Multiplexed changes in synaptic transmission underlie stress-induced reduction of persistent firing in the parietal cortex

突触传递的多重变化是应激导致顶叶皮质持续性放电减少的基础

Repeated exposure to stress disrupts cognitive processes, including attention and working memory. A key mechanism supporting these functions is the ability of neurons to sustain action potential firing, even after a stimulus is no longer present. How stress impacts this persistent neuronal activity is currently unknown. We found that repeated exposure to multiple concurrent stressors during adolescence (aRMS) impedes the ability of layer 5 pyramidal neurons (L5 PNs) in the posterior parietal cortex (PPC) to produce persistent firing. To determine the mechanisms underlying this effect, we complemented computational modelling with whole-cell patch clamp electrophysiology in acute brain slices from male mice. Our model predicted that altered intrinsic excitability, reduced local connectivity, diminished glutamatergic transmission, or enhanced inhibition could explain diminished persistent activity. In ex vivo experiments, we found minimal effect of aRMS on excitability and recurrent connectivity. However, stress exposure altered the properties of excitatory connections between L5 PNs, specifically affecting decay kinetics and short-term synaptic dynamics. In addition, aRMS increased inhibitory tone in the PPC, altering both GABAa and GABAb receptor-mediated responses. Incorporating the observed physiological changes into our network model, we found that no single parameter was sufficient alone to reproduce the stress-induced reduction in persistent firing. Rather, a combination of altered excitatory and inhibitory synaptic transmission was necessary to impact sustained activity. These data suggest that a multitude of converging changes in neural and circuit function underpin the effects of stress on cognitive processes.

反复暴露于压力会扰乱认知过程，包括注意力和工作记忆。支持这些功能的一个关键机制是神经元即使在刺激不再存在后仍能维持动作电位发放的能力。目前尚不清楚压力是如何影响这种持续的神经元活动的。我们发现，青春期反复暴露于多种并发应激源（aRMS）会阻碍顶后皮质（PPC）第5层锥体神经元（L5 PNs）产生持续发放的能力。为了确定这种影响的潜在机制，我们将计算建模与雄性小鼠急性脑片的全细胞膜片钳电生理学相结合。我们的模型预测，内在兴奋性改变、局部连接减少、谷氨酸能传递减弱或抑制增强都可以解释持续活动的减弱。在离体实验中，我们发现aRMS对兴奋性和循环连接的影响极小。然而，应激暴露改变了L5 PNs之间兴奋性连接的特性，具体影响了衰减动力学和短期突触动力学。此外，aRMS增加了PPC中的抑制性张力，同时改变了GABAA和GABAB受体介导的反应。将观察到的生理变化纳入我们的网络模型后，我们发现没有一个单一参数足以单独重现应激诱导的持续发放减少。相反，兴奋性和抑制性突触传递的改变相结合对于影响持续活动是必要的。这些数据表明，神经和回路功能的多种汇聚变化是压力对认知过程产生影响的基础。

REF: Proddutur A, Rindner DJ, Azouz G, Beier KT, Lur G. Multiplexed changes in synaptic transmission underlie stress-induced reduction of persistent firing in the parietal cortex. Prog Neurobiol. 2026;260:102895. doi:10.1016/j.pneurobio.2026.102895 PMID: 41763383

The VGLUT3 positive neurons of the median raphe region promote long-term spatial memory through time-dependent mechanisms

中缝核区域的VGLUT3阳性神经元通过时间依赖性机制促进长期空间记忆

Episodic memory and related forms of learning depend critically on the hippocampus, whose activity is regulated by brainstem inputs that remain incompletely understood. The midbrain median raphe region (MRR) is a key regulator of forebrain circuits and, while classically recognised as serotonergic, many of its neurons also release glutamate. Notably, a subset of MRR neurons projecting to the hippocampus expresses the vesicular glutamate transporter type 3 (VGLUT3), suggesting a glutamatergic contribution. Moreover, electrophysiological data indicate that these MRR-VGLUT3 + neurons influence hippocampal oscillations and therefore, hippocampus-dependent learning and memory. Our goal was to investigate the role of MRR-VGLUT3 + neurons in hippocampus-dependent learning and memory. Using VGLUT3-Cre mice of both sexes, we employed adeno-associated viral vectors to selectively activate MRR-VGLUT3 + neurons during the water maze task, a known hippocampus-dependent behavioural paradigm. Neuronal excitation was achieved by chemogenetics (DREADDs) or, to probe temporally restricted effects, by optogenetics (Channelrhodopsin2) during the spatial reference memory phase. Given the involvement of MRR and VGLUT3 + neurons in locomotion and anxiety-like behaviours, open field and elevated plus maze assays were also performed but yield inconclusive results. We found that chronic chemogenetic excitation did not alter learning but enhanced long-term memory performance, a finding replicated in an independent cohort. In contrast, acute optogenetic excitation had no effect, suggesting that MRR-VGLUT3 + neurons may contribute to memory related processes in a temporally specific manner.

