Brain Research Bulletin最新文献_第5页

Peroxiredoxin-5 alleviates early brain injury after subarachnoid hemorrhage by reducing oxidative stress 过氧化还原酶-5能通过减少氧化应激减轻蛛网膜下腔出血后的早期脑损伤。

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-24 DOI: 10.1016/j.brainresbull.2024.111087

Jinshuo Yang, Qiaowei Wu, Shuai Lan, Kaikun Yuan, Bowen Sun, Yuxiao Meng, Shancai Xu, Huaizhang Shi

Background and purpose

Following subarachnoid hemorrhage (SAH), excessive activation of oxidative stress and cell apoptosis plays a critical role in early brain injury (EBI). Peroxiredoxin-5 (Prdx5), predominantly expressed in neuronal mitochondria, acts as an antioxidant. However, the role of Prdx5 in EBI after SAH remains unclear. This study aims to elucidate the antioxidative stress and anti-apoptotic effects of Prdx5 in rats following SAH.

Methods

In this study, an SAH model was established in Sprague-Dawley rats using endovascular perforation. Recombinant Prdx5 (rPrdx5) was administered intranasally to upregulate Prdx5 expression after SAH in rats. Prdx5 small interfering RNA (Prdx5 siRNA) was administered prior to SAH modelling. The neuroprotective effects of Prdx5 were validated through SAH grading, brain water content, blood-brain barrier permeability, neurobehavioral tests, immunofluorescence, TUNEL staining, and Western blotting.

Results

The expression levels of endogenous Prdx5 significantly decreased after SAH. Treatment with rPrdx5 improved both short-term and long-term behaviour in rats, reduced brain water content and blood-brain barrier permeability, and exhibited anti-oxidative stress and anti-apoptotic effects. Measurements of oxidative stress-related indicators, including MDA, SOD, GSH-Px and GSH/GSSG, confirmed that Prdx5 can alleviate oxidative stress in rats after SAH. Western blot analysis showed that rPrdx5 significantly increased the expression of Bcl-XL and Bcl-2 and reduced the expression of Bax and Cleaved Caspase-3, thereby exerting anti-apoptotic effects. Additionally, Prdx5 siRNA reversed the neuroprotective effects of rPrdx5, exacerbated neuronal damage and blood-brain barrier permeability, and increased levels of oxidative stress and apoptosis.

Conclusion

In conclusion, our study demonstrated that specifically upregulating the expression of Prdx5 can reduce oxidative stress and apoptosis in rats after SAH, while also improving both short-term and long-term neurological impairments. Prdx5 is primarily expressed in the mitochondria of neuronal cells and is a crucial target for reducing ROS after SAH. rPrdx5 treatment may offer a promising therapeutic approach for clinical SAH patients.

背景和目的：蛛网膜下腔出血（SAH）后，氧化应激的过度激活和细胞凋亡在早期脑损伤（EBI）中起着至关重要的作用。过氧化物歧化酶-5（Prdx5）主要在神经元线粒体中表达，是一种抗氧化剂。然而，Prdx5 在 SAH 后 EBI 中的作用仍不清楚。本研究旨在阐明 Prdx5 在 SAH 后大鼠体内的抗氧化应激和抗凋亡作用：方法：本研究采用血管内穿孔法在 Sprague-Dawley 大鼠中建立 SAH 模型。腹腔注射重组 Prdx5（rPrdx5）以上调 SAH 后大鼠的 Prdx5 表达。在 SAH 建模前给大鼠注射 Prdx5 小干扰 RNA（Prdx5 siRNA）。通过SAH分级、脑含水量、血脑屏障通透性、神经行为测试、免疫荧光、TUNEL染色和Western印迹等方法验证了Prdx5的神经保护作用：结果：SAH后内源性Prdx5的表达水平明显下降。用rPrdx5治疗可改善大鼠的短期和长期行为，降低脑水含量和血脑屏障通透性，并具有抗氧化应激和抗细胞凋亡作用。对氧化应激相关指标（包括MDA、GSH-Px、SOD和GSH/GSSG）的测定证实，Prdx5能缓解SAH后大鼠的氧化应激。Western印迹分析表明，rPrdx5能显著增加Bcl-XL和Bcl-2的表达，降低Bax和Caspase-3的表达，从而发挥抗凋亡作用。此外，Prdx5 siRNA逆转了rPrdx5的神经保护作用，加剧了神经元损伤和血脑屏障通透性，增加了氧化应激和细胞凋亡水平：总之，我们的研究表明，特异性上调Prdx5的表达可减少SAH后大鼠的氧化应激和细胞凋亡，同时还能改善短期和长期的神经功能损伤。Prdx5 主要在神经细胞的线粒体中表达，是减少 SAH 后 ROS 的关键靶点。

