Andjela Stekic, Milorad Dragic, Jelena Stanojevic, Marina Zaric Kontic, Ivana Stevanovic, Milica Zeljkovic Jovanovic, Katarina Mihajlovic, Nadezda Nedeljkovic
{"title":"多发性硬化症大鼠模型的嗅觉表现和焦虑样行为受损与嗅球中通过 A1R、A2BR 和 A3R 的腺苷信号增强有关","authors":"Andjela Stekic, Milorad Dragic, Jelena Stanojevic, Marina Zaric Kontic, Ivana Stevanovic, Milica Zeljkovic Jovanovic, Katarina Mihajlovic, Nadezda Nedeljkovic","doi":"10.3389/fncel.2024.1407975","DOIUrl":null,"url":null,"abstract":"The present study shows that animals with experimental autoimmune encephalomyelitis (EAE) exhibit olfactory dysfunction and impaired general cognitive abilities, as well as anxiety-like behavior. Olfactory dysfunction occurs on average at 2 dpi, well before the onset of the first motor signs of EAE (8–10 dpi). After the initial olfactory dysfunction, the EAE animals show a fluctuation in olfactory performance that resembles the relapsing–remitting course of human MS. The study also shows severe neuroinflammation in the olfactory bulb (OB), with numerous infiltrated CD4<jats:sup>+</jats:sup> T cells and peripheral macrophages in the superficial OB layers, marked microgliosis, and massive induction of TNF-α, IL-1β, and IL-6. Reduced tyrosine hydroxylase activity in the glomerular layer, pronounced granule cell atrophy, and reduced numbers of type B neuroblasts in the rostral migratory stream also indicate altered plasticity of the neuronal network in the OB. Considering the exceptionally high purinome expression in the OB, the possible involvement of purinergic signaling was also investigated. The study shows that macrophages infiltrating the OB overexpress A<jats:sub>3</jats:sub>R, while highly reactive microglia overexpress the adenosine-producing enzyme eN/CD73 as well as A<jats:sub>2B</jats:sub>R, A<jats:sub>3</jats:sub>R, and P2X<jats:sub>4</jats:sub>R. Given the simultaneous induction of complement component C3, the results suggest that the microglial cells develop a functional phenotype of phagocytizing microglia. The study also demonstrates transcriptional and translational upregulation of A<jats:sub>1</jats:sub>R in mitral and tufted cells, which likely influence resting network activity in OB and likely contribute to olfactory dysfunction in EAE. Overall, our study shows that olfactory dysfunction and altered social and cognitive behavior in EAE are associated with increased adenosine signaling via A<jats:sub>1</jats:sub>R, A<jats:sub>2B</jats:sub>R, and A<jats:sub>3</jats:sub>R.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"35 1","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Impaired olfactory performance and anxiety-like behavior in a rat model of multiple sclerosis are associated with enhanced adenosine signaling in the olfactory bulb via A1R, A2BR, and A3R\",\"authors\":\"Andjela Stekic, Milorad Dragic, Jelena Stanojevic, Marina Zaric Kontic, Ivana Stevanovic, Milica Zeljkovic Jovanovic, Katarina Mihajlovic, Nadezda Nedeljkovic\",\"doi\":\"10.3389/fncel.2024.1407975\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The present study shows that animals with experimental autoimmune encephalomyelitis (EAE) exhibit olfactory dysfunction and impaired general cognitive abilities, as well as anxiety-like behavior. Olfactory dysfunction occurs on average at 2 dpi, well before the onset of the first motor signs of EAE (8–10 dpi). After the initial olfactory dysfunction, the EAE animals show a fluctuation in olfactory performance that resembles the relapsing–remitting course of human MS. The study also shows severe neuroinflammation in the olfactory bulb (OB), with numerous infiltrated CD4<jats:sup>+</jats:sup> T cells and peripheral macrophages in the superficial OB layers, marked microgliosis, and massive induction of TNF-α, IL-1β, and