Brain Research最新文献_第6页

Spatiotemporal profiling of endocytic regulators in the immunosuppressive TAM microenvironment of glioma 脑胶质瘤免疫抑制TAM微环境中内吞调节因子的时空特征分析。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-12-04 DOI: 10.1016/j.brainres.2025.150086

Shi Hua , Yanhao Cheng , Dai Chao , Qimin Song , Lei Han , Hongyan Li , Yucheng Lu , Mingguang Wang

Endocytosis plays a pivotal role in shaping the immunosuppressive landscape of gliomas, yet its spatial dynamics within the tumor microenvironment remain incompletely understood. Here, we integrated single-cell and spatial transcriptomic analyses to characterize endocytosis-related regulators involved in immune remodeling. Among them, FCGR2B, CLEC7A, and LYAR emerged as key modulators associated with the spatiotemporal heterogeneity of tumor-associated macrophages (TAMs) and malignant cells. These genes displayed regionally elevated transcript levels from the tumor–normal interface toward perivascular and necrotic regions, accompanied by progressively stronger spatial co-localization with M2-like macrophages across multiple spatial scales. Cell–cell communication analysis revealed that these regulators were linked to activation of endocytosis-associated signaling pathways, including SPP1, GRN, and PSAP. A prognostic risk score derived from their expression effectively stratified patients by molecular subtype and clinical outcome, and SHAP-based model interpretation quantified the contribution of each gene to risk prediction. Immunohistochemistry and Western blot analyses further validated their elevated protein expression in high-grade glioma tissues. Collectively, this spatial multi-omic framework delineates endocytosis-associated immune remodeling in glioma and identifies FCGR2B, CLEC7A, and LYAR as potential biomarkers and therapeutic targets for disrupting immunosuppressive niches.

内吞作用在形成神经胶质瘤的免疫抑制景观中起着关键作用，但其在肿瘤微环境中的空间动力学仍然不完全清楚。在这里，我们整合了单细胞和空间转录组学分析来表征参与免疫重塑的内吞相关调节因子。其中，FCGR2B、CLEC7A和LYAR是与肿瘤相关巨噬细胞（tumor-associated macrophages, tam）和恶性细胞时空异质性相关的关键调节因子。这些基因表现出从肿瘤-正常界面到血管周围和坏死区域的区域性转录水平升高，并伴随着与m2样巨噬细胞在多个空间尺度上逐渐增强的空间共定位。细胞间通讯分析显示，这些调节因子与胞吞相关信号通路的激活有关，包括SPP1、GRN和PSAP。根据其表达得出的预后风险评分有效地根据分子亚型和临床结果对患者进行分层，基于shap的模型解释量化了每个基因对风险预测的贡献。免疫组织化学和Western blot分析进一步证实了它们在高级别胶质瘤组织中的蛋白表达升高。总的来说，这个空间多组学框架描绘了胶质瘤中与内吞相关的免疫重塑，并确定了FCGR2B、cle7a和LYAR作为破坏免疫抑制生态位的潜在生物标志物和治疗靶点。

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引用次数: 0

MICU1 promotes Ca2+ homeostasis and curbs ferroptosis to attenuate brain tissue damage in rats with postoperative cognitive dysfunction MICU1促进Ca2+稳态和抑制铁下垂，以减轻术后认知功能障碍大鼠的脑组织损伤。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-12-03 DOI: 10.1016/j.brainres.2025.150087

Na Zhou , Yan Wang

Objective

Postoperative cognitive dysfunction (POCD) is severe in patients after anesthesia and surgery. This study investigates the mechanism by which MICU1 regulates Ca²⁺ homeostasis and ferroptosis in POCD rats.