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引用次数: 0

Remimazolam ameliorates postoperative cognitive dysfunction after deep hypothermic circulatory arrest through HMGB1-TLR4-NF-κB pathway 雷马唑仑通过 HMGB1-TLR4-NF-κB 通路改善深度低体温循环停止后的术后认知功能障碍

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-23 DOI: 10.1016/j.brainresbull.2024.111086

Qi Mao , Beiwei Liang , Zhiwei Leng , Wenjun Ma , Yanhua Chen , Yubo Xie

Background

Postoperative cognitive dysfunction (POCD) is a complication of deep hypothermic circulatory arrest (DHCA). Various amounts of neurologic dysfunctions have been shown after DHCA, which has often been attributed to systemic inflammatory response syndrome and cerebral ischemia/reperfusion injury. Remimazolam is one of the commonly used anesthetic drugs with protective actions against inflammatory diseases, such as sepsis and cerebral ischemia/reperfusion injury. Here, we determined the protective effect and potential mechanism of action of remimazolam against neuronal damage after DHCA.

Methods

A rat model of DHCA was established, and a gradient dosage of remimazolam was administered during cardiopulmonary bypass (CPB). The cognitive function of rats was evaluated by Morris water maze. Hematoxylin and eosin and TUNEL staining were performed to assess hippocampus tissue injury and neuronal apoptosis. Inflammatory cytokines concentration were analyzed by enzyme-linked immunosorbent assay. The protein expression was analyzed using automated electrophoresis western analysis and immunohistochemical analysis.

Results

The appropriate dosage of remimazolam reduced histologic injury, neuronal apoptosis, microglia activation, and secondary inflammatory cascades, as well as the downregulation of the expression of the HMGB1-TLR4-NF-κB pathway after DHCA, improved the memory and learning abilities in DHCA rats. Further, administration of a TLR4 antagonist TAK-242 had a similar effect to remimazolam, while the TLR4 agonist LPS attenuated the effect of remimazolam.

Conclusions

Remimazolam could ameliorate POCD after DHCA through the HMGB1-TLR4-NF-κB signaling pathway.

背景术后认知功能障碍（POCD）是深低温循环骤停（DHCA）的并发症之一。深低温循环骤停（DHCA）术后出现的各种神经功能障碍通常归因于全身炎症反应综合征和脑缺血/再灌注损伤。雷马唑仑是常用的麻醉药物之一，对败血症和脑缺血再灌注损伤等炎症性疾病具有保护作用。方法建立 DHCA 大鼠模型，在心肺旁路（CPB）期间给予梯度剂量的雷马唑仑。大鼠的认知功能通过莫里斯水迷宫进行评估。采用苏木精和TUNEL染色评估海马组织损伤和神经元凋亡。用酶联免疫吸附试验分析炎性细胞因子的浓度。结果适当剂量的雷马唑仑可减少 DHCA 后的组织学损伤、神经元凋亡、小胶质细胞活化和继发性炎症级联，并下调 HMGB1-TLR4-NF-κB 通路的表达，改善 DHCA 大鼠的记忆和学习能力。结论瑞马唑仑可通过 HMGB1-TLR4-NF-κB 信号通路改善 DHCA 后的 POCD。

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引用次数: 0

Receivers’ responses are integrated into costly third-party punishment in a way that interacts with the unfairness of allocations 接收者的反应被纳入代价高昂的第三方惩罚中，这种方式与分配的不公正性相互作用。

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-20 DOI: 10.1016/j.brainresbull.2024.111082

