Neurobiology of Disease最新文献_第9页

Corrigendum to “DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats” [Neurobiology of Disease 103 (2017) 133–143] 更正："DLK沉默通过JIP3/MA2K7/JNK通路减轻大鼠SAH后早期脑损伤中神经元的凋亡" [Neurobiology of Disease 103 (2017) 133-143]。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106712

Cheng Yin , Guang-fu Huang , Xiao-chuan Sun , Zongduo Guo , John H. Zhang

引用次数: 0

Specific analysis of SOD1 enzymatic activity in CSF from ALS patients with and without SOD1 mutations 对有和没有 SOD1 基因突变的 ALS 患者 CSF 中的 SOD1 酶活性进行特异性分析。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106718

Laura Leykam , Karin M.E. Forsberg , Ulrika Nordström , Karin Hjertkvist , Agneta Öberg , Eva Jonsson , Peter M. Andersen , Stefan L. Marklund , Per Zetterström

Mutations in superoxide dismutase-1 (SOD1) are a cause of hereditary amyotrophic lateral sclerosis (ALS) through a gain-of-function mechanism involving unfolded mutant SOD1. Intrathecal gene therapy using the antisense-oligo-nucleotide drug tofersen to reduce SOD1 expression delays disease progression and has recently been approved in the United States and the European Union. However, the discovery of children homozygous for inactivating SOD1 mutations developing the SOD1 Deficiency Syndrome (ISODDES) with injury to the motor system suggests that a too low SOD1 antioxidant activity may be deleterious in humans. Measuring SOD1 activity in cerebrospinal fluid (CSF) in tofersen-treated patients is recommended but difficult due to low concentration and the presence of the isoenzyme SOD3. We here present a sensitive method to assess SOD1 activity by removing SOD3 from CSF samples using highly specific immobilized antibodies and subsequent measurement of the SOD activity. We validated the method on 171 CSF samples from ALS patients with and without mutations and controls and used paired erythrocyte samples for comparison. We found that in ALS patients with wildtype SOD1, the SOD1 activity in CSF was equal to controls, but patients with mutant SOD1 show lower activity in CSF, even for patients with mutants previously reported to have full activity in erythrocytes. Activity variation in CSF was large among patients carrying the same SOD1 mutation and larger than in erythrocytes and in post-mortem nervous tissue. Additionally, we identified a discrepancy between the SOD1 activity and protein level measured with ELISA in both CSF and erythrocytes. Since antibodies used for SOD1 ELISA-quantification are raised against the natively folded wildtype SOD1, the concentration of mutant SOD1s may be underestimated. Analysis of SOD1 enzymatic activity in CSF is therefore a more reliable way to monitor the effect of SOD1-lowering drugs.

超氧化物歧化酶-1（SOD1）的突变是导致遗传性肌萎缩性脊髓侧索硬化症（ALS）的原因之一，其功能增益机制涉及未折叠的突变 SOD1。使用反义寡核苷酸药物托福森（tofersen）减少 SOD1 表达的鞘内基因疗法可延缓疾病进展，最近已在美国和欧盟获得批准。然而，发现同源SOD1失活突变的儿童会出现SOD1缺乏综合症（ISODDES），并对运动系统造成损伤，这表明SOD1抗氧化活性过低可能对人体有害。我们建议测量接受托福森治疗的患者脑脊液（CSF）中的 SOD1 活性，但由于其浓度较低且存在同工酶 SOD3，测量难度很大。我们在此介绍一种评估 SOD1 活性的灵敏方法，即使用高特异性固定抗体去除 CSF 样品中的 SOD3，然后测量 SOD 活性。我们在 171 份有突变和无突变的 ALS 患者以及对照组的 CSF 样本上验证了该方法，并使用配对的红细胞样本进行比较。我们发现，具有野生型 SOD1 的 ALS 患者 CSF 中的 SOD1 活性与对照组相同，但具有突变型 SOD1 的患者 CSF 中的 SOD1 活性较低，即使是以前报道过在红细胞中具有完全活性的突变型患者也是如此。携带相同 SOD1 基因突变的患者脑脊液中的活性差异很大，比红细胞和死后神经组织中的活性差异更大。此外，我们还发现在脑脊液和红细胞中用酶联免疫吸附法测得的 SOD1 活性和蛋白质水平之间存在差异。由于用于 SOD1 酶联免疫吸附测定的抗体是针对原生折叠的野生型 SOD1 的，因此突变型 SOD1 的浓度可能被低估。因此，分析 CSF 中的 SOD1 酶活性是监测降低 SOD1 药物效果的更可靠方法。