情景记忆及相关学习形式关键依赖于海马体，而海马体的活动受脑干输入调节，目前人们对这种调节机制的了解尚不全面。中脑正中缝核区域（MRR）是前脑回路的关键调节者，尽管传统上被认为是血清素能的，但其许多神经元也会释放谷氨酸。值得注意的是，投射到海马体的一部分MRR神经元表达囊泡谷氨酸转运体3型（VGLUT3），这表明存在谷氨酸能作用。此外，电生理数据表明，这些MRR - VGLUT3+神经元会影响海马体振荡，进而影响依赖海马体的学习和记忆。我们的目标是研究MRR - VGLUT3+神经元在依赖海马体的学习和记忆中的作用。我们使用雌雄VGLUT3 - Cre小鼠，在水迷宫任务（一种已知的依赖海马体的行为范式）期间，采用腺相关病毒载体选择性激活MRR - VGLUT3+神经元。在空间参考记忆阶段，通过化学遗传学（DREADDs）实现神经元兴奋，或者为了探究时间受限的影响，采用光遗传学（Channelrhodopsin2）。鉴于MRR和VGLUT3+神经元参与运动和焦虑样行为，我们还进行了旷场实验和高架十字迷宫实验，但结果并不明确。我们发现，慢性化学遗传学兴奋不会改变学习情况，但能增强长期记忆表现，这一发现在另一独立队列中得到了重复验证。相比之下，急性光遗传学兴奋没有效果，这表明MRR - VGLUT3+神经元可能以时间特异性的方式参与与记忆相关的过程。

REF: Fazekas CL, Török B, Szabó A, et al. The VGLUT3 positive neurons of the median raphe region promote long-term spatial memory through time-dependent mechanisms. Prog Neurobiol. 2026;260:102904. doi:10.1016/j.pneurobio.2026.102904 PMID: 41802696

Spinal motoneuron excitability is homeostatically regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice

在野生型和症状前超氧化物歧化酶 1（SOD1）小鼠中，脊髓运动神经元兴奋性通过β-肾上腺素能神经调节实现稳态调节。

Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that Adrb2 and Adrb3 adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the electrical properties of MNs, in particular the frequency-current gain, a crucial determinant of excitability. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon β-adrenergic neuromodulation.

稳态反馈回路对于稳定神经元和神经网络的活动至关重要。有假设认为，在肌萎缩侧索硬化症（ALS）的背景下，反馈回路的过度增益可能会使运动神经元（MNs）过度兴奋或兴奋不足，并导致疾病的发生。在这里，我们研究了在症状出现前的成年SOD1（G93A）小鼠和年龄匹配的对照野生型（WT）小鼠中，运动神经元固有特性的神经调节是如何受到稳态控制的。首先，我们确定了Adrb2和Adrb3肾上腺素能受体（它们是Gs偶联受体，受到严格且强大的反馈回路调控）在P45时的SOD1小鼠和WT小鼠的脊髓运动神经元中特异性表达。然后，我们证明了这些受体引发了对运动神经元电特性（特别是频率 - 电流增益，这是兴奋性的关键决定因素）的一种迄今被忽视的神经调节。在受体激活后，这些电特性会受到稳态调节，这会触发离子通道的转录变化并下调这些受体。在症状出现前的SOD1小鼠中，这些稳态反馈并未失调，并且它们在β - 肾上腺素能神经调节时设定了运动神经元的兴奋性。

REF: Antonucci S, Caron G, Dikwella N, et al. Spinal motoneuron excitability is homeostatically regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice. Prog Neurobiol. 2026;260:102905. doi:10.1016/j.pneurobio.2026.102905 PMID: 41812870

Normative modeling of brain function abnormalities in complex pathology requires a whole-brain approach