Li Zheng , Yujian Zhou , Hui Ouyang , Jiajia Xie , Yang Lu , Xiuyan Guo

Costly third-party punishment (TPP) is an effective way to enforce fairness norms and promote cooperation. Recent studies have shown that the third party considers not only the proposer’s suggested allocation but also the receiver’s response to the allocation, which was typically ignored in traditional TPP studies when making punishment decisions. However, it remains unclear whether and how the varying unfair allocations and receivers’ responses are integrated into third-party punishment. The current study addressed these issues at behavioral and electrophysiological levels by employing a modified third-party punishment task involving proposers’ highly or moderately unfair allocations and the receivers’ acceptance or rejection responses. At the behavioral level, participants punished proposers more often when receivers rejected relative to accepted unfair allocations. This effect was further modulated by the unfairness degree of allocations, indicated by a more pronounced rejection-sensitive effect when participants observed the moderately unfair offers. Electrophysiologically, when the receiver rejected the moderately unfair allocations, a stronger late-stage component P300/LPP, which was considered to be involved in allocations of attention resources, was found. Meanwhile, separated from the P300/LPP, the P200 associated with early attention capture demonstrated a rejection-sensitive effect. Together, in the costly TPP studies, the receiver is typically designated as passive and silent, and her/his responses to unfairness are conventionally ignored. However, our results indicate that except for the proposer’s distribution behavior, the receiver’s response does have an impact on third-party punishment in a way that interacts with the unfairness of allocations.

代价高昂的第三方惩罚（TPP）是执行公平准则和促进合作的有效方法。最近的研究表明，第三方在做出惩罚决定时，不仅会考虑提议者建议的分配，还会考虑接受者对分配的反应，而传统的第三方惩罚研究通常会忽略这一点。然而，不同的不公平分配和接收者的反应是否以及如何被纳入第三方惩罚中，目前仍不清楚。本研究通过采用一种改进的第三方惩罚任务，涉及提议者的高度或中度不公平分配以及接受者的接受或拒绝反应，在行为和电生理层面解决了这些问题。在行为层面，相对于接受不公平的分配，当接受者拒绝时，参与者会更频繁地惩罚提议者。这种效应还受到分配不公平程度的影响，当参与者观察到中度不公平的提议时，对拒绝更为敏感。在电生理学上，当接收者拒绝中度不公平的分配时，会发现一个更强的后期成分 P300/LPP，它被认为参与了注意力资源的分配。同时，与P300/LPP分离，与早期注意捕获相关的P200表现出了与分配的不公平程度无关的拒绝敏感效应。总之，在成本高昂的 TPP 研究中，接收者通常被指定为被动和沉默者，他们对不公平的反应通常会被忽略。然而，我们的研究结果表明，除了提议者的分配行为外，接受者的反应确实会对第三方惩罚产生影响，这种影响与分配的不公平程度相互影响。

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引用次数: 0

Investigating the mechanisms of inflammation and immune alterations in Parkinson's disease using spatial transcriptomics techniques 利用空间转录组学技术研究帕金森病的炎症和免疫改变机制。

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-19 DOI: 10.1016/j.brainresbull.2024.111076

Sen Zhang , Yifan Geng , Xing Jiang , Zhiyuan Sun , Min Yan , Jun Bi , Xuewen Tian , Qinglu Wang

In recent years, overwhelming evidence has emphasized the crucial role of inflammation in the pathogenesis of PD. However, the exact mechanisms by which inflammation damages dopaminergic neurons in PD are still unclear. Therefore, we generated a MPTP-induced PD mouse model and performed spatial transcriptomic sequencing to provide more insight into the process of PD development at specific brain regions. Our results indicate that the pathological changes of PD are mainly manifested in the midbrain, especially in the substantia nigra region, with significant reductions in oligodendrocytes and Agt-labeled astrocytes and an increase in Gfap-labeled astrocytes. Macrophages displayed an increasing trend in the PD environment, indicating a pattern of immune modulation induced by PD. Moreover, pathway analysis revealed significant impairments in ion migration ability, abnormal Ca²⁺ channels, cAMP signaling, and synaptic damage in PD. Significant downregulation of Mt1 and Mt2 and upregulation of Atp1b2, Gpi1, and Cox6a1 in PD further underscored the occurrence of intense inflammation and immune alterations. On the basis of these findings, we have validated the significant accumulation of Ca²⁺ in the midbrain tissue in the PD environment by measuring its content. Additionally, we have demonstrated a close association between the reduction of dopaminergic neurons, represented by the midbrain region, and ferroptosis by evaluating the iron content, malondialdehyde (MDA) levels, and the protein expression of GPX4 and TH in the tissue. We propose the hypothesis that PD-related inflammation and immune changes can induce neuronal and oligodendrocyte damage through the induction of ferroptosis, thereby further accelerating the progression of PD.