Methods

A POCD rat model was established, and hippocampal tissue was collected from the CA1 region to assess MICU1 expression. The lentivirus carrying Ad-MICU1 or the ferroptosis inducer Erastin was injected into the right lateral ventricle of POCD rats, followed by evaluation of motor function, learning ability, and memory capacity. Inflammatory cytokines were measured using ELISA. Nissl staining, NeuN staining, and HE staining were conducted to observe morphological changes in neurons, surviving neurons in the hippocampal CA1 subregion, and neuronal localization. ELISA was performed to assay the levels of ATP, Ca²⁺, Fe²⁺, MDA, SOD, LPO, and GSH in rat hippocampal tissue in the CA1 region. Flow cytometry was conducted to measure total ROS levels, mitochondrial ROS levels, and mitochondrial MPP. The Seahorse XFe 96 analyzer was employed to measure the mitochondrial oxygen consumption rate. Western blot was conducted to examine the levels of ferroptosis-related proteins.

Results

MICU1 was reduced in POCD rats. MICU1 overexpression partially improved motor function, learning ability, and memory capacity and alleviated central inflammation and hippocampal neuronal damage in POCD rats. MICU1 maintained Ca²⁺ homeostasis, reduced Ca²⁺, total ROS, and mitochondrial ROS levels, and inhibited ferroptosis. Erastin partially reversed the beneficial effects of MICU1 overexpression on POCD rats.

Conclusion

MICU1 promotes Ca²⁺ homeostasis, inhibits ferroptosis and ROS production, and alleviates brain tissue damage in POCD rats.

目的：术后认知功能障碍（POCD）在麻醉术后患者中较为严重。本研究探讨MICU1调控POCD大鼠Ca2+稳态和铁下垂的机制。方法：建立POCD大鼠模型，取CA1区海马组织检测MICU1表达。将携带Ad-MICU1或铁下垂诱导剂Erastin的慢病毒注入POCD大鼠右侧脑室，评估其运动功能、学习能力和记忆能力。采用ELISA法检测炎症因子。采用Nissl染色、NeuN染色、HE染色观察神经元形态学变化、海马CA1亚区存活神经元及神经元定位。ELISA法检测CA1区大鼠海马组织中ATP、Ca2+、Fe2+、MDA、SOD、LPO、GSH水平。流式细胞术检测总ROS水平、线粒体ROS水平和线粒体MPP。采用Seahorse XFe 96分析仪测定线粒体耗氧量。Western blot检测凋亡相关蛋白水平。结果：POCD大鼠MICU1降低。MICU1过表达可部分改善POCD大鼠的运动功能、学习能力和记忆能力，减轻中枢炎症和海马神经元损伤。MICU1维持Ca2+稳态，降低Ca2+、总ROS和线粒体ROS水平，并抑制铁下垂。Erastin部分逆转了MICU1过表达对POCD大鼠的有益作用。结论：MICU1促进Ca2+稳态，抑制铁下垂和ROS的产生，减轻POCD大鼠脑组织损伤。

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引用次数: 0

Yank-related changes in corticospinal recruitment gain in humans 人类皮质脊髓招募增益的张力相关变化。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-12-03 DOI: 10.1016/j.brainres.2025.150090

Abdulkerim Darendeli , Mathew Yarossi , Spencer Lake Jakobs-Skolik , Nathaniel Pinkes , Vaishnavi Sharma , Erica Kemmerling , Eugene Tunik , Oscar Soto

The generation of muscle force is a key component of movement. Force is generated by increasing the number and firing rates of motor units (MU), but limited information is available on the corticospinal (CS) recruitment gain across the spectrum of magnitude and rate of force (yank). To assess the effects of force magnitude and yank on motor outputs, we recorded force (motor evoked twitches, METs) and EMG (motor evoked potentials, MEPs) in response to transcranial magnetic stimulation (TMS) during nearly isometric hand gripping tasks in 20 healthy subjects. Motor cortex TMS was applied during force ramps at different levels of voluntary force magnitude and yank. Yank robustly facilitated METs, maximally at lowest magnitudes of voluntary force, but this facilitation saturated at forces > 50 % of the maximal voluntary contraction (MVC). At each level of force magnitude there was a linear relationship between the yank of voluntary force and MET amplitude. The slope of this relationship, representing the CS recruitment gain, decayed exponentially with increasing magnitude of force. Changes in CS recruitment gain associated with force magnitude and yank were better explained by METs than by MEPs. A positive yank resulted in larger estimated maximal MET at 0 % force compared to static contractions. These results suggest that METs capture a robust yank-related increase in CS recruitment gain, which is blunted by limited MU availability at high force magnitude. We showed that the estimation of maximal motor outputs is optimally achieved in tasks in which force production is achieved with high yank.

