Neuroscience最新文献_第7页

Effects of personalized vs. non-personalized neurostimulation protocols in improving speech and limb reaction times 个性化与非个性化神经刺激方案对改善言语和肢体反应时间的影响。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-11 DOI: 10.1016/j.neuroscience.2026.01.007

Fatemeh Tabari , Joel Isaac Berger , Arend W.A. Van Gemmert , Melda Kunduk , Karim Johari

Abnormal activity within supplementary motor area (SMA) has been associated with impaired speech and limb movement in neurological conditions. Normalizing aberrant neural activity through non-invasive neuromodulation techniques over SMA has demonstrated promising effects in ameliorating motor and non-motor functions. However, there is limited research on the application of transcranial electrical stimulation (tES) over the left SMA as a potential non-invasive protocol to improve speech production. In this study, we examined the effects of several tES protocols, including high-definition transcranial alternating current stimulation (HD-tACS), transcranial random noise stimulation (tRNS), and direct current stimulation (HD-tDCS), targeting the left SMA in neurotypical adults, on speech and limb reaction times. In a sham-controlled dual-experiment design, two groups of neurologically intact adult participants underwent multiple stimulation sessions: Experiment 1) sham HD-tACS, HD-tACS tuned to each individual’s frequency of maximal SMA beta activity (15–30 Hz) during speech (tuned-to-speech) or limb (tuned-to-limb), or HD-tRNS; Experiment 2) sham, anodal or cathodal HD-tDCS. Following the stimulation, the participants were instructed to perform a speech-limb interleaved task. Personalized beta HD-tACS and HD-tRNS – but not HD-tDCS – over the left SMA significantly improved reaction times for both speech and limb movement compared to sham. There was no difference in reaction times between HD-tACS and HD-tRNS for either speech or limb movement. These findings demonstrate comparable neuromodulatory effects of HD-tACS and HD-tRNS in improving speech and limb reaction times in younger adults. This study is exploratory and warrants replication with a larger sample within a single-group design.

在神经系统疾病中，辅助运动区（SMA）的异常活动与言语和肢体运动受损有关。通过非侵入性神经调节技术在SMA上正常化异常神经活动在改善运动和非运动功能方面显示出有希望的效果。然而，关于经颅电刺激（tES）在左侧SMA上的应用作为一种潜在的非侵入性方案来改善语音产生的研究有限。在这项研究中，我们研究了几种tES方案的影响，包括高分辨率经颅交流电刺激（HD-tACS），经颅随机噪声刺激（tRNS）和直流电刺激（HD-tDCS），针对神经典型成人的左侧SMA，对语言和肢体反应时间的影响。在假对照双实验设计中，两组神经功能完整的成年参与者接受了多次刺激：实验1)假HD-tACS， HD-tACS调节到每个人在说话（调节到说话）或肢体（调节到肢体）或HD-tRNS期间的最大SMA β活动频率（15-30 Hz）；实验2)假、阳极或阴极HD-tDCS。在刺激之后，参与者被要求执行一项言语肢体交织任务。与假手术相比，个性化的β HD-tACS和HD-tRNS（而不是HD-tDCS）在左侧SMA上显著改善了言语和肢体运动的反应时间。HD-tACS和HD-tRNS在言语和肢体运动方面的反应时间没有差异。这些发现表明，HD-tACS和HD-tRNS在改善年轻人的语言和肢体反应时间方面具有相当的神经调节作用。这项研究是探索性的，并保证在单组设计中使用更大的样本进行复制。

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引用次数: 0

Neurobiological and psychosocial mechanisms linking early life stress to the pathogenesis of eating disorders 将早期生活压力与饮食失调的发病机制联系起来的神经生物学和社会心理机制。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-10 DOI: 10.1016/j.neuroscience.2026.01.008

Amanda Gollo Bertollo , Camila Ferreira Puntel , Hans Fiedler Bastos Rievers , Eric Gabriel Serpa Brunhara , Zuleide Maria Ignácio

