首页 > 最新文献

Brain, Behavior, and Immunity最新文献

英文 中文
Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides 阻断 ATGL 介导的小胶质细胞脂滴分解可减轻对脂多糖的神经炎症反应和行为反应
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-24 DOI: 10.1016/j.bbi.2024.09.027
Lipid droplets (LD) are triglyceride storing organelles that have emerged as an important component of cellular inflammatory responses. LD lipolysis via adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral immune and non-immune cells. ATGL elicits both pro- and anti-inflammatory responses in the periphery in a cell-type dependent manner. The present study determined the impact of ATGL inhibition and microglia-specific ATGL genetic loss-of-function on acute inflammatory and behavioural responses to pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines and phagocytosis in mouse primary microglia cultures. Lipase inhibitors (ORlistat and ATGListatin) and LPS led to LD accumulation in microglia. Pan-lipase inhibition with ORlistat alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL had a similar action on CCL2, IL-1β and IL-6 expression in both neonatal and adult microglia cultures. CCL2 and IL-6 secretion were also reduced by ATGListatin or knockdown of ATGL. ATGListatin increased phagocytosis in neonatal cultures independently from LPS treatment. Second, targeted and untargeted lipid profiling revealed that ATGListatin reduced LPS-induced generation of pro-inflammatory prostanoids and modulated ceramide species in neonatal microglia. Finally, the role of microglial ATGL in neuroinflammation was assessed using a novel microglia-specific and inducible ATGL knockout mouse model. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and IL-1β and microglial density. LPS-induced sickness- and anxiety-like behaviours were also reduced in male mice with loss of ATGL in microglia. Together, our results demonstrate potent anti-inflammatory effects produced by pharmacological or genetic inhibition of ATGL-mediated triglyceride lipolysis and thereby propose that supressing microglial LD lipolysis has beneficial actions in acute neuroinflammatory conditions.
脂滴(LD)是储存甘油三酯的细胞器,已成为细胞炎症反应的重要组成部分。脂滴通过脂肪甘油三酯脂肪酶(ATGL)(一种催化甘油三酯脂肪分解限速步骤的酶)进行脂肪分解,从而调节外周免疫细胞和非免疫细胞的炎症反应。ATGL 以细胞类型依赖的方式在外周引起促炎和抗炎反应。本研究确定了抑制 ATGL 和小胶质细胞特异性 ATGL 基因功能缺失对急性炎症反应和对促炎症损伤的行为反应的影响。首先,我们评估了脂肪分解抑制对小鼠原代小胶质细胞培养物中脂多糖(LPS)诱导的细胞因子表达和分泌以及吞噬作用的影响。脂肪酶抑制剂(ORlistat 和 ATGListatin)和 LPS 会导致 LD 在小胶质细胞中积累。用ORlistat抑制泛脂肪酶可减轻LPS诱导的IL-1β和IL-6的表达。在新生儿和成年小胶质细胞培养物中,特异性抑制 ATGL 对 CCL2、IL-1β 和 IL-6 的表达也有类似作用。ATGListatin 或敲除 ATGL 也会减少 CCL2 和 IL-6 的分泌。ATGListatin 增加了新生儿培养物的吞噬能力,而与 LPS 处理无关。其次,靶向和非靶向脂质分析表明,ATGListatin 可减少 LPS 诱导的促炎前列腺素的生成,并调节新生小胶质细胞中的神经酰胺种类。最后,我们使用一种新型小胶质细胞特异性和诱导性 ATGL 基因敲除小鼠模型评估了小胶质细胞 ATGL 在神经炎症中的作用。成年雄性小鼠小胶质细胞 ATGL 的缺失抑制了 LPS 诱导的 IL-6 和 IL-1β 的表达以及小胶质细胞的密度。在小胶质细胞 ATGL 缺失的雄性小鼠中,LPS 诱导的病态和焦虑行为也有所减少。总之,我们的研究结果表明,通过药物或基因抑制 ATGL 介导的甘油三酯脂解作用可产生强大的抗炎效果,从而提出抑制小胶质细胞 LD 脂解作用对急性神经炎症有益处。
{"title":"Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides","authors":"","doi":"10.1016/j.bbi.2024.09.027","DOIUrl":"10.1016/j.bbi.2024.09.027","url":null,"abstract":"<div><div>Lipid droplets (LD) are triglyceride storing organelles that have emerged as an important component of cellular inflammatory responses. LD lipolysis via adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral immune and non-immune cells. ATGL elicits both pro- and anti-inflammatory responses in the periphery in a cell-type dependent manner. The present study determined the impact of ATGL inhibition and microglia-specific ATGL genetic loss-of-function on acute