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引用次数: 0

Neuronal ACE1 knockout disrupts the hippocampal renin angiotensin system leading to memory impairment and vascular loss in normal aging 神经元 ACE1 基因敲除会破坏海马肾素血管紧张素系统，导致正常衰老过程中的记忆损伤和血管损失。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106729

Sohee Jeon , Miranda A. Salvo , Alia O. Alia , Jelena Popovic , Mitchell Zagardo , Sidhanth Chandra , Malik Nassan , David Gate , Robert Vassar , Leah K. Cuddy

Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I into angiotensin II in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression of RAS genes in the hippocampus and discovered that Ace is mostly expressed in CA1 region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE1 cKO mice exhibited age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE1 and cerebrovascular function in the hippocampus.

血管紧张素 I 转换酶（ACE1）通过在肾素-血管紧张素系统（RAS）中将血管紧张素 I 转换为血管紧张素 II 来维持血压平衡。ACE1 在大脑中表达，大脑中的固有 RAS 调节着复杂的认知功能，包括学习和记忆。ACE1 与包括阿尔茨海默病和帕金森病在内的神经退行性疾病有牵连，但其机制仍不完全清楚。在这里，我们进行了单核 RNA 测序，以确定海马中 RAS 基因的表达特征，并发现 Ace 主要在 CA1 区兴奋性神经元中表达。为了更深入地了解神经元 ACE1 的功能，我们产生了 ACE1 条件性基因敲除（cKO）小鼠，这些小鼠特异性地在海马和皮层兴奋神经元中缺乏 ACE1 的表达。ACE1 cKO小鼠在莫里斯水迷宫、Y迷宫和恐惧条件反射测试中表现出海马依赖性记忆损伤。ACE1 cKO 小鼠大脑皮层和海马中的 ACE1 总含量明显降低，这表明兴奋性神经元是前脑中表达 ACE1 的主要细胞类型。尽管海马和大脑皮层中的 ACE1 总含量都有类似的降低，但只有海马的 RAS 通路出现了失调。重要的是，ACE1 cKO 小鼠选择性地在海马表现出与年龄相关的毛细血管缺失。在这里，我们展示了海马微血管和 RAS 通路对神经元 ACE1 基因敲除的选择性脆弱性。我们的研究结果为了解 ACE1 在大脑中的功能提供了重要见解，并证明了神经元 ACE1 与海马脑血管功能之间的联系。

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引用次数: 0

3D mapping of direct VTA-CA2 circuit with potential involvement in Parkinson's disease degeneration 可能与帕金森病变性有关的 VTA-CA2 直接回路三维绘图。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106723

Michael Siu-Lun Lai , Maja Højvang Sørensen , Krit Lee , John Man-Tak Chu , Raymond Chuen-Chung Chang

Parkinson's disease dementia (PDD) is commonly developed in patients at the late stage of Parkinson's disease (PD) with unknown progression mechanisms. From the post-mortem tissues and animal models, the ventral tegmental area (VTA) and the CA2 regions are closely associated with dementia development in PDD. However, the structural connection between the two regions has not been fully traced. In this study, we applied tissue clearing and adeno-associated virus (AAV) tracing to map the neural circuits in a 3D manner. Hence, we have confirmed the direct connection between the regions with two dual AAV tracing systems and traced the VTA-CA2 circuit in 3D reconstruction. With the immunostaining, we have shown that the GABAergic neurons are the potential subtype of the postsynaptic CA2 neurons in the VTA-CA2 circuit. Under the 6-hydroxydopamine (6-OHDA), we have demonstrated the degeneration of the VTA-CA2 circuit from the observation of fragmented axonal projections. Collectively, we have first traced the direct connection of the whole VTA-CA2 circuit in an intact 3D manner and monitored the fragmentation of this target circuit in the 6-OHDA model. This VTA-CA2 circuit can be a target for future studies of the pathological spreading and degeneration mechanism from PD to PDD.