Early life stress (ELS) is a significant factor in the development of eating disorders (ED), not as a single cause, but as a powerful influence that creates a vulnerability across an individual’s biology and psychology. This review explains how various forms of ELS, such as trauma, neglect, and chronic adversity, can permanently alter brain systems. For example, chronic stress hormone exposure can dysregulate the hypothalamic–pituitary–adrenal (HPA) axis, leading to abnormal cortisol levels and impaired stress self-regulation later in life. This dysregulation can lead to difficulties in managing emotions and coping with stress later in life. Furthermore, ELS impacts the brain’s neurochemical systems, including serotonin, dopamine, and norepinephrine, which are responsible for mood, reward, and impulse control. Lasting changes to these systems can explain why some people use food to cope with distress, leading to behaviors like binge eating or extreme restriction. ELS also leaves a biological memory via epigenetic modifications, notably DNA methylation, altering gene expression without changing the DNA sequence to link early experiences to long-term risk. From a psychological perspective, ELS often leads to low self-esteem, self-criticism, and an impaired ability to regulate emotions. These psychological traits, along with a person’s neurobiological profile, can make them more susceptible to developing an eating disorder as a way to gain a sense of control over their lives. By integrating genetic, epigenetic, neurobiological, and psychosocial factors, this review clarifies how ELS acts as a multifaceted embedder of vulnerability, contributing to the onset and persistence of EDs.

早期生活压力（ELS）是饮食失调（ED）发展的一个重要因素，不是一个单一的原因，而是一个强大的影响，在个体的生理和心理上造成脆弱性。这篇综述解释了各种形式的ELS，如创伤、忽视和慢性逆境，如何永久性地改变大脑系统。例如，慢性应激激素暴露会使下丘脑-垂体-肾上腺（HPA）轴失调，导致皮质醇水平异常，并在以后的生活中损害应激自我调节。这种失调会导致在以后的生活中难以管理情绪和应对压力。此外，ELS还会影响大脑的神经化学系统，包括血清素、多巴胺和去甲肾上腺素，它们负责情绪、奖励和冲动控制。这些系统的持续变化可以解释为什么有些人用食物来应对痛苦，导致暴饮暴食或极端限制等行为。ELS还通过表观遗传修饰留下生物记忆，特别是DNA甲基化，改变基因表达，而不改变DNA序列，将早期经历与长期风险联系起来。从心理学的角度来看，ELS通常会导致低自尊、自我批评和调节情绪的能力受损。这些心理特征，以及一个人的神经生物学特征，会使他们更容易患上饮食失调症，从而获得对生活的控制感。通过整合遗传、表观遗传、神经生物学和社会心理因素，本综述阐明了ELS如何作为脆弱性的多方面嵌入者，促进了EDs的发病和持续。

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引用次数: 0

Zebrafish neural regeneration: mechanistic insights into human nervous system repair 斑马鱼神经再生：人类神经系统修复的机理。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-10 DOI: 10.1016/j.neuroscience.2026.01.009

Lilesh Kumar Pradhan , Saroj Kumar Das

The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, stroke, epilepsy, autism spectrum disorders, and CNS injuries. Unlike mammals, they restore damaged axons and recover function through a permissive extracellular matrix, transient inflammation, and glial plasticity. In the retina, Müller glia reprograms after injury to generate progenitors that replace lost neurons, regulated by Wnt/β-catenin, Shh, EGF, Hippo/YAP, and ROCK signaling. In the spinal cord, ependymo-radial glia forms a laminin- and fibronectin-rich “glial bridge,” guided by FGF and CTGF signaling, supporting axon regrowth. In the brain, GFAP- and Olig2-positive radial glia drive neurogenesis within ventricular niches, integrating new neurons while maintaining circuit integrity. Regeneration involves transient Notch suppression, context-specific Wnt and FGF activation, and immune modulation without fibrosis. Advances in single-cell RNA sequencing, CRISPR-Cas9, lineage tracing, and multi-omics have identified injury-induced progenitor states, regulators (ascl1a, lin28, sox2, stat3), and epigenetic programs enabling regeneration. Emerging research on bioelectric signaling, microbiota–brain interactions, and lipid mediators further expands systemic understanding. Overall, zebrafish provide a unified model for decoding vertebrate CNS regeneration and guiding therapeutic strategies to restore neural repair in humans.