肌肉力量的产生是运动的关键组成部分。力是通过增加运动单元（MU）的数量和发射速率产生的，但是关于皮质脊髓（CS）在力的大小和速率（猛拉）范围内的招募增益的信息有限。为了评估力的大小和拉力对运动输出的影响，我们记录了20名健康受试者在近等距手握任务中经颅磁刺激（TMS）反应的力（运动诱发抽搐，METs）和肌电图（运动诱发电位，MEPs）。运动皮质经颅磁刺激在不同的自主力大小和张力水平的力斜坡中应用。猛拉有力地促进METs，最大限度地在最小的自主力，但这种促进饱和力 > 50 %的最大自主收缩（MVC）。在每个水平的力的大小有一个线性关系的自愿力的猛拉和MET振幅。这个关系的斜率，表示CS的吸收增益，随着力的增加呈指数衰减。与力大小和拉力相关的CS招募增益的变化用METs比MEPs更好地解释。与静态收缩相比，在0 %的力下，积极的拉伸导致更大的估计最大MET。这些结果表明，METs捕获了与猛拉相关的CS招募增益的强劲增长，这在高强度下被有限的MU可用性所钝化。我们表明，最大运动输出的估计是最理想的实现在任务中，力的生产是实现与高张力。

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引用次数: 0

Examining functional connectivity in metabolic syndrome and small vessel disease: A novel approach to understanding olfactory dysfunction and Alzheimer’s disease 检查代谢综合征和小血管疾病的功能连接：一种理解嗅觉功能障碍和阿尔茨海默病的新方法。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-12-01 DOI: 10.1016/j.brainres.2025.150084

Hector Reyes , Jaime Mondragon , Conner Frank , Claire Murphy

Introduction

The prevalence of Alzheimer’s Disease (AD) is projected to triple by 2050, highlighting the need to identify early markers and underlying mechanisms associated with its progression. Olfactory dysfunction has emerged as an early indicator of AD, with its neural basis linked to changes in the medial temporal lobe and associated networks. Cardiovascular risk factors, including metabolic syndrome (MetS) and cerebral small vessel disease (SVD), have been implicated in neurodegenerative processes, yet their impact on olfactory network connectivity remains underexplored. This study aimed to investigate task-based functional connectivity in the olfactory network, medial temporal lobe, and default mode network among cognitively unimpaired individuals with MetS or SVD.

Method

Participants were grouped based on MetS and SVD status. Using fMRI, functional connectivity patterns during olfactory processing were analyzed for group differences.

Results

Functional connectivity revealed hypoconnectivity between the right angular gyrus and secondary olfactory cortex between MetS groups and altered connectivity between the hippocampus and frontoparietal control network between SVD groups. Both conditions demonstrated increased within-network cerebellar connectivity compared to controls.

Discussion

These findings highlight distinct neural alterations in olfactory and cognitive control networks associated with cardiovascular risk factors, providing novel insights into early brain changes linked to cardiovascular risk factors for dementia.

到2050年，阿尔茨海默病（AD）的患病率预计将增加两倍，这突出了识别与其进展相关的早期标志物和潜在机制的必要性。嗅觉功能障碍已成为阿尔茨海默病的早期指标，其神经基础与内侧颞叶和相关网络的变化有关。心血管危险因素，包括代谢综合征（MetS）和脑血管疾病（SVD），与神经退行性过程有关，但它们对嗅觉网络连通性的影响仍未得到充分探讨。本研究旨在探讨认知功能未受损的met或SVD患者嗅觉网络、内侧颞叶和默认模式网络中基于任务的功能连通性。方法：根据MetS和SVD状态对参与者进行分组。利用功能磁共振成像（fMRI）分析嗅觉处理过程中的功能连接模式。结果：功能连通性显示MetS组右角回与次级嗅觉皮层之间的连通性降低，SVD组海马与额顶叶控制网络之间的连通性改变。与对照组相比，这两种情况下的小脑网络内连通性都有所增加。讨论：这些发现强调了与心血管危险因素相关的嗅觉和认知控制网络的独特神经改变，为痴呆症心血管危险因素相关的早期大脑变化提供了新的见解。