复杂病理状态下脑功能异常的规范性建模需要全脑方法

Many brain diseases and disorders lack objective measures of brain function as indicators of pathology. The search for brain function biomarkers is complicated by the fact that these conditions are often heterogeneous and described as a spectrum from normal to abnormal rather than a sick-healthy dichotomy. Normative modeling addresses these challenges by characterizing the normal variation of brain function given sex and age and identifying abnormalities as deviations from this norm. Focusing on functional connectivity (FC) as a way to capture the network properties of the brain's activity, we here argue that the pathological effects of neurological or psychiatric disease lie at the systemic level, and that whole-brain normative models are more suitable to capture individual variations associated to these complex conditions than existing localized approaches that analyze one connection at a time. To be able to capture the whole-brain effects of disease, we thus propose Functional Connectivity Integrative Normative Modeling (FUNCOIN) as a novel whole-brain approach to normative modeling of FC. Using FUNCOIN and UK Biobank resting-state fMRI data from 46,000 healthy subjects across training and testing sets, we found that subjects with bipolar disorder and Parkinson's disease were significantly, and substantially, more likely than healthy subjects to exhibit abnormal FC patterns, which was not seen in localized models. Subjects with bipolar disorder divided into two distinct subgroups characterized by different brain function deviations. In Parkinson's disease subjects, abnormal FC patterns were significant even on scans up to 8 years before diagnosis.

许多脑部疾病缺乏可作为病理指标的客观脑功能测量方法。由于这些病症往往具有异质性，且通常被描述为从正常到异常的连续谱，而非简单的患病 - 健康二分法，这使得寻找脑功能生物标志物的工作变得复杂。规范建模通过刻画给定性别和年龄下脑功能的正常变异，并将异常识别为偏离这一规范的情况，来应对这些挑战。我们聚焦于功能连接（FC），将其作为捕捉大脑活动网络特性的一种方式，并认为神经或精神疾病的病理效应处于系统层面，与现有的一次分析一个连接的局部方法相比，全脑规范模型更适合捕捉与这些复杂病症相关的个体差异。为了能够捕捉疾病的全脑效应，我们提出了功能连接整合规范建模（FUNCOIN），作为一种全新的全脑功能连接规范建模方法。利用FUNCOIN以及来自英国生物银行46000名健康受试者训练集和测试集的静息态功能磁共振成像数据，我们发现双相情感障碍和帕金森病患者比健康受试者显著且大幅度更有可能表现出异常的功能连接模式，而局部模型中并未观察到这种情况。双相情感障碍患者分为两个不同的亚组，其特征是不同的脑功能偏差。在帕金森病患者中，即使在诊断前长达8年的扫描中，异常的功能连接模式也很显著。

REF: Kobbersmed JRL, Gohil C, Marquand A, Vidaurre D. Normative modeling of brain function abnormalities in complex pathology requires a whole-brain approach. Prog Neurobiol. 2026;260:102906. doi:10.1016/j.pneurobio.2026.102906 PMID: 41856310

The reading brain – Transforming vision into language

阅读脑——将视觉转化为语言

Reading is built upon transformations that map representations of written words to their pronunciations, names, and meanings. However, unlike many other visual skills, literacy is unique to humans and has only become widespread in the past few hundred years, therefore neural circuits that underly reading cannot have evolved for reading. Thus, scientists have long debated the nature of the neural re-tuning of visual networks that must occur to support these transformations in a highly skilled manner. A key node of the reading brain, the visual word form area (VWFA), lies where circuits that underpin key aspects of visuolinguistic transformations diverge from earlier visual processing in ventral occipitotemporal cortex. Furthermore, different reading deficits co-occur with parallel deficits in these visuolinguistic transformations. Evidence suggests that as literacy is acquired during development, preexisting visuolinguistic circuits that support representational transformations compatible with reading become tuned for understanding written words. This model implies that the VWFA is where it is because reading requires functional capacities that are parallel to those needed to recognize and name objects on one hand and those needed for multimodal integration during speech/language comprehension on the other. The VWFA is at a key location that gets input from earlier visual regions and has lateral connectivity into the auditory-visual speech and language network and ventral connectivity into visual naming circuits. We review neurophysiological, neuroanatomical, and neurodevelopmental evidence that support a model in which literacy emerges from the specialization of preexisting circuits that have the natural capacities for vision to linguistic transformations needed to acquire and facilitate fluent reading.

