是许多免疫和成瘾相关基因的关键调节因子,如谷氨酸转运蛋白(GLT-1)的基因编码,它被认为是炎症的主要调节因子,据报道是精神疾病中小胶质细胞激活的关键驱动因素。然而,目前还没有研究检测NAcore内NF-κB信号在神经免疫和谷氨酸机制中的作用,从而支持应激诱导的可卡因自我给药易感性。在这里,我们研究了病毒对I κB激酶(IKKdn)(一种负责NF-κB活化的信号分子)的显性负抑制是否会阻止应激诱导的可卡因自我给药以及相关的伏核GLT-1和TNF-α表达的变化。我们还探讨了N-myc原癌基因蛋白(N-myc)水平在NF-κB和应激诱导的GLT-1下调之间的联系。7 d(第1-7天),成年雄性大鼠受限2 h/d。在第一次约束应激后的第14天,给动物注射含有IKKdn或空慢病毒的nacore。应激小鼠核核中NF-κB明显活化,星形胶质细胞中NF-κB表达升高。一致地,病毒NF-κB抑制阻止应激诱导的可卡因自我给药的促进。此外,NF-κB阻断可恢复应激诱导的GLT-1水平降低,并可有效抑制应激诱导的NAcore内TNF-α。这些发现表明伏隔NF-κB信号传导对应激改变的下游神经免疫和谷氨酸功能施加中枢控制,这是可卡因使用障碍易感性的基础。
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
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.
期刊介绍:
Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals.
As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.