近年来，大量证据强调了炎症在帕金森病发病机制中的关键作用。然而，炎症损伤多巴胺能神经元的确切机制仍不清楚。因此，我们建立了MPTP诱导的帕金森病小鼠模型，并进行了空间转录组测序，以深入了解帕金森病在特定脑区的发病过程。我们的结果表明，帕金森病的病理变化主要表现在中脑，尤其是黑质区域，少突胶质细胞和Agt标记的星形胶质细胞显著减少，而Gfap标记的星形胶质细胞增加。巨噬细胞在脊髓灰质炎环境中呈上升趋势，表明脊髓灰质炎诱发了一种免疫调节模式。此外，通路分析表明，在帕金森病中，离子迁移能力、异常 Ca2+ 通道、cAMP 信号转导和突触损伤都受到了显著影响。在帕金森病中，Mt1和Mt2显著下调，Atp1b2、Gpi1和Cox6a1上调，这进一步强调了强烈炎症和免疫改变的发生。在这些发现的基础上，我们通过测量中脑组织中 Ca2+ 的含量，验证了在帕金森病环境中 Ca2+ 的显著积累。此外，我们还通过评估组织中的铁含量、丙二醛（MDA）水平以及 GPX4 和 TH 的蛋白表达，证明了以中脑区域为代表的多巴胺能神经元减少与铁变态反应之间的密切联系。我们提出的假说是，与帕金森病相关的炎症和免疫变化可通过诱导铁蜕变诱发神经元和少突胶质细胞损伤，从而进一步加速帕金森病的进展。

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引用次数: 0

Chronic stress induces insulin resistance and enhances cognitive impairment in AD 慢性压力会诱发胰岛素抵抗，并加重注意力缺失症的认知障碍。

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-18 DOI: 10.1016/j.brainresbull.2024.111083

Jiaying Rong , Yanyong Wang , Na Liu , Li Shen , Qinying Ma , Mingwei Wang , Bing Han

Background

Chronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology.

Methods

Male 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT).

Results

Four weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aβ42 and Aβ40 in wild-type mice.

Conclusions

Chronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

背景：慢性压力可诱发认知障碍，甚至促进阿尔茨海默病（AD）的发生和发展。有证据表明，慢性应激会影响糖代谢，而这两者都与阿尔茨海默病有关。在此，我们重点研究了胰岛素抵抗对糖代谢的影响，并进一步评估了其在认知和病理方面的变化：雄性9月龄野生型小鼠和APP/PS1小鼠随机分为4组。方法：将9个月大的雄性野生型和APP/PS1小鼠随机分为4组，慢性不可预测轻度应激（CUMS）组小鼠暴露4周。利用稳态模型评估（HOMA）评价胰岛素敏感性。共检测了 84 个与胰岛素信号通路相关的基因，以进行快速筛选。此外，还检测了海马中胰岛素受体（IR）、IR底物1（IRS1）、c-Jun N-末端激酶（JNK）和淀粉样蛋白的磷酸化蛋白表达。认知功能通过伦理学方法进行评估。认知功能通过莫里斯水迷宫（MWM）和被动回避测试（PAT）进行评估：结果：暴露于 CUMS 四周后，HOMA 值明显升高，表明胰岛素敏感性降低。Insr和Lipe的基因表达下调。此外，分析表明基因型（野生型与 APP/PS1）和 CUMS 处理对胰岛素受体底物 1（IRS1）磷酸化蛋白表达有明显的交互作用。具体来说，在野生型小鼠和APP/PS1小鼠的海马中，CUMS暴露增加了胰岛素受体后信号通路中的抑制性磷酸化位点（IRS1-pSer636），减少了兴奋性磷酸化位点（IRS1-pTyr465）。此外，通过莫里斯水迷宫（MWM）和被动回避测试（PAT）评估，CUMS暴露诱导并加剧了野生型和APP/PS1小鼠的认知障碍。然而，CUMS对野生型小鼠的老年斑沉积或Aβ42和Aβ40水平没有明显影响：结论：慢性应激会通过胰岛素抵抗严重影响海马认知功能，并加剧老年痴呆症的病理变化。这项研究揭示了慢性应激、胰岛素抵抗和AD之间的复杂关系，为开发针对慢性应激和胰岛素抵抗的干预措施提供了新的见解。