inflammatory and behavioural responses to pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines and phagocytosis in mouse primary microglia cultures. Lipase inhibitors (ORlistat and ATGListatin) and LPS led to LD accumulation in microglia. Pan-lipase inhibition with ORlistat alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL had a similar action on CCL2, IL-1β and IL-6 expression in both neonatal and adult microglia cultures. CCL2 and IL-6 secretion were also reduced by ATGListatin or knockdown of ATGL. ATGListatin increased phagocytosis in neonatal cultures independently from LPS treatment. Second, targeted and untargeted lipid profiling revealed that ATGListatin reduced LPS-induced generation of pro-inflammatory prostanoids and modulated ceramide species in neonatal microglia. Finally, the role of microglial ATGL in neuroinflammation was assessed using a novel microglia-specific and inducible ATGL knockout mouse model. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and IL-1β and microglial density. LPS-induced sickness- and anxiety-like behaviours were also reduced in male mice with loss of ATGL in microglia. Together, our results demonstrate potent anti-inflammatory effects produced by pharmacological or genetic inhibition of ATGL-mediated triglyceride lipolysis and thereby propose that supressing microglial LD lipolysis has beneficial actions in acute neuroinflammatory conditions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326487","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}
引用次数: 0
Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia 雷米芬太尼诱导的小胶质细胞炎症:PAK4 介导的 NF-κB/NLRP3 通路的激活与痛觉减退的发生
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-24 DOI: 10.1016/j.bbi.2024.09.018

Background

The perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches.

Method

We established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1β and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes.

Results

Proteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1β and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3.

Conclusion

Remifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.
背景围手术期使用瑞芬太尼会导致术后痛感亢进,从而影响术后恢复并延长住院时间。最近的研究发现,小胶质细胞介导的 NLRP3 炎性体的激活在阿片类药物诱导的痛觉减退中起着关键作用,NF-κB 是 NLRP3 的关键激活点。尽管有这些发现,但瑞芬太尼诱导术后痛觉减退的具体分子机制仍不清楚。本研究旨在建立瑞芬太尼诱导的痛觉减退模型,并采用体外和体内方法研究其分子机制,重点关注 NF-κB/NLRP3 通路。在体内经皮下注射 NLRP3 或 PAK4 拮抗剂,并使用 Von Frey 试验测量大鼠后爪的机械痛阈值。在体外,我们应用 NLRP3 或 PAK4 抑制剂或使用慢病毒感染来沉默 PAK4、NF-κB 和 NLRP3 基因。蛋白质表达通过免疫组化、免疫荧光和 Western 印迹进行评估。结果蛋白质组学分析表明,手术两小时后,瑞芬太尼可上调脊髓组织中的 PAK4 蛋白。此外,瑞芬太尼诱导脊髓背角发生形态学变化,其特征是 PAK4、p-p65、NLRP3 和 Iba-1 蛋白表达增加,进而导致 IL-1β 和 IL-18 水平升高和炎症反应。鞘内注射 NLRP3 或 PAK4 抑制剂可减轻瑞芬太尼引起的痛觉减退及相关变化。在体外,下调 PAK4 可抑制 LPS 诱导的 PAK4、p-p65、NLRP3 和 Caspase-1 的增加。结论瑞芬太尼可通过激活 NF-κB/NLRP3 通路和介导微神经胶质细胞活化,增加脊髓背角细胞中 PAK4 的表达,从而导致术后痛觉减退。
{"title":"Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia","authors":"","doi":"10.1016/j.bbi.2024.09.018","DOIUrl":"10.1016/j.bbi.2024.09.018","url":null,"abstract":"<div><h3>Background</h3><div>The perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches.</div></div><div><h3>Method</h3><div>We established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1β and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes.</div></div><div><h3>Results</h3><div>Proteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1β and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3.</div></div><div><h3>Conclusion</h3><div>Remifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326488","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}
引用次数: 0