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引用次数: 0

Cross-Disease myeloid remodeling along the GMP–TAM axis predicts immunotherapy response in glioma 沿GMP-TAM轴的跨疾病骨髓重塑预测胶质瘤的免疫治疗反应。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-30 DOI: 10.1016/j.brainres.2025.150083

Yuanyuan Zhang , Xin Liu , Shi Hua

Backgrounds

Immune checkpoint inhibitor-induced colitis (CICs) represents a state of systemic immune activation and is paradoxically associated with superior anti-tumor responses. This study has been designed to explore gene signatures derived from CICs that could identify the key immunological drivers, and predict sensitivity of immunotherapy in immunologically cold tumors e.g. glioma. Methods: We integrated bulk, single-cell, and spatial transcriptomic data from CICs and glioma cohorts. Cross-disease analysis have been performed to identify an immunotherapy-responsive granulocyte-monocyte progenitor (IR-GMP) signature. Risk score (RS) model has been constructed through LASSO regression, and have been validated for its potential prognostic as well as predictive values. Results: We have identified 112 IR-GMP genes enriched in pathways that may cause myeloid immunosuppression. A four-gene RS model (RAC2, LAPTM5, HCLS1, CD74) has been developed, and glioma patients have been divided into high- and low-risk groups based on the model. RS is an independent prognostic factor, and demonstrated to exhibit superior accuracy for predicting survival when combining with clinical variables. High-RS tumors exhibited immunosuppressive TME characterized by M2 macrophage enrichment, SPP1-signaling hyperactivation, and an immune-tolerant genomic landscape (C4 subtype). Crucially, the high-RS group showed significantly higher immunophenoscores under PD-1 and combined PD-1/CTLA-4 blockade, indicating potential sensitivity to immunotherapy, and distinct chemotherapy susceptibility. Single-cell and spatial transcriptomic results confirmed the lineage specificity and regional colocalization of RS genes with M2 macrophages. Conclusions: Our cross-disease analysis unveils a conserved GMP–TAM myeloid remodeling axis in glioma. The derived RS model may serve as a powerful marker for predicting prognosis, and also for predicting the benefits derived from immunotherapy, offering a novel tool for precision immunotherapy in glioma.

背景：免疫检查点抑制剂诱导的结肠炎（CICs）代表了一种全身性免疫激活状态，并且矛盾地与优越的抗肿瘤反应相关。本研究旨在探索来自CICs的基因特征，这些特征可以识别关键的免疫驱动因素，并预测免疫治疗对免疫冷肿瘤（如胶质瘤）的敏感性。方法：我们整合了来自CICs和胶质瘤队列的大量、单细胞和空间转录组数据。已经进行了跨疾病分析，以确定免疫治疗反应性粒细胞-单核细胞祖细胞（IR-GMP）特征。通过LASSO回归构建了风险评分（RS）模型，并对其潜在的预后和预测价值进行了验证。结果：我们已经鉴定出112个富集于髓细胞免疫抑制通路的IR-GMP基因。建立了四基因RS模型（RAC2、LAPTM5、HCLS1、CD74），并根据模型将胶质瘤患者分为高危组和低危组。RS是一个独立的预后因素，当与临床变量相结合时，RS在预测生存方面表现出更高的准确性。高rs肿瘤表现出免疫抑制TME，其特征是M2巨噬细胞富集、spp1信号过度激活和免疫耐受基因组景观（C4亚型）。至关重要的是，高rs组在PD-1和PD-1/CTLA-4联合阻断下显示出显著更高的免疫表型，表明对免疫治疗的潜在敏感性和明显的化疗敏感性。单细胞和空间转录组学结果证实了RS基因与M2巨噬细胞的谱系特异性和区域共定位。结论：我们的跨疾病分析揭示了胶质瘤中保守的GMP-TAM髓系重塑轴。所建立的RS模型可作为预测预后的有力指标，也可用于预测免疫治疗的获益，为胶质瘤的精确免疫治疗提供了新的工具。