阅读建立在将书面文字表征转化为其发音、名称和含义的过程之上。然而，与许多其他视觉技能不同，读写能力是人类独有的，并且仅在过去几百年才广泛普及，因此支持阅读的神经回路不可能是为阅读而进化出来的。因此，长期以来，科学家们一直在争论视觉网络为高效支持这些转化而必须进行的神经重新调整的本质。阅读脑的一个关键节点——视觉词形区（VWFA），位于支持视觉语言转化关键方面的神经回路与腹侧枕颞叶皮层早期视觉处理相分离的位置。此外，不同的阅读障碍与这些视觉语言转化中的并行缺陷同时出现。有证据表明，在发育过程中习得读写能力时，支持与阅读兼容的表征转化的既有视觉语言回路会被调整以理解书面文字。该模型表明，VWFA处于现有的位置是因为阅读一方面需要与识别和命名物体所需的功能能力平行的能力，另一方面需要与言语/语言理解过程中的多模态整合所需的能力平行的能力。VWFA处于一个关键位置，它接收来自早期视觉区域的输入，并且与听觉 - 视觉言语和语言网络有横向连接，与视觉命名回路有腹侧连接。我们回顾了神经生理学、神经解剖学和神经发育学的证据，这些证据支持这样一种模型：读写能力源于既有回路的特化，这些回路具有将视觉转化为语言的自然能力，而这种转化对于习得和促进流畅阅读是必要的。

REF: Ghuman AS, Fiez JA, Boring MJ. The reading brain - Transforming vision into language. Prog Neurobiol. 2026;260:102894. doi:10.1016/j.pneurobio.2026.102894 PMID: 41724370

Human induced pluripotent stem cell-based models for studying neural repair

基于人类诱导多能干细胞的神经修复研究模型

Injuries and degenerative diseases of the human nervous system result in irreversible functional loss, reflecting the limited regenerative capacity of the central nervous system and the slow repair rate of the peripheral nervous system. Progress has been hindered by the lack of human-relevant experimental models that accurately capture the cellular diversity, long axonal architecture, and species-specific regulatory mechanisms underlying neural injury and repair. Human induced pluripotent stem cells (iPSCs) have emerged as a transformative platform to bridge this gap, enabling the generation of diverse neuronal and glial subtypes, reconstruction of complex neural circuits, and modeling of injury and regeneration in a human-specific context. In this review, we discuss the recent advances in the use of human iPSC-derived systems to study neural repair, spanning two-dimensional cultures, three-dimensional organoids and assembloids, microengineered axon injury platforms, and in vivo transplantation models. We highlight how these approaches have revealed key intracellular regulators of neurite growth, clarified the impact of disease-associated mutations on axonal integrity, and enabled high-throughput screening of neuroprotective and pro-regenerative compounds. We further discuss the role of iPSC-derived glial cells, Schwann cells, and neuromuscular junction models in elucidating axon-glia interactions, remyelination, and circuit-level repair mechanisms. Together, human iPSC-based models offer unprecedented insight into the cellular and molecular determinants of human neural regeneration, thereby overcoming the limitations of animal systems. While challenges remain in standardization, maturation, and clinical translation, these platforms are redefining regenerative neuroscience and hold promise for the development of patient-specific therapies aimed at restoring function after nervous system injury.

人类神经系统的损伤和退行性疾病会导致不可逆的功能丧失，这反映出中枢神经系统再生能力有限以及周围神经系统修复速度缓慢。由于缺乏能够准确反映细胞多样性、长轴突结构以及神经损伤和修复背后物种特异性调节机制的与人类相关的实验模型，相关研究进展受到阻碍。人类诱导多能干细胞（iPSCs）已成为弥补这一差距的变革性平台，它能够生成多种神经元和神经胶质细胞亚型，重建复杂的神经回路，并在人类特有的背景下模拟损伤和再生过程。在这篇综述中，我们讨论了利用人类iPSC衍生系统研究神经修复的最新进展，涵盖二维培养、三维类器官和组装体、微工程轴突损伤平台以及体内移植模型。我们强调了这些方法如何揭示了神经突生长的关键细胞内调节因子，阐明了疾病相关突变对轴突完整性的影响，并实现了对神经保护和促再生化合物的高通量筛选。我们还进一步探讨了iPSC衍生的神经胶质细胞、施万细胞和神经肌肉接头模型在阐明轴突 - 神经胶质细胞相互作用、髓鞘再生和回路水平修复机制方面的作用。总之，基于人类iPSC的模型为人类神经再生的细胞和分子决定因素提供了前所未有的见解，从而克服了动物模型的局限性。尽管在标准化、成熟化和临床转化方面仍存在挑战，但这些平台正在重新定义再生神经科学，并有望开发出针对神经系统损伤后恢复功能的个性化疗法。

REF: Agrawal M, Desai M, Ghumra S, Bhorkar Y, Sahoo PK. Human induced pluripotent stem cell-based models for studying neural repair. Prog Neurobiol. 2026;260:102907. doi:10.1016/j.pneurobio.2026.102907 PMID: 41856309