Neonatal inflammation impairs developmentally-associated microglia and promotes a highly reactive microglial subset 新生儿炎症损害了与发育相关的小胶质细胞,并促进了高反应性小胶质细胞亚群的形成。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-23 DOI: 10.1016/j.bbi.2024.09.019
Microglia and border-associated macrophages play critical roles in both immunity and neurodevelopment. The disruption of microglial development trajectories by neonatal inflammation is an important issue in research on neurodevelopmental disorders (NDDs), as models have suggested a strong association between inflammation and cognitive deficits. Here, we explored by single-cell RNA sequencing and flow cytometry the impact of neonatal inflammation in a mouse NDD model on brain myeloid cell subsets. A specific subset of microglia expressing the complement receptor C5ar1 has been identified, in which inflammatory pathways are most strongly activated. Based on transcriptional similarity, this subset appears to originate from the most mature and “homeostatic“ microglia at this stage of development and demonstrated hypersensitivity to inflammation. Besides that, Spp1-microglia supporting oligodendrocyte differentiation, primitive and proliferative microglia were reduced by inflammation. These findings suggest major changes in microglial subsets developmental trajectories and reactivity contributing to NDDs induced by neonatal inflammation.
小胶质细胞和边界相关巨噬细胞在免疫和神经发育中发挥着关键作用。新生儿炎症对小胶质细胞发育轨迹的破坏是神经发育障碍(NDDs)研究中的一个重要问题,因为模型表明炎症与认知障碍之间存在密切联系。在这里,我们通过单细胞 RNA 测序和流式细胞术探讨了小鼠 NDD 模型中新生儿炎症对大脑髓系细胞亚群的影响。我们发现了表达补体受体 C5ar1 的特定小胶质细胞亚群,在这些亚群中,炎症通路被最强烈地激活。根据转录的相似性,该亚群似乎源自发育阶段最成熟、最 "稳态 "的小胶质细胞,并表现出对炎症的超敏性。此外,支持少突胶质细胞分化的 Spp1-小胶质细胞、原始和增殖性小胶质细胞也因炎症而减少。这些发现表明,小胶质细胞亚群的发育轨迹和反应性发生了重大变化,导致新生儿炎症诱发 NDDs。
{"title":"Neonatal inflammation impairs developmentally-associated microglia and promotes a highly reactive microglial subset","authors":"","doi":"10.1016/j.bbi.2024.09.019","DOIUrl":"10.1016/j.bbi.2024.09.019","url":null,"abstract":"<div><div>Microglia and border-associated macrophages play critical roles in both immunity and neurodevelopment. The disruption of microglial development trajectories by neonatal inflammation is an important issue in research on neurodevelopmental disorders (NDDs), as models have suggested a strong association between inflammation and cognitive deficits. Here, we explored by single-cell RNA sequencing and flow cytometry the impact of neonatal inflammation in a mouse NDD model on brain myeloid cell subsets. A specific subset of microglia expressing the complement receptor C5ar1 has been identified, in which inflammatory pathways are most strongly activated. Based on transcriptional similarity, this subset appears to originate from the most mature and “homeostatic“ microglia at this stage of development and demonstrated hypersensitivity to inflammation. Besides that, Spp1-microglia supporting oligodendrocyte differentiation, primitive and proliferative microglia were reduced by inflammation. These findings suggest major changes in microglial subsets developmental trajectories and reactivity contributing to NDDs induced by neonatal inflammation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341885","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}
引用次数: 0
The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide Kupffer细胞在微生物群-大脑交流中的作用:睡眠和发热信号对脂多糖的反应
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-23 DOI: 10.1016/j.bbi.2024.09.028
Microbial molecules translocated from the intestinal lumen into the host’s internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain.