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引用次数: 0

Static and dynamic alterations in local brain activity and their association with dysfunctional connectivity in depressed adolescents with suicide attempts and non-suicidal self-injury 有自杀企图和非自杀性自伤的抑郁青少年局部脑活动的静态和动态变化及其与功能障碍连接的关系

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-29 DOI: 10.1016/j.brainres.2025.150064

Lianlian Yang , Shuai Wang , Zimo Zhou , Zhenru Guo , Shuaiyi Guo , Xiaoshan Gao , Yuanyuan Yang , Yu Xia , Haixia Huang , Jianhua Li , Haohao Zhu , Lin Tian

Suicide attempts (SA) and non-suicidal self-injury (NSSI) are critical public health concerns that frequently co-occur in depressed adolescents. However, the neurological mechanisms underlying these behaviors remain poorly understood. This study aimed to identify alterations in brain activity and examine the associations between these changes and clinical symptom severity in depressed adolescents with SA and NSSI. A total of 82 depressed adolescents with NSSI were divided into two groups: those with both SA and NSSI (SA + NSSI, n = 46) and those with NSSI only (n = 36). Static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF variability (dALFF variability) analyses were conducted to assess local brain activity differences between groups. Regions with abnormal neural activity were used as seeds to investigate static functional connectivity (sFC) and dynamic FC variability (dFC variability) alterations. Correlation analyses as exploratory analysis was subsequently performed. Compared to the NSSI group, the SA + NSSI group exhibited increased sALFF in the left cerebellum, increased dALFF variability in the orbitofrontal cortex and left cerebellum, and increased dFC variability between the orbitofrontal cortex and caudate. The SA + NSSI group also showed decreased sALFF and dALFF variability in the postcentral gyrus (cluster p < 0.05, FDR corrected, two-tailed). Additionally, for the SA + NSSI group, sALFF in the postcentral gyrus was negatively correlated with emotional neglect, while the dFC variability between the orbitofrontal cortex and caudate was positively correlated with internet addiction withdrawal symptoms. These findings provide novel insights into the neurological mechanisms of SA and NSSI, highlighting the potential value of combining static and dynamic functional metrics for clinical differentiation between these behaviors.

自杀企图（SA）和非自杀性自伤（NSSI）是严重的公共卫生问题，经常在抑郁青少年中同时发生。然而，这些行为背后的神经机制仍然知之甚少。本研究旨在确定青少年抑郁伴SA和自伤的大脑活动的变化，并研究这些变化与临床症状严重程度之间的关系。将82例有自伤的抑郁青少年分为两组：有自伤和有自伤的抑郁青少年（SA + 自伤，n = 46）和有自伤的抑郁青少年（n = 36）。通过静态低频波动幅度（sALFF）和动态低频波动幅度（dALFF变异性）分析来评估组间局部脑活动的差异。以神经活动异常区域为种子，研究静态功能连通性（sFC）和动态FC变异性（dFC变异性）的变化。随后进行相关性分析作为探索性分析。与自伤组相比，SA + 自伤组左侧小脑的sALFF增加，眶额皮质和左侧小脑的dALFF变异性增加，眶额皮质和尾状核之间的dFC变异性增加。SA + 自伤组也显示中枢后回sALFF和dALFF变异性降低(簇p

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引用次数: 0

Strength of associations between regional brain volumes and dual decline in gait and memory 区域脑容量与步态和记忆双重衰退之间的关联强度。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-28 DOI: 10.1016/j.brainres.2025.150072

Sadhani Karunarathna , Monique Breslin , Jane Alty , James Scott McDonald , Richard Beare , Velandai K. Srikanth , Taya A. Collyer , Michele L. Callisaya

Background

Dual decline in gait and memory is associated with a higher risk of dementia. However, little is known about specific brain regions and their association with dual decline. Therefore, this study examined the strength of associations between baseline regional brain volumes and dual decline in gait speed and memory.