斑马鱼（Danio rerio）是研究神经退行性疾病和再生医学的强大脊椎动物模型，因为它与人类遗传相似，并且具有再生中枢神经系统（CNS）的独特能力。这篇综述综合了斑马鱼视网膜、脊髓和大脑神经再生的关键发现，强调了翻译的相关性。斑马鱼可以有效地模拟疾病，如阿尔茨海默氏症、帕金森症、肌萎缩侧索硬化症、中风、癫痫、自闭症谱系障碍和中枢神经系统损伤。与哺乳动物不同，它们通过允许的细胞外基质、短暂的炎症和神经胶质可塑性来修复受损的轴突和恢复功能。在视网膜中，损伤后的突触神经胶质重编程产生替代丢失神经元的祖细胞，由Wnt/β-catenin、Shh、EGF、Hippo/YAP和ROCK信号调节。在脊髓中，室管膜-放射状胶质细胞形成一个层粘连蛋白和纤维连接蛋白丰富的“胶质桥”，由FGF和CTGF信号引导，支持轴突再生。在大脑中，GFAP-和olig2阳性的放射状胶质细胞驱动脑室壁龛内的神经发生，在维持回路完整性的同时整合新神经元。再生包括瞬时Notch抑制、上下文特异性Wnt和FGF激活以及无纤维化的免疫调节。单细胞RNA测序、CRISPR-Cas9、谱系追踪和多组学的进展已经确定了损伤诱导的祖细胞状态、调节因子（ascl1a、lin28、sox2、stat3）和能够再生的表观遗传程序。对生物电信号、微生物群-脑相互作用和脂质介质的新兴研究进一步扩展了对系统的理解。总的来说，斑马鱼为解码脊椎动物中枢神经系统再生和指导治疗策略提供了一个统一的模型，以恢复人类神经修复。

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引用次数: 0

A multi-target therapeutic framework for Alzheimer’s disease: an integrative mechanistic review 阿尔茨海默病的多靶点治疗框架：综合机制综述。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-09 DOI: 10.1016/j.neuroscience.2026.01.010

Ousman Bajinka , Lamarana Jallow , Guven Ozdemir

Background: Alzheimer’s disease (AD) is increasingly recognized as a multifactorial network disorder in which amyloid and tau pathology interact with mitochondrial dysfunction, neuroinflammation, metabolic impairment, vascular dysregulation, and synaptic failure. This review provides an integrative, systems-level synthesis of these mechanisms with emphasis on diagnostic and therapeutic implications. Methods: A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Embase (2010–2025). Eligible studies included clinical trials, biomarker validation studies, cohort analyses, and mechanistic investigations. Evidence was synthesized by mechanistic domain with focus on cross-system interactions and translational relevance. Findings: Convergent data indicate that soluble Aβ species, tau propagation, glial dysregulation, insulin resistance, mitochondrial bioenergetic failure, lipid imbalance, and BBB dysfunction form a self-reinforcing neurodegenerative network. Diagnostic advances—including plasma p-tau181/217, Aβ42/40 ratio, GFAP, sTREM2, neuronal exosomes, and multimodal machine-learning models—enable earlier staging and refinement of therapeutic selection. Therapeutic development is shifting from linear amyloid removal to multi-target strategies incorporating anti-tau agents, glial-modulating compounds, metabolic and microbiome interventions, medical nutrition, and multidomain lifestyle programs. Across trials, combined strategies targeting interacting mechanisms demonstrate stronger biomarker and cognitive effects than single-axis approaches. Conclusions: AD management requires a systems-oriented therapeutic architecture in which interventions are selected based on mechanistic dominance, biomarker stage, and potential synergy. We outline a multi-target strategy integrating amyloid/tau modulation, neuroimmune regulation, metabolic-vascular stabilization, and synaptic support. Future work should prioritize biomarker-guided stratification, treatment sequencing, and prevention-oriented combination designs.