帕金森病痴呆症（PDD）常见于帕金森病（PD）晚期患者，其发展机制不明。从尸体组织和动物模型来看，腹侧被盖区（VTA）和CA2区与帕金森病痴呆的发生密切相关。然而，这两个区域之间的结构联系尚未被完全追溯。在这项研究中，我们采用组织清除和腺相关病毒（AAV）追踪技术，以三维方式绘制了神经回路图。因此，我们通过两个双 AAV 追踪系统确认了两个区域之间的直接联系，并以三维重建的方式追踪了 VTA-CA2 回路。免疫染色表明，GABA能神经元是VTA-CA2回路中突触后CA2神经元的潜在亚型。在6-羟基多巴胺（6-OHDA）作用下，我们通过观察支离破碎的轴突投射证明了VTA-CA2的退化。总之，我们首次以完整的三维方式追踪了整个VTA-CA2回路的直接连接，并在6-OHDA模型中监测了这一目标回路的碎裂。这一VTA-CA2回路可作为未来研究从PD到PDD病理扩散和变性机制的目标。

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引用次数: 0

The role of adiponectin-AMPK axis in TDP-43 mislocalization and disease severity in ALS 脂肪蛋白-AMPK 轴在 TDP-43 错位和 ALS 疾病严重程度中的作用

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106715

Yu-Ju Liu , Chia-Wei Lee , Yi-Chu Liao , Joseph Jen-Tse Huang , Hung-Chih Kuo , Kang-Yang Jih , Yi-Chung Lee , Yijuang Chern

Hypermetabolism is a prominent characteristic of ALS patients. Aberrant activation of AMPK, an energy sensor regulated by adiponectin, is known to cause TDP-43 mislocalization, an early event in ALS pathogenesis. This study aims to evaluate the association between key energy mediators and clinical severity in ALS patients. We found that plasma adiponectin levels were significantly higher in ALS patients with ALSFRS-R scores below 38 compared to controls (p = 0.047). Additionally, adiponectin concentration was inversely correlated with ALSFRS-R scores (p = 0.021). Immunofluorescence staining of PBMCs revealed negative associations between AMPK activation, TDP-43 mislocalization, and ALSFRS-R scores. We then examined the hypothesis that adiponectin may activate the AMPK-TDP-43 axis in motor neurons. Our results demonstrated that adiponectin treatment of NSC34 cells and HiPSC-MNs induced AMPK activation and TDP-43 mislocalization in an adiponectin receptor-dependent manner. Collectively, these findings suggest that elevated plasma adiponectin may enhance AMPK activation, leading to TDP-43 mislocalization in both PBMCs and motor neurons of ALS patients. This highlights the potential involvement of the adiponectin-AMPK-TDP-43 axis in the dysregulated energy balance observed in ALS.

高代谢是渐冻症患者的一个显著特征。众所周知，AMPK（一种由脂肪连蛋白调控的能量传感器）的异常激活会导致 TDP-43 错位，而 TDP-43 错位是 ALS 发病机制中的早期事件。本研究旨在评估 ALS 患者关键能量介质与临床严重程度之间的关联。我们发现，与对照组相比，ALSFRS-R 评分低于 38 分的 ALS 患者血浆中的脂肪连素水平明显更高（p = 0.047）。此外，脂联素浓度与 ALSFRS-R 评分成反比（p = 0.021）。PBMC 的免疫荧光染色显示，AMPK 激活、TDP-43 错定位和 ALSFRS-R 评分之间存在负相关。我们随后研究了脂肪素可能激活运动神经元中 AMPK-TDP-43 轴的假设。我们的研究结果表明，对 NSC34 细胞和 HiPSC-MNs 进行脂肪连接素处理可诱导 AMPK 激活，并以脂肪连接素受体依赖的方式诱导 TDP-43 错位。总之，这些研究结果表明，血浆中脂联素的升高可能会增强 AMPK 的激活，从而导致 TDP-43 在 ALS 患者的 PBMCs 和运动神经元中的错位。这凸显了脂肪连接素-AMPK-TDP-43轴可能参与了渐冻症患者能量平衡失调的过程。

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引用次数: 0

The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases 神经退行性疾病中的 cGAS-STING 通路通过细胞和分子机制驱动神经炎症和神经退行性病变

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106710

Yuxin Zhang , Meijuan Zou , Hao Wu , Jie Zhu , Tao Jin

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.