Methods

Participants aged over 60 years were randomly selected from the Southern Tasmanian electoral roll. Participants (n = 266) were classified into four groups depending on tertiles of annual decline in gait speed and delayed memory recall: non-decline, gait-only decline, cognitive-only decline, and dual decline. Multinomial logistic regression was used to examine the strength of associations between baseline regional brain volumes and the four groups.

Results

The mean age of participants was 70.9 ± SD 6.7 years. For the dual decline group, eight regions (in order of strength − orbitofrontal cortex, middle frontal gyrus, superior frontal gyrus, thalamus, anterior cingulate cortex, brainstem, inferior temporal gyrus and hippocampus) had relative risk ratios below 0.60 for a 1 SD increase in volume. For gait-only and cognitive-only decline, only the thalamus and cerebellum respectively, had relative risk ratios below 0.60.

Conclusions

In this study, we observed that smaller volumes in regions related to memory, executive function, motor, and sensory-motor integration had the strongest associations with dual decline.

背景：步态和记忆的双重衰退与痴呆的高风险相关。然而，人们对特定的大脑区域及其与双重衰退的关系知之甚少。因此，本研究考察了基线区域脑容量与步态速度和记忆力双重衰退之间的关联强度。方法：从南塔斯马尼亚州选民名册中随机选择年龄在60岁 以上的参与者。参与者（n = 266）根据步态速度和延迟记忆回忆的年度下降的分位数分为四组：非下降，仅步态下降，仅认知下降和双重下降。使用多项逻辑回归来检查基线区域脑容量与四组之间的关联强度。结果：参与者的平均年龄为70.9 ± SD 6.7 岁。对于双衰退组，体积每增加1 SD， 8个区域（按强度排序为眶额皮质、额中回、额上回、丘脑、前扣带皮层、脑干、颞下回和海马）的相对风险比低于0.60。对于单纯步态衰退和单纯认知衰退，分别只有丘脑和小脑的相对风险比低于0.60。结论：在这项研究中，我们观察到，与记忆、执行功能、运动和感觉-运动整合相关的区域体积较小，与双重衰退有最强的关联。

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引用次数: 0

Sex differences in interactions between the muscarinic-1 and orexin-1 receptors on cognitive flexibility in rats 肌肉素-1和食欲素-1受体对大鼠认知灵活性相互作用的性别差异。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-27 DOI: 10.1016/j.brainres.2025.150081

Mutian Li , Jim R. Fadel , Joshua A. Burk

Previous research has shown that cognitive flexibility, the ability to adjust to different rules, is affected by manipulations of orexin and acetylcholine (ACh). Because there are strong neural connections between orexin and ACh, these two neurotransmitter systems may interact to impact cognitive flexibility. In the present experiment, the effects of pharmacological manipulations of orexin-1 and muscarinic-1 receptors in rats were tested on cognitive flexibility. Rats received intraperitoneal injections of VU0453595, a positive allosteric modulator for the M1 subtype of ACh receptors, for seven days prior to a rule switch in a measure of cognitive flexibility. On the day of the rule switch, rats were given the orexin-1 receptor antagonist, SB-334867 or vehicle prior to task performance. As expected, SB-334867 increased the number of trials to criterion during the rule switch. Compared to vehicle, when VU0453595 was administered, orexin-1 receptor blockade increased regressive errors for males and perseverative errors for females. These findings support the hypothesis that there are interactions between the orexin and cholinergic systems affecting cognitive flexibility, but that these interactions affect cognitive flexibility differently for males and females.