背景：阿尔茨海默病（AD）越来越被认为是一种多因子网络疾病，其中淀粉样蛋白和tau蛋白病理与线粒体功能障碍、神经炎症、代谢损伤、血管失调和突触衰竭相互作用。这篇综述提供了一个综合的，系统水平的综合这些机制，重点是诊断和治疗的意义。方法：使用PubMed、Scopus、Web of Science和Embase（2010-2025）进行结构化的叙述性综述。符合条件的研究包括临床试验、生物标志物验证研究、队列分析和机制调查。证据是由机械领域合成的，重点是跨系统的相互作用和翻译相关性。研究结果：趋同的数据表明，可溶性a β物种、tau增殖、胶质细胞失调、胰岛素抵抗、线粒体生物能量衰竭、脂质失衡和血脑屏障功能障碍形成了一个自我强化的神经退行性网络。诊断方面的进步——包括血浆p-tau181/217、a - β42/40比值、GFAP、sTREM2、神经元外泌体和多模态机器学习模型——使治疗选择的早期分期和细化成为可能。治疗发展正在从线性淀粉样蛋白去除转向多靶点策略，包括抗tau药物、神经胶质调节化合物、代谢和微生物组干预、医学营养和多领域生活方式计划。在所有试验中，针对相互作用机制的联合策略比单轴方法显示出更强的生物标志物和认知效果。结论：AD管理需要一个以系统为导向的治疗体系，其中干预措施的选择基于机制优势、生物标志物分期和潜在的协同作用。我们概述了一种整合淀粉样蛋白/tau调节、神经免疫调节、代谢血管稳定和突触支持的多靶点策略。未来的工作应优先考虑生物标志物引导的分层、治疗测序和预防导向的组合设计。

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引用次数: 0

Modulatory effects of genetic vs. pharmacological HCN4 channel inhibition on stimuli transmission during acute pain 急性疼痛时HCN4通道基因抑制与药理学抑制对刺激传递的调节作用。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-09 DOI: 10.1016/j.neuroscience.2026.01.011

Maximilian Häfele , Natalia K. Freus , Silke Kreitz , Maria Novella Romanelli , Andreas Ludwig , Isabel Wank , Andreas Hess

Acute pain processing emerges from complex interactions among multiple brain regions, with local ion channels critically shaping neuronal communication. To better understand the role of HCN4 channels during acute pain in mice, a genetic brain-specific HCN4-KO was compared with pharmacological inhibition by the selective HCN4 channel blocker EC18.

Stimulus-driven BOLD-fMRI measurements using graded peripheral thermal stimulation allowed brain-wide investigation of both discriminative and suppressive processes within ascending and descending pain pathways. Classical BOLD parameters and graph-theoretical analyses revealed that compared to controls, HCN4-KO showed a significant increase in brain activity in regions responsible for discriminative tasks, emotional pain processing and pain suppression including sensory cortex, amygdala and hypothalamus across both high and low thermal stimulation intensities. In striking contrast, acute inhibition of HCN4 with EC18 decreased activity in these same regions compared with both KO and control mice.

Furthermore, comparing pre- and post-stimulation resting-state measurements revealed that HCN4-KO and controls exhibited a stimulation-induced increase in functional connectivity, whereas EC18-treated mice demonstrated a connectivity decrease.

Taken together, genetic loss of HCN4 produced a hypersensitive phenotype in thermal pain processing, whereas acute pharmacological inhibition of the channel elicited an opposing hyposensitive phenotype.

急性疼痛处理出现在多个大脑区域之间复杂的相互作用中，局部离子通道对神经元的交流起着关键的作用。为了更好地了解HCN4通道在小鼠急性疼痛中的作用，将遗传脑特异性HCN4- ko与选择性HCN4通道阻滞剂EC18的药理抑制作用进行了比较。刺激驱动的BOLD-fMRI测量使用分级外周热刺激，可以对上升和下降疼痛通路中的辨别和抑制过程进行全脑调查。经典BOLD参数和图理论分析显示，与对照组相比，HCN4-KO在高强度和低强度热刺激下，大脑中负责判别任务、情绪疼痛处理和疼痛抑制的区域（包括感觉皮层、杏仁核和下丘脑）的活动显著增加。与此形成鲜明对比的是，与KO和对照小鼠相比，EC18对HCN4的急性抑制降低了这些区域的活性。此外，比较刺激前和刺激后的静息状态测量结果显示，HCN4-KO和对照组表现出刺激诱导的功能连接增加，而ec18处理的小鼠表现出连接减少。综上所述，HCN4基因缺失在热痛处理过程中产生了超敏表型，而该通道的急性药理抑制则引发了相反的低敏表型。