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引用次数: 0

Dl-3-n-Butylphthalide attenuates early brain injury and delayed neurological dysfunction by regulating NLRP3 inflammasome after subarachnoid hemorrhage Dl-3-正丁基苯酞通过调节蛛网膜下腔出血后的NLRP3炎性体，减轻早期脑损伤和迟发性神经功能障碍。

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-18 DOI: 10.1016/j.brainresbull.2024.111084

Fangfang Gao , Shujin Zeng , Dachong Chao , Liangmiao Wu

Subarachnoid hemorrhage (SAH) is a severe neurological event lacking of effective therapy. Early brain injury (EBI) and delayed neurological dysfunction are important cause in the poor prognosis of patients with SAH. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation has been implicated in many inflammatory lesion pathogeneses including SAH. Dl-3-n-butylphthalide (NBP) has been reported to possess substantial anti-inflammatory properties, which is beneficial for various neurodegenerative diseases. However, the effect and molecular mechanisms of NBP on SAH have not been clearly identified. We designed this study to investigate the effect of NBP against EBI and delayed neurological dysfunction after SAH and to reveal the possible underlying mechanism. The adult mice were subjected to endovascular perforation SAH model or sham operation. Mice were randomized to sham group, SAH group, or SAH+NBP group. The EBI (short-term study) was studied at 48 h post-SAH and delayed neurological dysfunction (long-term study) at 21 days post-SAH. The results suggested that NBP evidently alleviated the EBI in mice at 48 h post-SAH, as shown by elevating neurological score, reducing brain edema, blood–brain barrier disruption, neuronal loss, and astrocyte aggregation, as well as ameliorating cerebral vasospasm. Moreover, NBP was able to improve long-term neurobehavioral functions and decrease neuronal apoptosis at 21 days after SAH. Significantly, NBP treatment also inhibited the expressions of NLRP3, ASC, caspase-1, cleaved-caspase-1, IL-1β, IL-18, GSDMD and GSDMD-N in both EBI and delayed neurological dysfunction induced by SAH. Our findings suggested that NBP treatment exerts a profound neuroprotective effect against early brain injury and delayed neurological dysfunction induced by SAH, at least partially through regulating NLRP3 inflammasome signaling pathway and its related inflammation and pyroptosis,

蛛网膜下腔出血（SAH）是一种严重的神经系统疾病，缺乏有效的治疗手段。早期脑损伤（EBI）和迟发性神经功能障碍是导致蛛网膜下腔出血患者预后不良的重要原因。核苷酸结合寡聚化结构域（NOD）样受体含吡啶结构域3（NLRP3）炎性体的激活与包括 SAH 在内的许多炎症病变病因有关。据报道，Dl-3-正丁基邻苯二甲酸盐（NBP）具有很强的抗炎特性，对多种神经退行性疾病有益。然而，NBP 对 SAH 的影响和分子机制尚未明确。本研究旨在探讨 NBP 对 EBI 和 SAH 后延迟性神经功能障碍的影响，并揭示其可能的内在机制。成年小鼠接受血管内穿孔 SAH 模型或假手术。小鼠随机分为假手术组、SAH 组和 SAH+NBP 组。SAH术后48小时进行EBI（短期研究），SAH术后21天进行迟发性神经功能障碍（长期研究）。结果表明，NBP 能明显减轻小鼠在脑梗死后 48 小时的 EBI，表现为神经系统评分升高、脑水肿减轻、血脑屏障破坏、神经元丢失和星形胶质细胞聚集减少，以及脑血管痉挛得到改善。此外，NBP 还能改善 SAH 后 21 天的长期神经行为功能，减少神经元凋亡。值得注意的是，NBP 还能抑制 EBI 和 SAH 引起的延迟性神经功能障碍中 NLRP3、ASC、caspase-1、cleaved-caspase-1、IL-1β、IL-18、GSDMD 和 GSDMD-N 的表达。我们的研究结果表明，NBP治疗对SAH诱导的早期脑损伤和延迟性神经功能障碍具有深远的神经保护作用，至少部分是通过调节NLRP3炎症小体信号通路及其相关的炎症和脓毒症。

