Neurobiology of Disease最新文献_第9页

Nuclear ASC speck formation in microglia is associated with inflammasome priming and is exacerbated in LRRK2-G2019S Parkinson's disease 小胶质细胞核ASC斑点形成与炎症小体启动相关，并在LRRK2-G2019S帕金森病中加剧。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107237

Luca Ballotto , Thomas Baratta , Helena Winterberg , Cédric Dusanter , Sara Sambin , Jean Christophe Corvol , Ludovica Iovino , Luigi Bubacco , Olga Corti , Elisa Greggio , Salvatore Novello

Neuroinflammation is increasingly recognized as a central pathological mechanism in Parkinson's disease (PD), a progressive neurodegenerative disorder marked by dopaminergic neuron loss and diverse motor and non-motor symptoms. The NLRP3 inflammasome and its adaptor protein ASC are critical to initiating and sustaining inflammatory responses in the central nervous system. Although acute inflammasome activation supports host defence responses, chronic activation has been linked to the pathogenesis of PD. Increasing evidence indicates that mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2), particularly the PD-associated G2019S mutation, enhance inflammatory signalling in microglia and peripheral immune cells. However, how LRRK2 intersects with the NLRP3 pathway remains unclear. Here, we investigate the role of LRRK2-G2019S in the priming and activation of the inflammasome in mouse primary microglia and human monocyte-derived microglia-like cells (hMDMi). Under unstimulated conditions, LRRK2-G2019S microglia displayed elevated NLRP3 expression and spontaneous formation of ASC specks within the nucleus, a subcellular localization not previously reported in microglia. Nuclear ASC specks also emerged in Wild Type microglia and hMDMi after lipopolysaccharide priming, but progressed to cytosolic ASC specks and IL-1β release only after canonical activation of NLRP3. These findings suggest that nuclear ASC specks mark a primed state of inflammasome activation in microglia. The LRRK2-G2019S mutation enhances this phenotype, potentially predisposing microglia to exaggerated inflammatory responses. This work identifies a novel cellular feature associated with PD-linked LRRK2 and uncovers a previously unrecognized layer of inflammasome regulation in microglia, offering new avenues to understand and target neuroinflammation in PD.

神经炎症越来越被认为是帕金森病（PD）的中心病理机制，帕金森病是一种进行性神经退行性疾病，以多巴胺能神经元丧失和多种运动和非运动症状为特征。NLRP3炎症小体及其适配蛋白ASC对中枢神经系统炎症反应的启动和维持至关重要。尽管急性炎性小体激活支持宿主防御反应，但慢性激活与帕金森病的发病机制有关。越来越多的证据表明，富含亮氨酸重复激酶2 （LRRK2）的突变，特别是pd相关的G2019S突变，增强了小胶质细胞和外周免疫细胞的炎症信号传导。然而，LRRK2如何与NLRP3通路相交仍不清楚。在这里，我们研究了LRRK2-G2019S在小鼠原代小胶质细胞和人单核细胞源性小胶质样细胞（hMDMi）中炎症小体的启动和激活中的作用。在非刺激条件下，LRRK2-G2019S小胶质细胞显示NLRP3表达升高，核内自发形成ASC斑点，这是以前未在小胶质细胞中报道的亚细胞定位。在脂多糖引发后，野生型小胶质细胞和hMDMi中也出现了核ASC斑点，但只有在NLRP3的典型激活后，才发展为细胞质ASC斑点和IL-1β释放。这些发现表明核ASC斑点标志着小胶质细胞炎症小体激活的启动状态。LRRK2-G2019S突变增强了这种表型，可能使小胶质细胞容易产生夸大的炎症反应。这项工作确定了与PD相关的LRRK2相关的一个新的细胞特征，并揭示了小胶质细胞中一个以前未被识别的炎性体调节层，为理解和靶向PD中的神经炎症提供了新的途径。