从肠腔转运到宿主体内环境的微生物分子在各种生理功能中发挥作用。此前,我们发现肠道细菌产生的一种短链脂肪酸丁酸盐、革兰氏阳性细菌细胞壁的一种成分硫代胆酸和革兰氏阴性细菌细胞壁的一种成分脂多糖(LPS),在模仿它们自然发生的转运并直接输送到门静脉时,会诱发睡眠。我们的研究结果表明,这些微生物分子在肝门静脉区域内发挥了促进睡眠的作用。在本实验中,我们检验了这样一个假设,即肝脏的常驻巨噬细胞(即 Kupffer 细胞)在肝门静脉区域内的 LPS 反应性睡眠促进机制中起着至关重要的作用。肝门静脉内注射 LPS 可诱导对照组大鼠增加睡眠和发热。值得注意的是,在去除了 Kupffer 细胞的动物中,这两种反应都被显著抑制。这些发现凸显了 Kupffer 细胞在介导从肠道微生物群转移到门静脉循环的 LPS 的非快速眼动睡眠促进和发热效应中的潜在作用。Kupffer 细胞在肝门区域内的战略位置,加上其快速吸收 LPS 和其他微生物分子的能力,以及其多种信号分子的高分泌活性,是它们在肠道微生物群与大脑之间的沟通中发挥关键作用的基础。
{"title":"The role of Kupffer cells in microbiota-brain communication: Sleep and fever signaling in response to lipopolysaccharide","authors":"","doi":"10.1016/j.bbi.2024.09.028","DOIUrl":"10.1016/j.bbi.2024.09.028","url":null,"abstract":"<div><div>Microbial molecules translocated from the intestinal lumen into the host’s internal environment play a role in various physiological functions. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, lipoteichoic acid, a cell wall component of gram-positive bacteria, and lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Our findings suggested that these microbial molecules exert their sleep-promoting effects within the hepatoportal region. In the present experiments, we tested the hypothesis that resident liver macrophages, known as Kupffer cells, play a crucial role in the LPS-responsive, sleep-promoting mechanisms within the hepatoportal region. Intraportal administration of LPS induced increased sleep and fever in control rats. Remarkably, in Kupffer cell-depleted animals, both of these responses were significantly suppressed. These findings highlight the potential role of Kupffer cells in mediating the non-rapid-eye movement sleep-promoting and febrile effects of LPS translocated from the intestinal microbiota into the portal circulation. The strategic location of Kupffer cells within the hepatoportal region, coupled with their ability to rapidly take up LPS and other microbial molecules, together with their high secretory activity of multiple signaling molecules, underlie their key role in the communication between the intestinal microbiota and the brain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322977","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}
引用次数: 0
Dietary EPA and DHA enrichment of a high fat diet during doxorubicin-based chemotherapy attenuated neuroinflammatory gene expression in the brain of C57bl/6 ovariectomized mice 多柔比星化疗期间,高脂肪饮食中富含的 EPA 和 DHA 可减轻 C57bl/6 卵巢切除小鼠脑部神经炎症基因的表达。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-21 DOI: 10.1016/j.bbi.2024.09.021
Chemotherapy agents in breast cancer are associated with chemotherapy-related cognitive impairments (CRCI). Mechanisms are not fully clear, but alterations of glucose and lipid metabolism, neuroinflammation and neurodegeneration may contribute to CRCI. The aim of this study was to investigate the combined effects of a high fat (HF) diet combined with doxorubicin-based chemotherapy on glucose and lipid metabolism, neuroinflammation, and neurodegeneration in mice. Additionally, we examined the therapeutic potential of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to attenuate these effects. Female C57Bl/6 mice (n = 42) were fed HF, HFn-3 (2 % kcals as EPA + DHA) or Low Fat (LF) diets for seven weeks, with and without chemotherapy. In this study, two chemotherapy injections led to weight and body fat loss associated with a decrease in insulin resistance measured by HOMA-IR. HOMA-IR was significantly greater in HF versus LF groups; but HOMA-IR in HFn-3 group did not significantly differ from either HF or LF groups. Chemotherapy resulted in higher brain concentrations of the inflammatory chemokine KC/GRO. Compared to LF diet plus chemotherapy, HF diet plus chemotherapy upregulated multiple genes involved in neuroinflammation and neurodegeneration pathways. HFn-3 diet plus chemotherapy attenuated gene expression by downregulating multiple genes involved in neuroinflammation and blood brain barrier regulation, including Mapkapk2, Aqp4, and s100b, and upregulating Kcnb1 and Atxn3, genes involved in reduction of oxidative stress and anxiety, respectively. Overall, a HF diet combined with chemotherapy is associated with neuroinflammatory and neurodegenerative gene expression changes in this mouse model; dietary enrichment of EPA and DHA attenuated these effects. Further studies are needed to understand how diet impacts behavioral outcomes of CRCI.