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引用次数: 0

Changed resting-state connectivity of anterior insular cortex affects subjective pain reduction after knee arthroplasty: A longitudinal study 前岛叶皮层静息态连接的改变影响膝关节置换术后主观疼痛的减轻：一项纵向研究

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-14 DOI: 10.1016/j.brainresbull.2024.111073

Kai Ushio , Kazuyoshi Nakanishi , Atsuo Yoshino , Masahiro Takamura , Yuji Akiyama , Noboru Shimada , Kazuhiko Hirata , Masakazu Ishikawa , Atsuo Nakamae , Yukio Mikami , Yasumasa Okamoto , Nobuo Adachi

The mechanism of chronic knee osteoarthritis (OA) pain and postoperative pain due to knee arthroplasty has not been elucidated. This could be involved neuroplasticity in brain connectivity. To clarify the mechanism of chronic knee OA pain and postoperative pain, we examined the relationship between resting-state functional connectivity (rs-FC) and clinical measurements in knee OA before and after knee arthroplasty, focusing on rs-FCs with the anterior insular cortex (aIC) as the key region. Fifteen patients with knee OA underwent resting-state functional magnetic resonance imaging and clinical measurements shortly before and 6 months after knee arthroplasty, and 15 age- and sex-matched control patients underwent an identical protocol. Seed-to-voxel analysis was performed to compare the clinical measurements and changed rs-FCs, using the aIC as a seed region, between the preoperative and postoperative patients, as well as between the operative and control patients. In preoperative patients, rs-FCs of the aIC to the OFC, frontal pole, subcallosal area, and medial frontal cortex increased compared with those of the control patients. The strength of rs-FC between the left aIC and right OFC decreased before and after knee arthroplasty. The decrease in rs-FC between the left aIC and right OFC was associated with decreased subjective pain score. Our study showed a correlation between longitudinally changed rs-FC and clinical measurement before and after knee arthroplasty. Rs-FC between the aIC and OFC have the potential to elucidate the mechanisms of knee OA pain and postoperative pain due to knee arthroplasty.

慢性膝关节骨关节炎（OA）疼痛和膝关节置换术后疼痛的机制尚未阐明。这可能与大脑连接的神经可塑性有关。为了阐明慢性膝关节OA疼痛和术后疼痛的机制，我们研究了膝关节置换术前后膝关节OA静息态功能连接（rs-FC）与临床测量之间的关系，重点研究了以前部岛叶皮层（aIC）为关键区域的rs-FC。15名膝关节OA患者在膝关节置换术前不久和术后6个月接受了静息态功能磁共振成像和临床测量，15名年龄和性别匹配的对照组患者接受了相同的方案。以 aIC 为种子区域，对术前和术后患者以及手术患者和对照组患者的临床测量结果和 rs-FCs 变化进行了种子到象素分析比较。与对照组患者相比，术前患者的 aIC 至 OFC、额极、胼胝体下区和内侧额叶皮层的 rs-FCs 均有所增加。膝关节置换术前后，左侧 aIC 与右侧 OFC 之间的 rs-FC 强度下降。左侧aIC和右侧OFC之间rs-FC的降低与主观疼痛评分的降低有关。我们的研究表明，在膝关节置换术前后，rs-FC的纵向变化与临床测量之间存在相关性。aIC 和 OFC 之间的 rs-FC 有可能阐明膝关节 OA 疼痛和膝关节置换术后疼痛的机制。

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引用次数: 0

Bleomycin triggers chronic mechanical nociception by activating TRPV1 and glial reaction-mediated neuroinflammation via TSLP/TSLPR/pSTAT5 signals 博莱霉素通过 TSLP/TSLPR/pSTAT5 信号激活 TRPV1 和神经胶质反应介导的神经炎症，从而引发慢性机械痛觉

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-12 DOI: 10.1016/j.brainresbull.2024.111081

Ying-Yi Lu , Chia-Yang Lin , Chun-Ching Lu , Hung-Pei Tsai , Wei-Ting Wang , Zi-Hao Zhang , Chieh-Hsin Wu