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引用次数: 0

Diabetes increases SCO-spondin secretion but reduces Wnt5a interaction with ependymal cells, inducing ciliary stiffness and Frizzled-2 downregulation 糖尿病增加SCO-spondin分泌，但减少Wnt5a与室管膜细胞的相互作用，诱导纤毛僵硬和frizzed -2下调。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107225

Manuel Cifuentes , Eder Ramírez , María José Barahona , Fernando Martínez , Isabelle de Lima , Luciano Ferrada , Romina Bertinat , Felipe Ávila , Natalia Saldivia , Margarita Pérez-Martín , Begoña Oliver-Martin , Nicolás Ciano-Petersen , María del Mar Fernández-Arjona , Katterine Salazar , Francisco Nualart

Diabetes is a chronic metabolic disorder with systemic complications. Hyperglycemia damages multiple organs, including the brain, increasing the risks of stroke, dementia, and oxidative stress. Diabetes is also linked to ventricular enlargement in the human brain. Here, we examine how diabetes alters the secretion of subcommissural organ spondin (SCO-spondin) and Wnt5a by SCO cells, which subsequently affects ependymal ciliary beating and cerebrospinal fluid (CSF) circulation. Under diabetic conditions, SCO-spondin secretion by SCO cells increased. CSF-borne SCO-spondin was observed interacting with ependymal cilia, which showed increased stiffness. Control SCO cells were Wnt5a-positive, indicating active biosynthesis and secretion; in contrast, Wnt5a immunostaining was negative under diabetic conditions, and its interaction with ependymal cells decreased. Additionally, the Wnt5a receptor Frizzled-2 and the proteoglycan testican, essential for Wnt5a–receptor engagement, were not detected in ependymal cells during diabetes. To further explore downstream changes, we examined aquaporin-4 (AQP4) in control and diabetic samples and found condition-dependent differences in its subcellular distribution within ependymal cells. Accordingly, peri-ependymal edema and periventricular lucency were observed. Conversely, GLUT1, MCT2, and Cx-43 remained unchanged, suggesting that diabetes selectively modifies specific ependymal properties. Proteomic analysis of CSF from diabetic patients confirmed the presence of spondin-1 and thrombospondins, which may replace SCO-spondin in humans. Overall, these findings support a model where increased SCO-spondin release and decreased Wnt5a-Frizzled-2–testican signaling in ependymal cells promote ciliary stiffening and periventricular edema in the diabetic brain.

糖尿病是一种具有全身并发症的慢性代谢紊乱。高血糖会损害包括大脑在内的多个器官，增加中风、痴呆和氧化应激的风险。糖尿病还与人类大脑的心室增大有关。在这里，我们研究了糖尿病如何改变SCO细胞的关节下器官spondin （SCO-spondin）和Wnt5a的分泌，从而影响室管膜纤毛跳动和脑脊液（CSF）循环。在糖尿病条件下，SCO细胞分泌的SCO-spondin增加。观察到csf携带的SCO-spondin与室管膜纤毛相互作用，其硬度增加。对照SCO细胞wnt5a阳性，表明生物合成和分泌活跃；相比之下，糖尿病患者的Wnt5a免疫染色为阴性，其与室管膜细胞的相互作用减弱。此外，糖尿病患者室管膜细胞中未检测到Wnt5a受体frizzled2和蛋白聚糖睾丸，这是Wnt5a受体结合所必需的。为了进一步探索下游的变化，我们检测了对照和糖尿病样本中的水通道蛋白-4 (AQP4)，发现其在室管膜细胞内的亚细胞分布存在条件依赖性差异。相应的，室管膜周围水肿和室室周围透光。相反，GLUT1、MCT2和Cx-43保持不变，表明糖尿病选择性地改变了特定的室管膜特性。糖尿病患者脑脊液的蛋白质组学分析证实了spondin-1和血栓反应蛋白的存在，它们可能取代人类的SCO-spondin。总的来说，这些发现支持一个模型，即室管膜细胞中SCO-spondin释放增加和wnt5a - frizzled2 -testican信号减少可促进糖尿病脑纤毛硬化和心室周围水肿。