神经退行性疾病（NDs）是一种常见的慢性进行性疾病，其特征是神经系统中的特定细胞群逐渐受损，最终导致残疾或死亡。这些疾病的病因涉及多种细胞和分子途径，由于对病因的了解有限，目前仍缺乏有效的治疗方法。引发免疫反应是神经退行性疾病的一个共同特征。神经炎症、神经退行性病变和免疫反应之间错综复杂的相互作用是一个严峻的挑战，而这些因素的特征尚未完全确定。近年来，环GMP-AMP合成酶（cGAS）-干扰素基因刺激器（STING）通路逐渐受到关注，它是细胞内DNA感应的关键免疫反应。然而，该通路在免疫细胞、神经胶质细胞和神经元细胞等细胞类型中的具体作用及其对 ND 发病机制的贡献仍未完全阐明。在这篇综述中，我们系统地探讨了 cGAS-STING 信号如何在 ND 的背景下将各种细胞类型与相关的细胞效应通路联系起来，从而为多方面的治疗指明方向。我们强调了在 cGAS-STING 通路中发现的条件依赖性细胞异质性，这对于理解不同的细胞反应和潜在的治疗靶点是不可或缺的。此外，我们还回顾了 cGAS-STING 激活在帕金森病、共济失调性脊髓侧索硬化症和肌萎缩侧索硬化症中的致病作用。我们重点研究了 cGAS-STING 通路在阿尔茨海默病、亨廷顿氏病和多发性硬化症中复杂的双向作用，揭示了其在疾病进展中的双刃性。本综述旨在阐明 cGAS-STING 通路在 ND 发病机制中的关键作用，并为促进新型治疗策略的开发提供新的见解。

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引用次数: 0

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2 家族性偏瘫偏头痛 2 型新型小鼠皮层下的自发扩散性去极化。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106714

Nico A. Jansen , Chelsey Linnenbank , Maarten Schenke , Rob A. Voskuyl , Maria S. Jorge , Georgii Krivoshein , Cor Breukel , Margot M. Linssen , Jill W.C. Claassens , Conny Brouwers , Sandra H. van Heiningen , Anders Heuck , Karin Lykke-Hartmann , Else A. Tolner , Arn M.J.M. van den Maagdenberg

The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na⁺/K⁺ adenosine triphosphatase pump (Atp1a2^T345A). Homozygous Atp1a2^T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2^T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2^T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.

由于缺乏自发发生的疾病模型，人们对扩散性去极化（SD）的启动机制研究不足。我们在这里展示了一种新型家族性偏瘫偏头痛2型（FHM2）小鼠模型，该模型表达了Na+/K+腺苷三磷酸酶泵（Atp1a2T345A）α2亚基的错义T345A突变。高通量 Atp1a2T345A 小鼠表现出有规律的自发 SD，这种 SD 表现出昼夜节律，通常源自海马。杂合子 Atp1a2T345A 小鼠很少表现出自发 SD，而且在电诱导 SD 时，仅表现出传播速度增加，而同合子则表现出传播速度增加和阈值降低。值得注意的是，尽管海马兴奋性过高，Atp1a2T345A小鼠的自发性SD只在极少数情况下与癫痫行为有关，而且在点燃过程中癫痫发作表现减少。自发性SD可通过调节持续性钠电流来预防。海马SD在NMDA受体拮抗剂存在的情况下发生，但这些事件并没有到达皮层，这表明SD的启动和传播在该模型中依赖于不同的机制。

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引用次数: 0

Diagnostic and mechanistic roles of MicroRNAs in neurodevelopmental & neurodegenerative disorders MicroRNA 在神经发育和神经退行性疾病中的诊断和机理作用。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106717

Mohamed Adil Shah Khoodoruth , Widaad Nuzhah Chut-kai Khoodoruth , Maira Uroos , Majid Al-Abdulla , Yasser Saeed Khan , Farhan Mohammad