Chronic pain is a universal public health problem with nearly one third of global human involved, which causes significant distressing personal burden. After painful stimulus, neurobiological changes occur not only in peripheral nervous system but also in central nervous system where somatosensory cortex is important for nociception. Being an ion channel, transient receptor potential vanilloid 1 (TRPV1) act as an inflammatory detector in the brain. Thymic stromal lymphopoietin (TSLP) is a potent neuroinflammation mediator after nerve injury. Bleomycin is applied to treat dermatologic diseases, and its administration elicits local painful sensation. However, whether bleomycin administration can cause chronic pain remains unknown. In the present study, we aimed to investigate how mice develop chronic pain after receiving repeated bleomycin administration. In addition, the relevant neurobiological brain changes after noxious stimuli were clarified. C57BL/6 mice aged five- to six-weeks were randomly classified into two group, PBS (normal) group and bleomycin group which bleomycin was intradermally administered to back five times a week over a three-week period. Calibrated forceps testing was used to measure mouse pain threshold. Western blots were used to assess neuroinflammatory response; immunofluorescence assay was used to measure the status of neuron apoptosis, glial reaction, and neuro-glial communication. Bleomycin administration induced mechanical nociception and activated both TRPV1 and TSLP/TSLPR/pSTAT5 signals in mouse somatosensory cortex. Through these pathways, bleomycin not only activates glial reaction but also causes neuronal apoptosis. TRPV1 and TSLP/TSLPR/pSTAT5 signaling had co-labeled each other by immunofluorescence assay. Taken together, our study provides a new chronic pain model by repeated intradermal bleomycin injection by activating TRPV1 and glial reaction-mediated neuroinflammation via TSLP/TSLPR/pSTAT5 signals.

慢性疼痛是一个普遍的公共卫生问题，全球近三分之一的人都有慢性疼痛的困扰，这给个人造成了极大的痛苦。疼痛刺激后，神经生物学变化不仅发生在外周神经系统，也发生在中枢神经系统，其中躯体感觉皮层对痛觉非常重要。作为一种离子通道，瞬时受体电位香草素 1（TRPV1）在大脑中起着炎症检测器的作用。胸腺基质淋巴细胞生成素（TSLP）是神经损伤后一种有效的神经炎症介质。博莱霉素被用于治疗皮肤病，使用博莱霉素会引起局部疼痛。然而，博莱霉素是否会引起慢性疼痛仍是未知数。本研究旨在探讨小鼠在反复服用博莱霉素后如何产生慢性疼痛。此外，还阐明了有害刺激后大脑神经生物学的相关变化。我们将五至六周龄的C57BL/6小鼠随机分为两组，即PBS（正常）组和博莱霉素组。用校准镊子测试小鼠的痛阈值。用 Western 印迹评估神经炎症反应；用免疫荧光测定神经元凋亡、神经胶质细胞反应和神经胶质细胞通讯的状况。博莱霉素能诱导机械痛觉，并激活小鼠躯体感觉皮层中的TRPV1和TSLP/TSLPR/pSTAT5信号。通过这些途径，博莱霉素不仅能激活神经胶质反应，还能导致神经细胞凋亡。通过免疫荧光检测，TRPV1和TSLP/TSLPR/pSTAT5信号相互共标记。综上所述，我们的研究提供了一种新的慢性疼痛模型，即反复皮内注射博莱霉素，通过TSLP/TSLPR/pSTAT5信号激活TRPV1和神经胶质反应介导的神经炎症。

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引用次数: 0

Quercetin alleviates microglial-induced inflammation after traumatic brain injury via the PGC-1α/Nrf2 pathway dependent on HDAC3 inhibition 槲皮素通过PGC-1α/Nrf2途径减轻脑外伤后小胶质细胞诱导的炎症，而PGC-1α/Nrf2途径依赖于HDAC3抑制作用

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-12 DOI: 10.1016/j.brainresbull.2024.111080