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引用次数: 0

Memory-guided saccade latency as a potential biomarker for axial symptoms and freezing of gait in Parkinson's disease 记忆引导的扫视潜伏期作为帕金森病轴向症状和步态冻结的潜在生物标志物

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107238

Miao Wang , Yifan Li , Jiarui Yao , Wuji Zhao , Chunyu Yin , Junru Wu , Jiao Zhao , Wei Wang , Mingsha Zhang , Zhenfu Wang , Xi Yin , Xuemei Li , Zhongbao Gao

Background

Freezing of gait (FOG), a debilitating axial symptom of Parkinson's disease (PD), lacks objective detection methods. While antisaccade (AS) latency prolongation correlates with FOG, the more complex memory-guided saccade (MGS), which requires multistage motor sequence integration (a proposed FOG mechanism), remains unexplored in FOG.

Methods

We assessed prosaccade (PS), AS, and MGS via infrared eye tracking in 75 PD patients (25 with FOG [PD-FOG], 50 without FOG [PD-nFOG]) and 75 healthy controls (HCs). The clinical assessments included the MDS-UPDRS III, the NFOG-Q, and cognitive/affective scales. Group differences were analyzed using appropriate comparative tests. Spearman's rank correlation was employed to examine associations between the saccade metrics and demographics/clinical features. Multivariate logistic regression was used to identify saccade metrics and demographics/clinical features associated with FOG.

Results

Compared to PD-nFOG patients and HCs, PD-FOG patients presented significantly prolonged MGS latency (p < 0.001) but not PS or AS latency. MGS latency showed the strongest correlation with axial symptoms [ρ = 0.494, p (FDR) < 0.01], remaining significant after adjusting for confounders (ρ = 0.262, p = 0.026). Multivariate logistic regression identified MGS latency [OR per SD increase = 4.814, 95 % CI: 1.457–15.910, p (FDR) = 0.044] and axial subscore [OR = 1.711, 95 % CI: 1.129–2.592, p (FDR) = 0.044] is associated with FOG. The MGS latency distinguished PD-FOG patients from PD-nFOG patients with high accuracy (AUC = 0.840, 95 % CI: 0.738–0.942; sensitivity/specificity = 84 % at the 407.5 ms cutoff). MGS latency was also correlated with NFOG-Q score in PD-FOG patients (ρ = 0.423, p = 0.035).

Conclusions

Prolonged MGS latency is an independent indicator associated with axial symptoms and FOG in PD patients, suggesting that saccade represents a promising noninvasive approach for indirect identification of FOG and reflection of its severity.

背景：步态冻结（FOG）是帕金森病（PD）的一种衰弱的轴向症状，缺乏客观的检测方法。虽然反扫视（AS）延迟延长与FOG相关，但更复杂的记忆引导扫视（MGS），需要多级运动序列整合（一种拟议的FOG机制），在FOG中仍未被探索。方法：我们通过红外眼动仪对75例PD患者（25例有FOG [PD-FOG]， 50例无FOG [PD- nfog]）和75例健康对照（hc）进行了proaccade （PS）、AS和MGS的评估。临床评估包括MDS-UPDRS III、NFOG-Q和认知/情感量表。采用适当的比较试验分析组间差异。采用Spearman等级相关来检验扫视指标与人口统计学/临床特征之间的关联。使用多变量逻辑回归来确定与FOG相关的扫视指标和人口统计学/临床特征。结果：与PD-nFOG患者和hc患者相比，PD-FOG患者的MGS潜伏期明显延长（p ≤ 0.001），但PS或AS潜伏期无明显延长。MGS潜伏期与轴向症状相关性最强[ρ = 0.494,p (FDR) < 0.001]，校正混杂因素后仍显著（ρ = 0.262,p = 0.026）。多变量逻辑回归确定MGS延迟(或每SD增加 = 4.814,95 % CI: 1.457 - -15.910, p(罗斯福) = 0.044]和“轴”的得分(或 = 1.711,95 % CI: 1.129 - -2.592, p(罗斯福) = 0.044]与雾相关联。MGS潜伏期对PD-FOG患者和PD-nFOG患者的区分准确率很高（AUC = 0.840,95 % CI: 0.738-0.942；灵敏度/特异性 = 84 %，截止时间为407.5 ms）。PD-FOG患者的MGS潜伏期也与nfogg - q严重程度相关（ρ = 0.423,p = 0.035）。结论：MGS潜伏期延长是与PD患者轴向症状和FOG相关的独立指标，提示跳眼是一种有希望的非侵入性方法，可以间接识别FOG并反映其严重程度。