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引用次数: 0

The efficacy of combination therapy versus monotherapy in patients with glioblastoma with abnormal epidermal growth factor receptor (EGFR) genes, a systematic review and network meta-analysis 联合治疗与单药治疗对表皮生长因子受体（EGFR）基因异常的胶质母细胞瘤患者的疗效，系统综述和网络荟萃分析。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-08 DOI: 10.1016/j.neuroscience.2025.12.064

Liding Fan , Hao Wu , Yi Zhang , Bo Yu , Junjie Feng , Yuejiao Du , Xiaokai Yan , Luhao Che , Songbai Xu , Yanhua Li

The primary objective of this study is to evaluate the efficacy of various pharmaceuticals (combination therapy versus monotherapy) in patients with glioblastoma (GB) with abnormal epidermal growth factor receptor (EGFR) genes. Clinical trials to investigate the therapeutic effects of different therapy was searched by PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar. The Cochrane Risk of Bias Assessment Tool and data analysis software will be applied. Data collection spanned from the earliest available date up to April 2025. Eight studies involving a total of 2,137 individuals were included, with 657 of these receiving combination therapies and 1,480 receiving monotherapies. The analysis revealed that combination therapies generally demonstrated superior efficacy compared to the single ones, while monotherapies exhibited greater potency than temozolomide (TMZ). In terms of median progression-free survival (PFS), the combinations of Afatinib plus TMZ (SUCRA: 62.28%), rindopepimut (CDX-110) plus TMZ (SUCRA: 62.27%), and depatuxizumab mafodotin (Depatux M) plus TMZ (SUCRA: 54.4%) ranked among the top tier. For median overall survival (OS), the combinations of CDX-110 plus TMZ (SUCRA: 68.8%), Depatux M plus TMZ (SUCRA: 68.3%), and Nimotuzumab plus TMZ (SUCRA: 52.5%) were positioned in the upper echelon. In terms of prolonging both median PFS and median OS in GB, CDX-110 plus TMZ and Depatux M plus TMZ have shown slightly better than comparable therapies. However, further clinical trials are needed to confirm the effectiveness of other drugs in this respect.

本研究的主要目的是评估各种药物（联合治疗与单一治疗）对表皮生长因子受体（EGFR）基因异常的胶质母细胞瘤（GB）患者的疗效。通过PubMed， Embase, Web of Science， Cochrane Library和谷歌Scholar检索临床试验以研究不同疗法的治疗效果。应用Cochrane偏倚风险评估工具和数据分析软件。数据收集的时间跨度从最早的可用日期一直到2025年4月。8项研究共纳入2137人，其中657人接受联合治疗，1480人接受单一治疗。分析显示，与单一治疗相比，联合治疗通常表现出更好的疗效，而单一治疗表现出比替莫唑胺（TMZ）更强的效力。在中位无进展生存期（PFS）方面，Afatinib + TMZ （SUCRA: 62.28%）、rindopepimut (CDX-110) + TMZ （SUCRA: 62.27%）和depatuzumab mafodotin (Depatux M) + TMZ （SUCRA: 54.4%）的组合位居前列。在中位总生存期（OS）方面，CDX-110 + TMZ （SUCRA: 68.8%）、Depatux M + TMZ （SUCRA: 68.3%）和尼莫单抗+ TMZ （SUCRA: 52.5%）的组合处于较高水平。在延长GB患者的中位PFS和中位OS方面，CDX-110 + TMZ和Depatux M + TMZ的治疗效果略好于同类治疗。然而，需要进一步的临床试验来证实其他药物在这方面的有效性。

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引用次数: 0

Cross-fostering affects microglia and cell death in the hippocampus of female and male degu pups 交叉饲养对雌雄大鼠幼崽海马小胶质细胞和细胞死亡有影响。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-06 DOI: 10.1016/j.neuroscience.2026.01.004

Gurprince Attlas , Mallory Duprey , Cassandra Carlson , Kaja S. Arusha , Krystle D. Boadi , Sabrina S. Ellah , Daniela Kim , Charlis Raineki , Carolyn M. Bauer , Paula Duarte-Guterman