Xiaofu Zhai , Ziyu Wang , Juemin Gao

Inflammation and neuronal apoptosis play a key role in traumatic brain injury (TBI). Quercetin (Que) has been shown to exhibit a neuroprotective effect after TBI, but the underlying molecular mechanism remains unclear. In this study, We established a weight-drop mouse model to illustrate the effects of Que on microglial-induced inflammation in TBI. Mice were divided into four groups: the Sham group, TBI group, TBI+vehicle group, and TBI+Que group. The TBI+Que group was treated with Que 30 min after TBI. Brain water content, neurological score, and neuronal apoptosis were measured. Western blotting, TUNEL staining, Nissl staining, quantitative polymerase chain reaction, and immunofluorescence staining were performed to assess the activation of the PGC-1α/Nrf2 pathway and nuclear translocation of HDAC3 with Que treatment. The results showed that Que administration alleviated TBI-induced neurobehavioral deficits, encephaledema, and neuron apoptosis. Que also restrained TBI-induced microglial activity and the subsequent expression of the inflammatory factor in the contusion cortex. Moreover, Que treatment activated the PGC-1α/Nrf2 pathway, attributable to the inhibition of HDAC3 translocation to the nucleus. Overall, these results reveal the role of Que in protecting against TBI-induced neuroinflammation and promoting neurological functional recovery, which is achieved through the negative regulation of HDAC3.

炎症和神经细胞凋亡在创伤性脑损伤（TBI）中起着关键作用。槲皮素（Que）已被证明在创伤性脑损伤后具有神经保护作用，但其潜在的分子机制仍不清楚。在本研究中，我们建立了一个体重下降的小鼠模型，以说明阙对创伤性脑损伤中小胶质细胞诱导的炎症的影响。小鼠被分为四组：Sham 组、TBI 组、TBI+车辆组和 TBI+Que 组。TBI+Que 组在 TBI 后 30 分钟用 Que 治疗。测量脑含水量、神经系统评分和神经细胞凋亡。通过 Western 印迹、TUNEL 染色、Nissl 染色、定量聚合酶链反应和免疫荧光染色来评估阙治疗对 PGC-1α/Nrf2 通路的激活和 HDAC3 的核转位。结果表明，服用阙可减轻创伤性脑损伤引起的神经行为障碍、脑水肿和神经元凋亡。阙还抑制了创伤性脑损伤诱发的小胶质细胞活性以及随后在挫伤皮层中炎症因子的表达。此外，阙治疗激活了 PGC-1α/Nrf2 通路，这归因于抑制了 HDAC3 转位至细胞核。总之，这些结果揭示了阙在防止创伤性脑损伤引起的神经炎症和促进神经功能恢复中的作用，而这是通过对 HDAC3 的负调控实现的。

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引用次数: 0

Projections from the ventral tegmental area to zona incerta regulate fear generalization in a mouse model of PTSD 在创伤后应激障碍小鼠模型中，从腹侧被盖区向内侧区的投射调节恐惧泛化

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin

Pub Date : 2024-09-11 DOI: 10.1016/j.brainresbull.2024.111079

Kun Tong , Shuang Wang , Yi-Jie Zhu , Zhi-Peng Chen , Si-Qi Jing

Generalized fear is a maladaptive behavior in which non-threatening stimuli elicit a fearful response. The ventral tegmental area (VTA) has been demonstrated to play important roles in fear response and fear memory generalization, but the precious neural circuit mechanism is still unclear. Here, we demonstrated that VTA-zona incerta (ZI) glutamatergic projection is involved in regulating high-intensity threatening training induced generalization and anxiety. Combining calcium signal recording and chemogentics, our work reveals that VTA glutamatergic neurons respond to closed arm entering in the model of PTSD. Inhibition of VTA glutamatergic neurons or the glutamatergic projection to ZI could both relieve fear generalization and anxiety. Together, our study proves the VTA - ZI glutamatergic circuit is involved in mediating fear generalization and anxiety, and provides a potential target for treating post-traumatic stress disorder.

泛化恐惧是一种适应不良行为，即非威胁性刺激引起恐惧反应。腹侧被盖区（VTA）已被证实在恐惧反应和恐惧记忆泛化中发挥重要作用，但其重要的神经回路机制仍不清楚。在这里，我们证明了VTA-zona incerta（ZI）谷氨酸能投射参与调节高强度威胁训练诱导的泛化和焦虑。结合钙信号记录和化学效应，我们的研究揭示了在创伤后应激障碍模型中，VTA 谷氨酸能神经元对手臂闭合进入有反应。抑制VTA谷氨酸能神经元或谷氨酸能投射到ZI都能缓解恐惧泛化和焦虑。总之，我们的研究证明了VTA-ZI谷氨酸能回路参与介导恐惧泛化和焦虑，并为治疗创伤后应激障碍提供了一个潜在的靶点。

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引用次数: 0