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引用次数: 0

Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study 脊髓回路机制限制了ALS干预的治疗窗口：一项计算模型研究。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-30 DOI: 10.1016/j.nbd.2025.107253

Beck Strohmer , Kaitlyn Grosh , Roser Montañana-Rosell , Santiago Mora , Jessica Ausborn , Ilary Allodi

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1–motoneuron connections improved motor function and saved motoneurons in the SOD1^G93A ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor–extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1^G93A ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.

肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是神经回路的进行性破坏导致运动神经元死亡。我们实验室早期的研究表明，抑制性V1中间神经元的失调先于兴奋性V2a中间神经元和运动神经元的退化，在SOD1G93A ALS小鼠模型中，稳定V1-运动神经元连接改善了运动功能并保存了运动神经元。然而，这种干预的最佳时机仍不清楚。为了解决这个问题，我们开发了脊髓运动回路的尖峰神经网络模型来模拟健康和als样疾病。通过模拟网络连通性和突触动力学的变化，我们预测V1失调会引起运动神经元输出的不平衡，从而导致屈肌偏倚活动，导致屈肌-伸肌协调的破坏，并可能导致屈肌运动神经元的选择性易感性。稳定V1突触即使在运动神经元丢失后也能保持运动输出，这表明治疗效果可能进入症状阶段。然而，模型预测也强调，在持续的突触丢失和网络内突触动力学发展缓慢后，突触稳定导致伸展肌偏向活动的不适应，这表明兴奋/抑制平衡影响治疗效果。最后，该模型表明V1稳定可导致V2a兴奋性中间神经元的拯救，这一发现在SOD1G93A ALS小鼠模型中得到了实验证实。通过探索突触稳定过程中突触丢失和细胞失调的不同情况，我们的模型为预测脊髓回路干预的候选时间窗提供了一个框架，这可能指导未来的临床前研究。

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引用次数: 0

The effects of alcohol dependence on the CSF proteome in mice: Evidence for blood-brain barrier dysfunction and neuroinflammation 酒精依赖对小鼠脑脊液蛋白质组的影响：血脑屏障功能障碍和神经炎症的证据。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-30 DOI: 10.1016/j.nbd.2025.107254

Natalie P. Turner , Michal Bajo , Amanda J. Roberts , Marisa Roberto , John R. Yates III

Alcohol use disorder (AUD) represents a significant neurological health burden, yet the biological mechanisms underlying alcohol-induced brain pathology remain incompletely understood. Moreover, the molecular underpinnings of the transition from alcohol exposure to alcohol dependence are not well-characterized. We used mass spectrometry (MS)-based proteomics in a preliminary discovery study to compare cerebrospinal fluid (CSF) of alcohol-exposed Non-dependent (Non-dep) versus alcohol-dependent (Dep) mice that underwent the chronic intermittent ethanol (alcohol) – two-bottle choice (CIE-2 BCE) procedure and systemic anti-IL-6 Receptor antibody administration (n = 9; female = 5, male = 4). CSF samples from individual mice were processed for proteomic analysis and digested with trypsin overnight. Peptides were analyzed via data-independent acquisition (DIA)-MS and data were processed in DIA-NN at 1 % FDR. We identified 595 unique proteins across both groups, with 140 proteins differentially detected in CSF from Dep mice and 62 proteins specific to alcohol-exposed but Non-dep controls. The Dep-specific proteins revealed signatures of blood-brain barrier (BBB) disruption, neuroinflammation, cellular stress responses, and complement system activation. In contrast, Non-dep-specific proteins indicated preserved protective mechanisms including complement regulation, anti-inflammatory signaling, and neuronal calcium homeostasis. Ethanol-dependent-specific findings include MMP2, BIP, and to a lesser extent VE-cadherin (CDH5) and VCAM1, indicative of the beginnings of endothelial damage and BBB disruption, alongside established neuroinflammation markers GFAP, CHI3L1, and CX3CL1. This work provides novel preliminary protein-level evidence that alcohol exposure and alcohol dependence are dichotomous; despite the small sample size and limited power for moderate effect sizes, there appears to be a clear molecular transition from maintained protective mechanisms to vascular damage, BBB breakdown, and sustained neuroinflammation.