IL-6. Reduced tyrosine hydroxylase activity in the glomerular layer, pronounced granule cell atrophy, and reduced numbers of type B neuroblasts in the rostral migratory stream also indicate altered plasticity of the neuronal network in the OB. Considering the exceptionally high purinome expression in the OB, the possible involvement of purinergic signaling was also investigated. The study shows that macrophages infiltrating the OB overexpress A<jats:sub>3</jats:sub>R, while highly reactive microglia overexpress the adenosine-producing enzyme eN/CD73 as well as A<jats:sub>2B</jats:sub>R, A<jats:sub>3</jats:sub>R, and P2X<jats:sub>4</jats:sub>R. Given the simultaneous induction of complement component C3, the results suggest that the microglial cells develop a functional phenotype of phagocytizing microglia. The study also demonstrates transcriptional and translational upregulation of A<jats:sub>1</jats:sub>R in mitral and tufted cells, which likely influence resting network activity in OB and likely contribute to olfactory dysfunction in EAE. 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引用次数: 0
摘要
本研究表明,实验性自身免疫性脑脊髓炎(EAE)动物表现出嗅觉功能障碍、一般认知能力受损以及焦虑样行为。嗅觉功能障碍平均发生在 2 dpi,远远早于 EAE 最初的运动症状(8-10 dpi)。在最初的嗅觉功能障碍之后,EAE 动物的嗅觉表现会出现波动,这与人类多发性硬化症的复发-缓解过程相似。研究还显示,嗅球(OB)存在严重的神经炎症,OB浅层有大量CD4+ T细胞和外周巨噬细胞浸润,小神经胶质增生明显,TNF-α、IL-1β和IL-6大量诱导。肾小球层酪氨酸羟化酶活性降低,颗粒细胞明显萎缩,喙移行流中B型神经细胞数量减少,这些也表明OB神经元网络的可塑性发生了改变。考虑到 OB 中嘌呤基因组的表达量特别高,研究人员还对嘌呤能信号传导可能的参与进行了调查。研究显示,浸润 OB 的巨噬细胞过度表达 A3R,而高反应性小胶质细胞则过度表达腺苷生成酶 eN/CD73、A2BR、A3R 和 P2X4R。鉴于补体成分 C3 的同时诱导,结果表明小胶质细胞形成了吞噬小胶质细胞的功能表型。该研究还证明了有丝分裂细胞和簇细胞中 A1R 的转录和翻译上调,这可能会影响 OB 中的静息网络活动,并可能导致 EAE 中的嗅觉功能障碍。总之,我们的研究表明,EAE 的嗅觉功能障碍以及社会和认知行为的改变与通过 A1R、A2BR 和 A3R 的腺苷信号传导增加有关。
Impaired olfactory performance and anxiety-like behavior in a rat model of multiple sclerosis are associated with enhanced adenosine signaling in the olfactory bulb via A1R, A2BR, and A3R
The present study shows that animals with experimental autoimmune encephalomyelitis (EAE) exhibit olfactory dysfunction and impaired general cognitive abilities, as well as anxiety-like behavior. Olfactory dysfunction occurs on average at 2 dpi, well before the onset of the first motor signs of EAE (8–10 dpi). After the initial olfactory dysfunction, the EAE animals show a fluctuation in olfactory performance that resembles the relapsing–remitting course of human MS. The study also shows severe neuroinflammation in the olfactory bulb (OB), with numerous infiltrated CD4+ T cells and peripheral macrophages in the superficial OB layers, marked microgliosis, and massive induction of TNF-α, IL-1β, and IL-6. Reduced tyrosine hydroxylase activity in the glomerular layer, pronounced granule cell atrophy, and reduced numbers of type B neuroblasts in the rostral migratory stream also indicate altered plasticity of the neuronal network in the OB. Considering the exceptionally high purinome expression in the OB, the possible involvement of purinergic signaling was also investigated. The study shows that macrophages infiltrating the OB overexpress A3R, while highly reactive microglia overexpress the adenosine-producing enzyme eN/CD73 as well as A2BR, A3R, and P2X4R. Given the simultaneous induction of complement component C3, the results suggest that the microglial cells develop a functional phenotype of phagocytizing microglia. The study also demonstrates transcriptional and translational upregulation of A1R in mitral and tufted cells, which likely influence resting network activity in OB and likely contribute to olfactory dysfunction in EAE. Overall, our study shows that olfactory dysfunction and altered social and cognitive behavior in EAE are associated with increased adenosine signaling via A1R, A2BR, and A3R.
期刊介绍:
Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.