Parental care is essential for social, behavioural, and neural development of offspring. Disruption of parental care, for example through parental separation, can negatively affect offspring development in rodents. While previous work has focused on maternal and paternal deprivation, the effects of cross-fostering, another form of parental-offspring instability, on brain development remain poorly understood. Such disruptions are thought to induce stress, which in turn can suppress neurogenesis and increases inflammation and apoptosis in the hippocampus, with effects that often differ between sexes. Given that degus (Octodon degus) are born precocial and form strong attachments with their parents early in life, this study investigated the effect of cross-fostering on hippocampal development in female and male degu pups. At postnatal day 8, degus were assigned to either control (remaining with parents and littermates), partial cross-foster (one pup exchanged per litter), or full cross-foster (entire litter exchanged) conditions. At weaning (5-weeks-old), brains were collected for immunohistochemistry to examine dentate gyrus volume, pyknotic cell density, immature neuron density, and microglia number and morphology. Both types of cross-fostering reduced hippocampal cell death in both sexes relative to controls, with no significant effects on dentate gyrus volume or density of immature neurons. Cross-fostering did not affect total microglia density in either sex, however full cross-fostered females had fewer amoeboid microglia compared to female controls. These findings indicate that cross-fostering affects hippocampal microglia and cell death during development, potentially disrupting circuit refinement and plasticity, with effects that vary by cross-fostering type, sex, and hippocampal region.

亲代抚育对后代的社会、行为和神经发育至关重要。破坏亲代照顾，例如通过亲代分离，会对啮齿动物的后代发育产生负面影响。虽然之前的研究主要集中在父亲和母亲的剥夺上，但交叉抚养（另一种形式的父母与子女的不稳定）对大脑发育的影响仍然知之甚少。这种破坏被认为会引起压力，而压力反过来又会抑制神经发生，增加海马体中的炎症和细胞凋亡，其影响往往因性别而异。考虑到degu （degu）出生早熟，并且在生命早期就与父母形成强烈的依恋关系，本研究探讨了交叉抚养对雌性和雄性degu幼崽海马发育的影响。在出生后第8天，deg被分配到对照组（与父母和窝友呆在一起），部分交叉寄养（每窝换一只幼崽）或完全交叉寄养（整窝换一只幼崽）条件。断奶后（5周龄）采集大鼠脑进行免疫组化，检测齿状回体积、缩缩细胞密度、未成熟神经元密度、小胶质细胞数量和形态。与对照组相比，两种类型的交叉培养均减少了两性海马细胞死亡，但对齿状回体积或未成熟神经元密度没有显著影响。交叉培养不影响两性小胶质细胞的总密度，但完全交叉培养的雌性与雌性对照组相比，变形虫小胶质细胞较少。这些发现表明，交叉培养会影响发育过程中的海马小胶质细胞和细胞死亡，潜在地破坏回路的完善和可塑性，其影响因交叉培养的类型、性别和海马区域而异。

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引用次数: 0

Comprehensive analysis of spinal cord inflammatory factors in HIV Tat-induced neuropathy in mice HIV - tat诱导小鼠神经病变脊髓炎症因子的综合分析。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-06 DOI: 10.1016/j.neuroscience.2026.01.005

Ahmad Kohsar , Peter Wilson-Braun , Elizabeth N. Bean , Madison Philhower , Benjamin J. Harrison , Ling Cao

Despite advancements in HIV treatment, HIV neuropathy, caused by nerve damage following HIV infection, continues to be a major cause of morbidity. Inflammatory responses both in the central and peripheral nervous systems have been implicated as contributing mechanisms, but the role of the HIV protein Trans-Activator of Transcription (Tat) in HIV neuropathy is not well understood. In this study, we report the development of neuropathy-like behavioral changes in doxycycline-inducible HIV Tat transgenic (iTat) mice using comprehensive behavioral assessments. These changes include increased hind paw mechanical sensory sensitivities in both sexes, and increased cold sensitivity and reduced hind paw grip strength predominantly in females. Hind paw skin intra-epidermal nerve fiber (IENF) density showed a small but significant transient increase in the density of CGRP+ fibers at day 21 post-Tat induction in both sexes, while the recovery was faster in females. As Tat is induced primarily in the central nervous system in iTat mice, we therefore focused on elucidating central mechanisms by performing inflammation-targeted RNA profiling in lumbar spinal cord via NanoString assay followed by bioinformatic analysis to identify signaling pathways that may be responsible for the observed symptomatic changes. Three key signaling pathways − apoptosis, inflammation mediated by chemokine and cytokine, and Toll-like receptor signaling pathways − were identified. Subsequent qRT-PCR assays confirmed Tat-induced changes of selected genes. Altogether, we demonstrated that Tat induction is associated with sex-dependent neuropathy-like changes. The concurrent changes in selected inflammation-related signaling pathways within lumbar spinal cord shed light on potential underlying central mechanisms.