酒精使用障碍（AUD）是一种重要的神经系统健康负担，但酒精引起的脑病理的生物学机制仍不完全清楚。此外，从酒精暴露到酒精依赖过渡的分子基础还没有很好地表征。在一项初步发现研究中，我们使用质谱（MS）为基础的蛋白质组学来比较酒精暴露非依赖（Non-dep）和酒精依赖（Dep）小鼠的脑脊液（CSF），这些小鼠接受了慢性间歇乙醇（酒精）两瓶选择（CIE-2 BCE）程序和全身抗il -6受体抗体给药（n = 9；雌性 = 5，雄性 = 4）。个体小鼠的脑脊液样本进行蛋白质组学分析，并用胰蛋白酶消化过夜。肽通过数据独立采集(DIA)-MS进行分析，数据在DIA- nn中以1 % FDR进行处理。我们在两组中鉴定出595种独特的蛋白质，其中140种蛋白质在Dep小鼠的CSF中检测到差异，62种蛋白质在酒精暴露但非Dep对照组中特异性检测到。深度特异性蛋白揭示了血脑屏障（BBB）破坏、神经炎症、细胞应激反应和补体系统激活的特征。相反，非深度特异性蛋白表明保留的保护机制包括补体调节、抗炎信号和神经元钙稳态。乙醇依赖性特异性结果包括MMP2、BIP，以及较小程度的VE-cadherin （CDH5）和VCAM1，表明内皮损伤和血脑屏障破坏的开始，以及已建立的神经炎症标志物GFAP、CHI3L1和CX3CL1。这项工作提供了新的初步蛋白质水平的证据，酒精暴露和酒精依赖是二分法；尽管样本量小，中等效应的能力有限，但似乎有一个明确的分子转变，从维持的保护机制到血管损伤、血脑屏障破坏和持续的神经炎症。

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引用次数: 0

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-30 DOI: 10.1016/j.nbd.2025.107255

Barbara Pakula , Agata Wydrych , Magdalena Lebiedzinska-Arciszewska , Patrycja Jakubek-Olszewska , Marta Skowrońska , Iwona Kurkowska-Jastrzębska , Justyna Janikiewicz , Aneta M. Dobosz , Emre Hakli , Jędrzej Szymański , Paolo Pinton , Agnieszka Dobrzyń , Werner J.H. Koopman , Mariusz R. Wieckowski

Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) is the third most common genetically-defined subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), a group of rare, clinically heterogeneous disorders. The MPAN pathomechanism, including the link between C19orf12 mutations, iron accumulation, and metabolic alterations, is still poorly understood. While earlier research pointed to impaired autophagy in MPAN, a comprehensive understanding remains elusive. Here, we investigated the autophagy-linked proteome in primary fibroblasts derived from 18 MPAN patients and identified distinct alterations in autophagy-related protein expression. Importantly, a subset of these proteomic changes showed significant associations with disease severity, highlighting their potential relevance as biomarkers of clinical progression. Functional analyses further revealed increased lysosomal acidification as the most consistently affected autophagy-related process in MPAN fibroblasts. Notably, both proteomic and functional alterations were associated with C19orf12 mutation zygosity, underscoring its modulatory role in disease-relevant cellular pathways.