乳腺癌化疗药物与化疗相关认知障碍(CRCI)有关。其机制尚不完全清楚,但葡萄糖和脂质代谢的改变、神经炎症和神经变性可能是导致 CRCI 的原因。本研究旨在探讨高脂饮食与多柔比星化疗对小鼠糖脂代谢、神经炎症和神经变性的综合影响。此外,我们还研究了饮食中的二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)对减轻这些影响的治疗潜力。雌性 C57Bl/6 小鼠(n = 42)在接受或不接受化疗的情况下,连续七周喂食高脂肪、HFn-3(2 % 千卡热量,即 EPA + DHA)或低脂肪(LF)饮食。在这项研究中,注射两次化疗会导致体重和体脂下降,与此同时,用 HOMA-IR 测量的胰岛素抵抗也会下降。HF组的HOMA-IR明显高于LF组;但HFn-3组的HOMA-IR与HF组或LF组无明显差异。化疗导致脑内炎症趋化因子KC/GRO浓度升高。与低密度脂蛋白饮食加化疗相比,高密度脂蛋白饮食加化疗上调了多个涉及神经炎症和神经退行性病变通路的基因。HFn-3饮食加化疗通过下调多个参与神经炎症和血脑屏障调节的基因(包括Mapkapk2、Aqp4和s100b),上调分别参与减少氧化应激和焦虑的基因Kcnb1和Atxn3,从而减轻基因表达。总之,在该小鼠模型中,高密度脂蛋白饮食结合化疗与神经炎症和神经退行性基因表达变化有关;饮食中富含的 EPA 和 DHA 可减轻这些影响。要了解饮食如何影响 CRCI 的行为结果,还需要进一步的研究。
{"title":"Dietary EPA and DHA enrichment of a high fat diet during doxorubicin-based chemotherapy attenuated neuroinflammatory gene expression in the brain of C57bl/6 ovariectomized mice","authors":"","doi":"10.1016/j.bbi.2024.09.021","DOIUrl":"10.1016/j.bbi.2024.09.021","url":null,"abstract":"<div><div>Chemotherapy agents in breast cancer are associated with chemotherapy-related cognitive impairments (CRCI). Mechanisms are not fully clear, but alterations of glucose and lipid metabolism, neuroinflammation and neurodegeneration may contribute to CRCI. The aim of this study was to investigate the combined effects of a high fat (HF) diet combined with doxorubicin-based chemotherapy on glucose and lipid metabolism, neuroinflammation, and neurodegeneration in mice. Additionally, we examined the therapeutic potential of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to attenuate these effects. Female C57Bl/6 mice (n = 42) were fed HF, HFn-3 (2 % kcals as EPA + DHA) or Low Fat (LF) diets for seven weeks, with and without chemotherapy. In this study, two chemotherapy injections led to weight and body fat loss associated with a decrease in insulin resistance measured by HOMA-IR. HOMA-IR was significantly greater in HF versus LF groups; but HOMA-IR in HFn-3 group did not significantly differ from either HF or LF groups. Chemotherapy resulted in higher brain concentrations of the inflammatory chemokine KC/GRO. Compared to LF diet plus chemotherapy, HF diet plus chemotherapy upregulated multiple genes involved in neuroinflammation and neurodegeneration pathways. HFn-3 diet plus chemotherapy attenuated gene expression by downregulating multiple genes involved in neuroinflammation and blood brain barrier regulation, including <em>Mapkapk2</em>, <em>Aqp4,</em> and <em>s100b</em>, and upregulating <em>Kcnb1</em> and <em>Atxn3</em>, genes involved in reduction of oxidative stress and anxiety, respectively. Overall, a HF diet combined with chemotherapy is associated with neuroinflammatory and neurodegenerative gene expression changes in this mouse model; dietary enrichment of EPA and DHA attenuated these effects. Further studies are needed to understand how diet impacts behavioral outcomes of CRCI.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307052","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}