先前的研究表明，认知灵活性，即适应不同规则的能力，受到食欲素和乙酰胆碱（ACh）的影响。因为食欲素和乙酰胆碱之间有很强的神经联系，这两种神经递质系统可能相互作用，影响认知灵活性。本实验研究了食欲素-1和肌碱-1受体的药理作用对大鼠认知灵活性的影响。在认知灵活性测量的规则转换之前，大鼠接受了VU0453595腹腔注射，VU0453595是一种阳性的乙酰胆碱受体M1亚型的变构调节剂。在规则转换当天，大鼠在执行任务前给予食欲素-1受体拮抗剂SB-334867或对照品。正如预期的那样，SB-334867在规则切换期间增加了到标准的试验次数。与对照组相比，当给药VU0453595时，食欲素-1受体阻断增加了雄性的回归误差和雌性的持久性误差。这些发现支持了一种假设，即食欲素和胆碱能系统之间存在影响认知灵活性的相互作用，但这些相互作用对男性和女性认知灵活性的影响不同。

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引用次数: 0

Crosstalk between ApoE-expressing cells and genotoxic stress in the mouse brain 小鼠脑内表达apoe细胞与基因毒性应激之间的串扰。

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-27 DOI: 10.1016/j.brainres.2025.150080

Ummay Ayman , Takayoshi Otsuka , Godfried Dougnon , Hideaki Matsui

Apolipoprotein E (ApoE) plays an important role in cerebral lipid transport. Beyond lipid transport, ApoE also contributes to the maintenance of neuronal integrity. Although DNA damage and dysfunction in the DNA damage response are recognized as early contributors to neuropathology, the connection between ApoE and DNA damage remains poorly understood. In this study, we investigated cells expressing endogenous mouse ApoE (mApoE) in the brain under both normal condition and etoposide-induced DNA damage. Immunohistochemical analysis revealed that mApoE was predominantly expressed in astrocytes and a subset of neurons across various brain regions, with minimal expression in microglia and no detectable expression in oligodendrocytes. Induction of DNA damage through etoposide treatment did not alter the expression level or distribution pattern of mApoE in brain. However, a correlation between neuronal mApoE expression and DNA damage was observed: mApoE-positive neurons were more affected and exhibited a higher number of γH2A.X foci upon etoposide treatment. This observation warrants further investigation to determine whether the increased sensitivity of mApoE-positive neurons to DNA damage is neuroprotective or contributes to neurodegeneration. Our study provides a foundation for understanding the physiological role of mApoE in response to DNA damage and suggests a potential involvement of neuronal mApoE in neurodegeneration.

载脂蛋白E （ApoE）在脑脂质转运中起重要作用。除了脂质转运，ApoE还有助于维持神经元的完整性。虽然DNA损伤和DNA损伤反应中的功能障碍被认为是神经病理学的早期贡献者，但ApoE与DNA损伤之间的联系仍然知之甚少。在这项研究中，我们研究了在正常情况下和依托泊苷诱导的DNA损伤下，大脑中表达内源性小鼠ApoE （mApoE）的细胞。免疫组织化学分析显示，mApoE主要表达在星形胶质细胞和大脑各区域的神经元亚群中，在小胶质细胞中表达最少，在少突胶质细胞中未检测到表达。依托泊苷诱导DNA损伤不改变脑内mApoE的表达水平和分布模式。然而，观察到神经元mApoE表达与DNA损伤之间的相关性：mApoE阳性神经元受到的影响更大，并且在etopo苷处理后表现出更多的γ - h2ax灶。这一观察结果值得进一步研究，以确定mapoe阳性神经元对DNA损伤的敏感性增加是神经保护作用还是导致神经退行性变。我们的研究为理解mApoE在DNA损伤反应中的生理作用提供了基础，并提示神经元mApoE可能参与神经退行性变。

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引用次数: 0

DDX3X promotes ILF3 stability to accelerate neuroblastoma progression via M2 macrophage polarization DDX3X促进ILF3稳定性，通过M2巨噬细胞极化加速神经母细胞瘤进展