线粒体膜蛋白相关神经变性（MPAN）是第三种最常见的遗传定义的神经变性伴脑铁积累（NBIA）亚型，这是一组罕见的临床异质性疾病。MPAN的病理机制，包括C19orf12突变、铁积累和代谢改变之间的联系，仍然知之甚少。虽然早期的研究指出MPAN的自噬受损，但全面的理解仍然难以捉摸。在这里，我们研究了来自18名MPAN患者的原代成纤维细胞中自噬相关蛋白质组，并发现了自噬相关蛋白表达的明显改变。重要的是，这些蛋白质组学变化的一个子集显示出与疾病严重程度的显著关联，突出了它们作为临床进展生物标志物的潜在相关性。功能分析进一步显示，溶酶体酸化增加是最一致地影响MPAN成纤维细胞自噬相关过程的因素。值得注意的是，蛋白质组学和功能改变都与C19orf12突变合子性相关，强调了其在疾病相关细胞通路中的调节作用。

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引用次数: 0

Genetic disruption of leucine rich repeat transmembrane protein 4 like 1 induces a pro-social behavioural phenotype in zebrafish 富亮氨酸重复跨膜蛋白4样1的遗传破坏诱导斑马鱼亲社会行为表型。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-26 DOI: 10.1016/j.nbd.2025.107251

Courtney Hillman , Giulia Petracco , Barbara D. Fontana , María Florencia Scaia , Elisa Dalla-Vecchia , Jon H. Wetton , William H.J. Norton , Matthew O. Parker , Florian Reichmann

Background

In humans, disruptions in social behaviour are characteristic of many neuropsychiatric disorders, where both genetic risk factors and synaptic dysfunctions can contribute to the phenotype. Among the genes implicated in synaptic regulation, the synaptic adhesion protein leucine-rich repeat transmembrane protein 4 (LRRTM4) has been identified as a key player in maintaining synaptic function and neuronal circuit integrity. However, the potential involvement of LRRTM4 in modulating social behaviour and its contribution to social deficits has yet to be explored.

Methods

In the current study, we used zebrafish to study how deficiency in lrrtm4l1, a zebrafish orthologue of LRRTM4, affects sociality. For this, the social behaviour of homozygous lrrtm4l1^−/− mutant zebrafish was analysed in multiple behavioural assays and the brain transcriptome of mutant animals was investigated by RNAseq.

Results

Mutant zebrafish displayed a pro-social phenotype in multiple behavioural assays. Groups of lrrtm4l1^−/− zebrafish formed more cohesive shoals and mutant individuals spent more time in the vicinity of conspecifics during a social interaction test. They were also less aggressive and in contrast to wild-type zebrafish did not differentiate in their interactions with known and unknown groups of fish. Neurotranscriptomic analysis revealed 560 differentially expressed genes including changes in glutamatergic neurotransmitter signalling, tryptophan-kynurenine metabolism and synaptic plasticity.

Conclusion

These findings suggest that lrrtm4l1 is an important regulator of social behaviour in zebrafish. In a translational perspective, LRRTM4 is a promising potential therapeutic target that warrants further investigation in the framework of neuropsychiatric conditions characterized by major social impairments.