引用次数: 0
Response Letter to “Cumulative infection burden, cognitive impairment and dementia” 对 "累积感染负担、认知障碍和痴呆症 "的回信。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.bbi.2024.09.024
{"title":"Response Letter to “Cumulative infection burden, cognitive impairment and dementia”","authors":"","doi":"10.1016/j.bbi.2024.09.024","DOIUrl":"10.1016/j.bbi.2024.09.024","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280418","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}
引用次数: 0
Cumulative infection burden, cognitive impairment and dementia 累积感染负担、认知障碍和痴呆症。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.bbi.2024.09.025
{"title":"Cumulative infection burden, cognitive impairment and dementia","authors":"","doi":"10.1016/j.bbi.2024.09.025","DOIUrl":"10.1016/j.bbi.2024.09.025","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280407","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}
引用次数: 0
Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation 剖析抑郁症状:多组学聚类发现免疫相关亚群和细胞类型特异性失调
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-18 DOI: 10.1016/j.bbi.2024.09.013
In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.
在抑郁症等精神障碍患者中,可以观察到低度炎症和免疫标记物浓度的改变。然而,这些免疫改变往往只能通过一种数据类型和小标记物面板来评估。在这里,我们采用了一种跨诊断方法,并结合了两个队列的数据,通过对 237 人进行大规模多组学聚类分析,定义了诊断范围内的抑郁症状亚组。该方法结合了年龄、体重指数(BMI)、43 种血浆免疫标记物和外周单核血细胞(PBMCs)的 RNA-seq 数据。我们的初步聚类发现了四个聚类,包括两个与免疫相关的抑郁症状聚类,其特点是体重指数升高、抑郁症严重程度较高以及白细胞介素-1受体拮抗剂(IL-1RA)、C反应蛋白(CRP)和C-C motif趋化因子2(CCL2或MCP-1)等免疫标记物水平升高。相比之下,RNA-seq 数据主要区分出一个抑郁严重程度较低的群组,该群组富含与大脑相关的基因组。心电图数据也能区分出这个群组,而结构成像数据则显示了各群组心室容积的差异。将预测的细胞类型比例纳入聚类后,产生了三个聚类,其中一个显示出免疫标记物浓度升高。细胞类型比例和与细胞类型相关的基因在抑郁症状中间集群中最为明显,这表明 RNA-seq 和免疫标记物测量的是免疫失调的不同方面。最后,通过整合免疫标记物和 RNA-seq 数据,我们发现了树突状细胞特有的 SERPINF1/VEGF-A 通路失调。这显示了结合不同数据模式的优势,并突出了进一步对抑郁症状进行分层研究的可能标志物。
{"title":"Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation","authors":"","doi":"10.1016/j.bbi.2024.09.013","DOIUrl":"10.1016/j.bbi.2024.09.013","url":null,"abstract":"<div><div>In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the <em>SERPINF1</em>/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280416","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}
引用次数: 0
Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice 二甲双胍通过肠道微生物衍生的胆汁酸代谢物重编程色氨酸代谢,从而改善小鼠的抑郁样行为。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-18 DOI: 10.1016/j.bbi.2024.09.014
As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.