IF 2.6 4区医学 Q3 NEUROSCIENCES

Brain Research

Pub Date : 2025-11-26 DOI: 10.1016/j.brainres.2025.150071

Tian Lin, Xinghe Chen, He Huang, Jianxing Zhang, Junshan Lin

Neuroblastoma (NB) is a common pediatric solid tumor with poor prognosis, in which macrophage polarization is increasingly recognized as a key driver of progression. However, the roles of RNA-binding proteins such as DEAD-box helicase 3 X-linked (DDX3X) and interleukin enhancer-binding factor 3 (ILF3) in this process remain unclear. This study aims to explore the role of the DDX3X–ILF3 axis in modulating macrophage polarization and promoting the malignant progression of NB. ILF3 expression was analyzed by RT-qPCR and Western blotting. Lentiviral-mediated knockdown of ILF3 or DDX3X was performed, followed by evaluation of cell viability, proliferation, invasion, and migration, respectively. In a Transwell co-culture system, the expression of polarization markers was examined by Western blotting, and the secretion of inflammatory cytokines was measured by enzyme-linked immunosorbent assay. Actinomycin D treatment combined with RT-qPCR was used to assess ILF3 mRNA stability. RIP-qPCR was employed to explore the interaction of DDX3X with ILF3 mRNA. NB xenograft and metastasis mouse model (lung, liver, and kidney) was established to evaluate the regulatory effects of the DDX3X inhibitor RK-33 and ILF3 overexpression on NB growth and metastasis. ILF3 expression was significantly upregulated in NB cells. Knockdown of ILF3 or DDX3X suppressed NB cell viability, proliferation, invasion, and migration, while promoting M1 macrophage polarization accompanied by increased secretion of inflammatory cytokines. Silencing DDX3X reduced ILF3 mRNA stability and protein expression, whereas ILF3 overexpression negated the suppressive impacts of DDX3X knockdown on malignant behaviors and polarization status. In vivo, DDX3X inhibitor, RK-33, markedly inhibited NB tumor growth and metastasis and enhanced M1 macrophage polarization, which was partially reversed by ILF3 overexpression. DDX3X promotes NB progression by stabilizing ILF3 mRNA, thereby facilitating M2 macrophage polarization.

神经母细胞瘤（NB）是一种常见的儿童实体肿瘤，预后较差，其中巨噬细胞极化越来越被认为是进展的关键驱动因素。然而，rna结合蛋白如DEAD-box解旋酶3x -linked （DDX3X）和白细胞介素增强子结合因子3 （ILF3）在这一过程中的作用尚不清楚。本研究旨在探讨DDX3X-ILF3轴在调节巨噬细胞极化、促进NB恶性进展中的作用。采用RT-qPCR和Western blotting检测ILF3的表达。慢病毒介导的ILF3或DDX3X的敲低，随后分别评估细胞活力、增殖、侵袭和迁移。在Transwell共培养系统中，用Western blotting检测极化标记物的表达，用酶联免疫吸附法检测炎症细胞因子的分泌。放线菌素D联合RT-qPCR检测ILF3 mRNA的稳定性。采用RIP-qPCR方法研究DDX3X与ILF3 mRNA的相互作用。建立NB异种移植转移小鼠模型（肺、肝、肾），评价DDX3X抑制剂RK-33和ILF3过表达对NB生长和转移的调节作用。NB细胞中ILF3表达显著上调。敲低ILF3或DDX3X抑制NB细胞活力、增殖、侵袭和迁移，促进M1巨噬细胞极化，并伴有炎性细胞因子分泌增加。沉默DDX3X降低了ILF3 mRNA的稳定性和蛋白表达，而ILF3过表达则否定了DDX3X敲低对恶性行为和极化状态的抑制作用。在体内，DDX3X抑制剂RK-33显著抑制NB肿瘤的生长和转移，增强M1巨噬细胞极化，这一作用被ILF3过表达部分逆转。DDX3X通过稳定ILF3 mRNA促进NB进展，从而促进M2巨噬细胞极化。

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