尽管艾滋病毒治疗取得了进展，但由艾滋病毒感染后神经损伤引起的艾滋病毒神经病变仍然是发病率的主要原因。中枢和外周神经系统的炎症反应被认为是促成机制，但HIV蛋白反式转录激活因子（Tat）在HIV神经病变中的作用尚不清楚。在这项研究中，我们使用综合行为评估报告了多西环素诱导的HIV Tat转基因（iTat）小鼠神经病变样行为变化的发展。这些变化包括两性后爪机械感觉敏感性的增加，以及冷敏感性的增加和后爪握力的减少，主要发生在雌性。后爪皮肤表皮内神经纤维（IENF）密度在诱导后第21天两性CGRP+纤维密度均有短暂性的小幅但显著的增加，雌性恢复较快。由于Tat主要在iTat小鼠的中枢神经系统中诱导，因此，我们将重点放在阐明中枢机制上，通过纳米串测定在腰椎脊髓中进行炎症靶向RNA分析，然后进行生物信息学分析，以确定可能导致观察到的症状变化的信号通路。三个关键的信号通路-细胞凋亡，炎症介导的趋化因子和细胞因子，和toll样受体信号通路-确定。随后的qRT-PCR分析证实了tat诱导的选定基因的变化。总之，我们证明了Tat诱导与性别依赖性神经性病变样改变有关。腰椎内炎症相关信号通路的同步变化揭示了潜在的中枢机制。

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引用次数: 0

Modulation of cofilin 1 phosphorylation induces juvenile-like plasticity in the adult mouse visual cortex 调节cofilin 1磷酸化诱导成年小鼠视觉皮层的青少年样可塑性。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-06 DOI: 10.1016/j.neuroscience.2026.01.003

Agustina Dapueto , Emilia Hayek , Alejo Acuña , Bruno Pannunzio , Leonel Gomez , Francesco M. Rossi

Cofilin 1 is an actin-depolymerizing protein that plays a fundamental role in actin dynamics, particularly within dendritic spines, where it has been implicated in both structural and functional plasticity. We recently demonstrated, using a combination of differential proteomics, western blot and immunohistochemistry, that the expression of cofilin 1 and its inactive phosphorylated form is dynamically regulated in the mouse visual cortex. Expression levels change across critical periods of postnatal development and are modulated by visual experience, suggesting that cofilin 1 plays a dynamic role in synaptic remodeling during windows of heightened cortical plasticity.

In this study, we sought to determine whether cofilin 1 influences experience-dependent plasticity in the adult visual cortex, a stage where plasticity is more restricted but still inducible under specific conditions. Specifically, we administered a synthetic peptide inhibitor of cofilin 1 activity in vivo (PCOF). Following monocular deprivation, adult mice received either the PCOF peptide or a control peptide. Structural plasticity was assessed by quantifying dendritic spine density using Golgi-like staining, while visual plasticity was evaluated by measuring visual acuity through the optomotor response test.

Our results show that, in adult mice treated with the PCOF peptide − but not in controls − monocular deprivation led to a significant reduction in dendritic spine density in the contralateral visual cortex, as well as a decrease in visual acuity of the previously deprived eye. These findings indicate that cofilin 1 activity is crucial for the regulation of experience-dependent plasticity in the adult mouse visual cortex.