作为一种辅助疗法,二甲双胍可增强传统抗抑郁药物的疗效。然而,二甲双胍的作用模式仍不清楚。在这里,研究人员发现二甲双胍能通过使菌群失调的肠道微生物组正常化来改善长期暴露于束缚应激(CRS)的小鼠的抑郁样行为。二甲双胍处理过的小鼠的粪便移植可以改善应激小鼠的抑郁行为。微生物组图谱分析表明,二甲双胍能显著增加肠道中的Akkermansia muciniphila(A. muciniphila),而且仅口服该物种就足以逆转CRS诱导的抑郁行为,并使应激诱导的大脑和肠道中异常的5-羟色胺(5-HT)代谢正常化。非靶向代谢组学分析进一步确定了胆汁酸代谢物牛磺胆硷酸和脱氧胆硷酸是直接从粘蛋白蛛衍生的分子,它们足以单独挽救 CRS 诱导的 5-HT 代谢受损和抑郁样行为。因此,我们报告了二甲双胍通过微生物组与大脑的相互作用重编程 5-HT 代谢,从而缓解抑郁综合征,为肠道微生物组衍生的胆汁酸作为抑郁情绪障碍的潜在候选疗法提供了从实验到临床的新见解。
{"title":"Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice","authors":"","doi":"10.1016/j.bbi.2024.09.014","DOIUrl":"10.1016/j.bbi.2024.09.014","url":null,"abstract":"<div><div>As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed tha<em>t Akkermansia muciniphila (A. muciniphila</em>), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct <em>A. muciniphila</em>-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280417","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}
引用次数: 0
Maternal immune activation alters temporal precision of spike generation of CA1 pyramidal neurons by unbalancing GABAergic inhibition in the Offspring 母体免疫激活通过失衡子代的 GABA 能抑制作用,改变了 CA1 锥体神经元尖峰生成的时间精确性
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.bbi.2024.09.012

Infection during pregnancy represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that maternal inflammation induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced maternal immune activation (MIA) model. Our data indicate that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition predominantly mediated by cholecystokinin-expressing Interneurons but not parvalbumin-expressing interneurons impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. These findings collectively contribute to understanding the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.

孕期感染是导致与神经发育改变相关的神经精神疾病的一个危险因素。越来越多来自啮齿类动物和非人灵长类动物的证据表明,病毒或细菌感染诱发的母体炎症会导致后代出现多种神经生物学改变。这些改变可能在精神分裂症和自闭症谱系障碍等精神疾病的病理生理学中发挥重要作用,这些疾病的临床特征包括认知处理和社交表现的障碍。这种改变与母体对感染的炎症反应而非感染本身有因果关系。此前,我们曾报道,暴露于 MIA 的小鼠 CA1 锥体神经元表现出兴奋性增加,同时树突复杂性降低。然而,塑造后代神经元计算特性的细胞和突触规则的潜在改变仍有待确定。在这项研究中,我们以小鼠为研究对象,确定了在脂多糖诱导的母体免疫激活(MIA)模型中,海马背侧CA1锥体神经元所承受的一系列细胞和突触变化。我们的数据表明,母体免疫激活通过降低主要由表达胆囊收缩素的中间神经元介导的GABA能抑制,而不是表达副缬氨酸的中间神经元介导的对CA1锥体神经元的冲击,重塑了兴奋-抑制平衡。这些改变导致时间和空间突触整合的放大失调。此外,暴露于 MIA 的后代表现出社交和焦虑样异常。这些发现共同有助于理解与MIA相关的神经发育障碍中出现的行为症状背后的细胞和突触改变。
{"title":"Maternal immune activation alters temporal precision of spike generation of CA1 pyramidal neurons by unbalancing GABAergic inhibition in the Offspring","authors":"","doi":"10.1016/j.bbi.2024.09.012","DOIUrl":"10.1016/j.bbi.2024.09.012","url":null,"abstract":"<div><p>Infection during pregnancy represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that maternal inflammation induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced maternal immune activation (MIA) model. Our data indicate that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition predominantly mediated by cholecystokinin-expressing Interneurons but not parvalbumin-expressing interneurons impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. These findings collectively contribute to understanding the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.</p></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0889159124006160/pdfft?md5=476831e42ccdb4ee53e7fb836a2472b5&pid=1-s2.0-S0889159124006160-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271482","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}
引用次数: 0
期刊
Brain, Behavior, and Immunity
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1