背景：在人类中，社会行为紊乱是许多神经精神疾病的特征，其中遗传风险因素和突触功能障碍都可能导致表型。在参与突触调控的基因中，突触粘附蛋白富亮氨酸重复跨膜蛋白4 （LRRTM4）已被确定为维持突触功能和神经元回路完整性的关键角色。然而，LRRTM4在调节社会行为及其对社会缺陷的贡献方面的潜在参与尚未被探索。方法：在本研究中，我们以斑马鱼为研究对象，研究lrrtm4l1 （LRRTM4的斑马鱼同源物）缺乏如何影响社会性。为此，我们通过多种行为分析分析了纯合子lrrtm4l1-/-突变斑马鱼的社会行为，并通过RNAseq研究了突变动物的脑转录组。结果：突变斑马鱼在多种行为分析中表现出亲社会表型。在社会互动测试中，lrrtm4l1-/-斑马鱼群体形成了更有凝聚力的鱼群，突变个体在同种鱼附近呆的时间更长。与野生型斑马鱼相比，它们的攻击性也更低，在与已知和未知鱼群的互动中没有区别。神经转录组学分析显示560个差异表达基因，包括谷氨酸神经递质信号，色氨酸-犬尿氨酸代谢和突触可塑性的变化。结论：lrrtm4l1是斑马鱼社会行为的重要调节因子。从翻译的角度来看，LRRTM4是一个有希望的潜在治疗靶点，值得在以主要社交障碍为特征的神经精神疾病的框架下进一步研究。

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引用次数: 0

Astrocytic GABA controls fidelity of temporal cortical processing in Fragile X Syndrome 星形细胞GABA控制脆性X综合征颞皮质加工的保真度。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-22 DOI: 10.1016/j.nbd.2025.107233

Victoria A. Wagner , Ritika Thapa , Anna O. Norman , Alexandra Varallo , Jordan Wimberly , Maham Rais , Dmytro Gerasymchuk , Timo P. Piepponen , Khaleel A. Razak , Maija L. Castren , Iryna M. Ethell

Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse Fmr1 knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific Fmr1 KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Abnormal GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and abnormal behaviors in cKO mice. Blocking astrocyte GABA transport enables higher PV expression, improves EEG responses to frequency-modulated sound, and corrects aberrant exploratory behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes.

星形胶质细胞通过摄取和合成GABA来影响GABA能的传递，从而控制神经通讯。gaba能信号的受损被认为是自闭症患者皮层亢进的基础。本研究表明，脆性X综合征（FXS）中星形胶质细胞GABA运输的失调，是自闭症的主要遗传原因，有助于神经回路的高兴奋性。来自患者特异性诱导多能干细胞的人FXS星形胶质细胞和小鼠Fmr1敲除（KO）星形胶质细胞显示GABA和GABA合成酶GAD65/67水平显著升高。我们的星形胶质细胞特异性Fmr1 KO （cKO）小鼠模型显示抑制连接减少和皮层对声音的反应受损。皮层星形胶质细胞中GABA转运异常导致cKO小鼠时间加工保真度受损和行为异常。阻断星形胶质细胞GABA转运可以提高PV表达，改善脑电图对调频声音的反应，并纠正异常的探索行为。我们的研究结果表明，星形胶质细胞GABA转运在调节皮质抑制中起关键作用，并有助于自闭症相关的表型。

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引用次数: 0

Wirelessly transmitted subthalamic nucleus signals decode endogenous pain levels in Parkinson's disease patients 无线传输的丘脑下核信号解码帕金森病患者的内源性疼痛水平。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-22 DOI: 10.1016/j.nbd.2025.107235

Abdi Reza , Takufumi Yanagisawa , Naoki Tani , Ryohei Fukuma , Takuto Emura , Satoru Oshino , Ben Seymour , Haruhiko Kishima

Pain is a prominent non-motor symptom of Parkinson's disease (PD); it may appear in various levels (elevated or diminished) during waking hours and substantially reduces quality of life. Although subthalamic nucleus (STN) signal analysis has dramatically advanced our comprehension of PD, the roles of bilateral STN, the relevant biomarkers, and objective recognition of the pain levels in PD patients remain less understood.

We recorded bilateral STN signals from PD patients implanted with adaptive deep brain stimulation (DBS) systems and collected pain rating series during in-hospital recovery. Patients provided pain annotations prior to surgery that inform the location (specific or non-specific) and PD-association with pain (PD-related or non-PD-related). A machine learning model was trained to classify higher versus lower pain states, from the eight pain annotation series of the six patients, using features derived from STN signals.