Cofilin 1是一种肌动蛋白解聚蛋白，在肌动蛋白动力学中起着重要作用，特别是在树突棘中，它与结构和功能可塑性都有关系。我们最近通过结合差异蛋白质组学、western blot和免疫组织化学证明，cofilin 1及其无活性磷酸化形式的表达在小鼠视觉皮层中受到动态调节。在出生后发育的关键时期，cofilin 1的表达水平会发生变化，并受到视觉经验的调节，这表明在皮层可塑性增强的窗口期，cofilin 1在突触重塑中起着动态作用。在本研究中，我们试图确定cofilin 1是否会影响成人视觉皮层的经验依赖性可塑性，在这个阶段，可塑性受到更多限制，但在特定条件下仍可诱导。具体来说，我们在体内使用了合成的cofilin 1活性肽抑制剂（PCOF）。在单眼剥夺后，成年小鼠接受PCOF肽或对照肽。通过高尔基样染色定量树突棘密度评估结构可塑性，通过视动反应测试测量视力评估视觉可塑性。我们的研究结果表明，在接受PCOF肽治疗的成年小鼠（而不是对照组）中，单眼剥夺导致对侧视觉皮层树突棘密度显著降低，同时先前被剥夺的眼睛的视力也有所下降。这些发现表明，cofilin 1的活性对成年小鼠视觉皮层经验依赖性可塑性的调节至关重要。

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引用次数: 0

Tk2 deficiency–mediated mitochondrial dysfunction drives neuroinflammation and seizure frequency in epilepsy Tk2缺乏介导的线粒体功能障碍驱动癫痫患者的神经炎症和发作频率。

IF 2.8 3区医学 Q2 NEUROSCIENCES

Neuroscience

Pub Date : 2026-01-05 DOI: 10.1016/j.neuroscience.2026.01.001

Xi Zhang , Jiahao Lian , Yongbin Pang , Haohao Cui , Xiaobo Ye , Qiang Meng , Yong Liu , Huanfa Li , Yutao Ren , Ying Zhang , Hua Zhang , Hao Wu

Seizure frequency is a key indicator of disease severity and treatment response in epilepsy, yet its molecular determinants remain unclear. We performed proteomic profiling of resected epileptogenic brain tissue from patients, stratified by seizure frequency and by temporal versus extratemporal origin, and functionally validated candidate differentially expressed proteins (DEPs). Seizure foci of high and low frequencies in distinct brain regions displayed region-specific proteomic profiles. However, bioinformatic analyses of both temporal and extratemporal cohorts consistently showed that the down-regulated proteins converge on mitochondrial localization and function. Among these, mitochondrial thymidine kinase 2 (Tk2) exhibited a robust inverse correlation with seizure frequency, a finding confirmed in patient tissues across different frequency groups. Consistently, Tk2 expression was reduced across multiple brain regions in two seizure models induced by pilocarpine or ferric chloride. Mechanistically, loss of Tk2 activated the cGAS-STING pathway, upregulated inflammatory genes, and then increased seizure susceptibility. These findings identify Tk2 as a mitochondrial kinase that couples energetic failure to neuroinflammation, and provide a mechanistic basis for targeting the Tk2-mitochondria-inflammation axis in epilepsy.

癫痫发作频率是癫痫疾病严重程度和治疗反应的关键指标，但其分子决定因素尚不清楚。我们对患者切除的癫痫性脑组织进行了蛋白质组学分析，按癫痫发作频率和颞颞起源分层，并在功能上验证了候选差异表达蛋白（DEPs）。不同脑区的高、低频率癫痫发作灶显示区域特异性蛋白质组谱。然而，对时间和时间外队列的生物信息学分析一致表明，下调的蛋白质集中在线粒体定位和功能上。其中，线粒体胸苷激酶2 （Tk2）与癫痫发作频率呈显著负相关，这一发现在不同频率组的患者组织中得到证实。同样，在匹罗卡品或氯化铁诱导的两种癫痫发作模型中，Tk2在多个脑区表达减少。从机制上讲，Tk2的缺失激活了cGAS-STING通路，上调了炎症基因，然后增加了癫痫发作的易感性。这些发现确定了Tk2是一种线粒体激酶，将能量衰竭与神经炎症结合在一起，并为靶向癫痫患者的Tk2-线粒体-炎症轴提供了机制基础。

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引用次数: 0