MicroRNAs (miRNAs) are emerging as crucial elements in the regulation of gene expression, playing a significant role in the underlying neurobiology of a wide range of neuropsychiatric disorders. This review examines the intricate involvement of miRNAs in neuropsychiatric disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Fragile X syndrome (FXS), autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), schizophrenia (SCZ), and mood disorders. This review highlights how miRNA dysregulation can illuminate the molecular pathways of these diseases and potentially serve as biomarkers for early diagnosis and prognosis. Specifically, miRNAs' ability to target genes critical to the pathology of neurodegenerative diseases, their role in the development of trinucleotide repeat and neurodevelopmental disorders, and their distinctive patterns in SCZ and mood disorders are discussed. The review also stresses the value of miRNAs in precision neuropsychiatry, where they could predict treatment outcomes and aid in disease management. Furthermore, the study of conserved miRNAs in model organisms like Drosophila underscores their broad utility and provides deeper mechanistic insights into their biological functions. This comprehensive examination of miRNAs across various conditions advocates for their integration into clinical practice, promising advancements in personalized healthcare for neurological and psychiatric conditions.

微RNA（miRNA）正在成为调控基因表达的关键因素，在多种神经精神疾病的潜在神经生物学中发挥着重要作用。本综述探讨了 miRNA 在神经精神疾病中的复杂参与，如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）、脆性 X 综合征（FXS）、自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）、抽动秽语综合征（TS）、精神分裂症（SCZ）和情绪障碍。这篇综述重点介绍了 miRNA 失调如何阐明这些疾病的分子途径，并有可能成为早期诊断和预后的生物标志物。具体来说，本综述讨论了 miRNA 靶向神经退行性疾病病理学关键基因的能力、它们在三核苷酸重复和神经发育障碍发展过程中的作用，以及它们在 SCZ 和情绪障碍中的独特模式。综述还强调了 miRNA 在精准神经精神病学中的价值，因为它们可以预测治疗结果并帮助疾病管理。此外，对果蝇等模式生物中保守的 miRNAs 的研究强调了它们的广泛用途，并提供了对其生物学功能的更深入的机理认识。通过对不同病症的 miRNA 进行全面研究，倡导将 miRNA 与临床实践相结合，为神经和精神疾病的个性化医疗带来希望。

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引用次数: 0

Differential induction of Parieto-motor plasticity in writer's cramp and cervical dystonia 作家痉挛和颈肌张力障碍对副运动可塑性的不同诱导作用

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106724

Hyun Joo Cho , Hae-Won Shin , Pattamon Panyakaew , Panagiotis Kassavetis , Traian Popa , Tianxia Wu , Giorgio Leodori , Terance Camacho , Shivangi Singh , Sabine Meunier , Mark Hallett

Objectives

To investigate the plastic effects of parieto-motor (PAR-MOT) cortico-cortical paired associative paired stimulation (cc-PAS) in patients with two forms of focal dystonia, writer's cramp and cervical dystonia, compared to healthy volunteers (HVs).

Methods

We used cc-PAS to induce associative plasticity using repeated time-locked paired transcranial magnetic stimulation (TMS) pulses over the parietal and motor cortices in 16 patients with writer's cramp (WC), 13 patients with cervical dystonia (CD), and 23 healthy volunteers. We measured parieto-motor corticocortical connectivity using posterior parietal cortex (PPC) to primary motor cortex (M1) facilitation and input-output curves (IOC) of the motor-evoked potential (MEP) before and after PAR-MOT cc-PAS. The PAR-MOT cc-PAS consisted of 100 pairs of TMS pulses every 5 s, with the conditioning pulse applied to the left angular gyrus in the intraparietal sulcus and the test pulse applied to the M1 hotspot of the first dorsal interosseous muscle.

Results

The cc-PAS increased the area under the IOC by increasing its maximum level in patients with WC but not in patients with CD or healthy volunteers. The cc-PAS had no significant effect on other IOC parameters. There were no significant differences in PPC to M1 facilitation changes after PAR-MOT cc-PAS among all groups.

Conclusions

This study suggests that PAR-MOT cc-PAS abnormally increases M1 excitability in patients with WC but not in those with CD. Additionally, this increased plastic response in patients with WC does not appear to be directly linked to PPC to M1 corticocortical connectivity.