STN activity significantly classified the pain intensity in the PD-related pain group. Feature analysis indicated that STN activity from both sides can impact pain classification, with gamma and beta bands in the contralateral STN and delta and theta bands in the ipsilateral STN exhibiting a prominent role. Our observational study demonstrates a novel approach to decoding pain states and identifying STN biomarkers linked to PD-related pain.

疼痛是帕金森病（PD）的一个突出的非运动症状；在醒着的时候，它可能以不同的程度出现（升高或降低），并大大降低生活质量。尽管丘脑下核（STN）信号分析极大地促进了我们对PD的理解，但双侧STN的作用、相关生物标志物以及PD患者疼痛水平的客观识别仍然知之甚少。我们记录了PD患者植入适应性深部脑刺激（DBS）系统后的双侧STN信号，并收集了住院康复期间的疼痛评分序列。患者在手术前提供疼痛注释，告知部位（特异性或非特异性）以及pd与疼痛的关联（pd相关或非pd相关）。通过训练机器学习模型，利用STN信号衍生的特征，从6名患者的8个疼痛注释系列中对高疼痛状态和低疼痛状态进行分类。STN活动对pd相关疼痛组的疼痛强度有显著的分类作用。特征分析表明，两侧STN的活动可以影响疼痛的分类，对侧STN的gamma和beta带以及同侧STN的delta和theta带发挥了突出的作用。我们的观察性研究展示了一种解码疼痛状态和识别与pd相关疼痛相关的STN生物标志物的新方法。

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引用次数: 0

Review on the role of hippocampus in autism spectrum disorder: Recent insights into neuropathology, genetics, and emerging therapeutic strategies 海马体在自闭症谱系障碍中的作用综述：神经病理学、遗传学和新兴治疗策略的最新见解。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-12-16 DOI: 10.1016/j.nbd.2025.107227

Poorna Manasa Bhamidimarri , Khalood Alhosani , Heng Cai , Haya Al-Ali , Yara Marwan Abukhaled , Hasan Tawamie , Sahar Abdelaziz , Mouna Fawaz , Junaid Kashir , Yasmin Sajjad , Lamiya Mohiyiddeen , Michael Fakih , Hamdan Hamdan

The hippocampus, central to learning, memory, and social behavior, is increasingly implicated in the pathophysiology of autism spectrum disorder (ASD). Structural and functional disruptions in this region contribute to core ASD traits through impaired neurogenesis, abnormal dendritic morphology, excitatory/inhibitory imbalance, and altered connectivity with large-scale brain networks. Neuroimaging studies revealed changes in hippocampal volume, subfield-specific anomalies in the CA1 and dentate gyrus, and reduced functional connectivity within these regions. Genetic mutations in Shank3, Syngap1, Fmr1, and Nlgn3 disrupt synaptic plasticity and social memory circuits, while epigenetic alterations and environmental exposures further impair regulatory processes. Neuroinflammation exacerbates ASD pathology through microglial activation and cytokine release. Collectively, current evidence positions hippocampal dysfunction as central to ASD, emphasizing its relevance as both a biomarker and a therapeutic target to improve clinical outcomes.

海马体是学习、记忆和社会行为的中枢，在自闭症谱系障碍（ASD）的病理生理学中越来越有牵连。该区域的结构和功能破坏通过神经发生受损、树突形态异常、兴奋/抑制失衡以及与大尺度脑网络的连接改变而导致核心ASD特征。神经影像学研究显示海马体积的变化，CA1和齿状回的亚场特异性异常，以及这些区域的功能连通性降低。Shank3、Syngap1、Fmr1和Nlgn3的基因突变破坏突触可塑性和社会记忆回路，而表观遗传改变和环境暴露进一步损害调控过程。神经炎症通过小胶质细胞激活和细胞因子释放加剧ASD病理。总的来说，目前的证据表明海马功能障碍是ASD的核心，强调其作为生物标志物和改善临床结果的治疗靶点的相关性。

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引用次数: 0