研究目的研究顶叶-运动（PAR-MOT）皮层-皮层成对联想刺激（cc-PAS）对两种局灶性肌张力障碍（作家痉挛和颈性肌张力障碍）患者与健康志愿者（HVs）的可塑性影响：我们使用cc-PAS对16名写作痉挛（WC）患者、13名颈肌张力障碍（CD）患者和23名健康志愿者的顶叶和运动皮层进行重复锁时配对经颅磁刺激（TMS）脉冲，诱导他们产生联想可塑性。在 PAR-MOT cc-PAS 之前和之后，我们使用顶叶后皮层（PPC）到初级运动皮层（M1）的促进作用和运动诱发电位（MEP）的输入-输出曲线（IOC）测量了顶叶-运动皮层的连通性。PAR-MOT cc-PAS由100对TMS脉冲组成，每5秒一次，调节脉冲作用于顶内沟左侧角回，测试脉冲作用于第一背侧骨间肌的M1热点：cc-PAS增加了WC患者的IOC下面积，提高了其最大值，但对CD患者或健康志愿者没有影响。cc-PAS对其他IOC参数没有明显影响。PAR-MOT cc-PAS后，PPC对M1的促进作用在各组间无明显差异：本研究表明，PAR-MOT cc-PAS 会异常增加 WC 患者的 M1 兴奋性，但 CD 患者不会。此外，WC 患者的这种可塑性反应的增加似乎与 PAR-MOT cc-PAS 与 M1 皮层连接没有直接联系。

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引用次数: 0

Cognitive impairments and neurobiological changes induced by unilateral vestibular dysfunction in mice 单侧前庭功能障碍诱发的小鼠认知障碍和神经生物学变化

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2024-11-01 DOI: 10.1016/j.nbd.2024.106719

Zhanghong Zhou , E. Tian , Jun Wang , Zhaoqi Guo , Jingyu Chen , Jiaqi Guo , Shiyu Shi , Wandi Xu , Xixi Yu , Caijuan Qiao , Yuejin Zhang , Yisheng Lu , Sulin Zhang

The vestibular system is essential for balance and spatial orientation, and its dysfunction can lead to cognitive deficits. This study investigates the effects of unilateral vestibular dysfunction (UVL) on cognitive function and the underlying neurobiological changes in mice. We established a unilateral labyrinthectomy (UL) model in mice and assessed cognitive function at 28 days post-surgery using a comprehensive battery of behavioral tests. We found significant impairments in spatial reference memory, working memory, and synaptic plasticity in UL mice, which persisted despite compensation for vestibular and postural motor deficits. Immunofluorescence staining revealed enhanced activation of c-Fos in the hippocampal dentate gyrus (DG) at various time points post-UL, suggesting a role of the hippocampus in cognitive deficits following UVL. RNA sequencing of the DG identified differentially expressed genes (DEGs) and altered pathways related to cognitive function, synaptic plasticity, and neuronal activation. Quantitative real-time PCR (qRT-PCR) validated the expression changes of selected genes. Our findings indicate that UVL leads to persistent cognitive impairments in mice, associated with altered neuronal activation and gene expression in the hippocampus. This study offers valuable insights into the neurobiological mechanisms underlying cognitive deficits associated with UVL. Moreover, it underscores the importance of early cognitive screening in patients with vestibular diseases, as this approach is instrumental in comprehensive condition assessment, precise diagnosis, targeted treatment, and effective rehabilitation.

前庭系统对平衡和空间定向至关重要，其功能障碍可导致认知障碍。本研究探讨了单侧前庭功能障碍（UVL）对小鼠认知功能的影响及其潜在的神经生物学变化。我们在小鼠体内建立了单侧迷路切除术（UL）模型，并在术后 28 天使用一系列综合行为测试来评估小鼠的认知功能。我们发现，UL 小鼠的空间参照记忆、工作记忆和突触可塑性都有明显的损伤，尽管前庭和姿势运动障碍得到了补偿，但这些损伤依然存在。免疫荧光染色显示，在UL后的不同时间点，海马齿状回（DG）中的c-Fos活化增强，这表明海马在UVL后的认知障碍中发挥了作用。海马齿状回的 RNA 测序确定了与认知功能、突触可塑性和神经元激活相关的差异表达基因（DEGs）和改变的通路。定量实时 PCR（qRT-PCR）验证了所选基因的表达变化。我们的研究结果表明，UVL会导致小鼠出现持续性认知障碍，这与海马中神经元激活和基因表达的改变有关。这项研究为了解 UVL 相关认知缺陷的神经生物学机制提供了宝贵的见解。此外，它还强调了对前庭疾病患者进行早期认知筛查的重要性，因为这种方法有助于全面的病情评估、精确诊断、针对性治疗和有效康复。

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