Progress in Neurobiology最新文献_第7页

Glutamine transport via amino acid transporter NTT4 (SLC6A17) maintains presynaptic glutamate supply at excitatory synapses in the CNS 通过氨基酸转运体NTT4 （SLC6A17）运输谷氨酰胺维持中枢神经系统兴奋性突触的突触前谷氨酸供应。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-07-01 Epub Date: 2025-05-26 DOI: 10.1016/j.pneurobio.2025.102785

Angela L. Nicoli , A. Shaam Al Abed , Sarah R. Hulme , Abhijit Das , Gregory Gauthier-Coles , Angelika Bröer , Sarojini Balkrishna , Gaetan Burgio , Nathalie Dehorter , Caroline D. Rae , Stefan Bröer , Brian Billups

The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and forms glutamine, before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle are established, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of ¹³C metabolites in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is eliminated when NTT4 is removed or inhibited. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning, and alterations in anxiety behaviour and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter, which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are important regulators of memory retention and normal behaviour.

谷氨酸-谷氨酰胺循环被认为是突触中谷氨酸循环的主要代谢途径。在这个循环中，突触释放的谷氨酸被星形胶质细胞隔离并形成谷氨酰胺，然后返回突触前末端转化为谷氨酸，以补充神经递质池。虽然这个循环的许多方面已经确定，但一个关键的组成部分仍然未知：负责突触前谷氨酰胺摄取的转运体的性质。我们假设神经递质转运蛋白4 （NTT4/SLC6A17）发挥了这一作用。因此，我们产生了NTT4敲除小鼠，以评估其对突触前谷氨酰胺运输和突触谷氨酸供应的贡献。通过对清醒小鼠13C代谢物的生化示踪，我们观察到NTT4缺失时神经元谷氨酸供应减少。此外，海马苔藓纤维钮扣的直接电记录显示，当NTT4被移除或抑制时，突触前谷氨酰胺运输电流被消除。海马电生理记录证实了NTT4在神经传递中的作用，这表明NTT4是维持水泡谷氨酸含量和在高频神经元活动期间维持足够水平的谷氨酸供应所必需的。最后，对老鼠的行为研究表明，老鼠在恐惧条件反射方面存在缺陷，焦虑行为和社会偏好也会发生改变。这些结果表明，NTT4是突触前谷氨酰胺转运蛋白，是谷氨酸-谷氨酰胺循环的核心组成部分。NTT4和谷氨酸-谷氨酰胺循环在高频突触活动中维持神经兴奋性神经传递的谷氨酸供应，并且是记忆保留和正常行为的重要调节因子。

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引用次数: 0

Neural dynamics encoding risky choices during deliberation reveal separate choice subspaces 在审议过程中编码风险选择的神经动力学揭示了单独的选择子空间。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-07-01 Epub Date: 2025-05-07 DOI: 10.1016/j.pneurobio.2025.102776

Logan M. Peters , Alec Roadarmel , Jacqueline A. Overton , Matthew P. Stickle , Zhaodon Kong , Ignacio Saez , Karen Anne Moxon

Human decision-making involves the coordinated activity of multiple brain areas, acting in concert, to enable humans to make choices. Most decisions are carried out under conditions of uncertainty, where the desired outcome may not be achieved if the wrong decision is made. In these cases, humans deliberate before making a choice. The neural dynamics underlying deliberation are unknown and intracranial recordings in clinical settings present a unique opportunity to record high temporal resolution electrophysiological data from many (hundreds) brain locations during behavior. Combined with dynamic systems modeling, these allow identification of latent brain states that describe the neural dynamics during decision-making, providing insight into these neural dynamics and computations. Results show that the neural dynamics underlying risky decisions, but not decisions without risk, converge to separate subspaces depending on the subject’s preferred choice and that the degree of overlap between these subspaces declines as choice approaches, suggesting a network level representation of evidence accumulation. These results bridge the gap between regression analyses and data driven models of latent states and suggest that during risky decisions, deliberation and evidence accumulation toward a final decision are represented by the same neural dynamics, providing novel insights into the neural computations underlying human choice.

人类的决策涉及多个大脑区域的协调活动，协同行动，使人类能够做出选择。大多数决策都是在不确定的情况下进行的，如果做出错误的决策，预期的结果可能无法实现。在这些情况下，人类在做出选择之前会深思熟虑。思考背后的神经动力学是未知的，在临床环境下的颅内记录提供了一个独特的机会，可以记录行为过程中来自许多（数百个）大脑位置的高时间分辨率电生理数据。与动态系统建模相结合，可以识别决策过程中描述神经动力学的潜在大脑状态，从而深入了解这些神经动力学和计算。结果表明，基于风险决策（而非无风险决策）的神经动力学根据受试者的偏好收敛到独立的子空间，并且这些子空间之间的重叠程度随着选择的接近而下降，表明证据积累的网络级表示。这些结果弥合了回归分析和潜在状态数据驱动模型之间的差距，并表明在风险决策过程中，深思熟虑和最终决策的证据积累由相同的神经动力学表示，为人类选择背后的神经计算提供了新的见解。

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引用次数: 0

Switching state to engage and sustain attention: Dynamic synchronization of the frontoparietal network 转换状态以吸引和维持注意力：额顶叶网络的动态同步。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-07-01 Epub Date: 2025-05-17 DOI: 10.1016/j.pneurobio.2025.102777

Grace Ross , Wei A. Huang , Jared Reiling , Mengsen Zhang , Jimin Park , Susanne Radtke-Schuller , Joseph Hopfinger , Agnieszka Zuberer , Flavio Frohlich

Sustained attention (SA) is essential for maintaining focus over time, with disruptions linked to various neurological and psychiatric disorders. The oscillatory dynamics and functional connectivity in the dorsal frontoparietal network (dFPN) are crucial in SA. However, the neuronal mechanisms that control the level of SA, especially in response to heightened attentional demands, remain poorly understood. To examine the role of rhythmic synchronization in the dFPN in SA, we recorded local field potential and single unit activity in ferrets that performed the 5-Choice Serial Reaction Time Task (5-CSRTT) under both low and high attentional load. Under high attentional load, dFPN exhibited a pronounced state shift that corresponded with behavioral changes in the animal. Prior to the onset of the target stimulus, animals transitioned from a stationary state, characterized by frontal theta oscillations and dFPN theta connectivity, to an active exploration state associated with sensory processing. This shift was indexed by a suppression of inhibitory alpha oscillations and an increase in excitatory theta and gamma oscillations in parietal cortex. We further show that dFPN theta connectivity predicts performance fluctuations under high attentional load. Together, these results suggest that behavioral strategies for maintaining SA are tightly linked to neuronal state dynamics in the dFPN. Importantly, these findings identify rhythmic synchronization within the FPN as a potential neural target for novel therapeutic strategies for disrupted attention.

持续注意力（SA）对于长期保持注意力至关重要，其中断与各种神经和精神疾病有关。背侧额顶叶网络（dFPN）的振荡动力学和功能连通性在SA中至关重要。然而，控制SA水平的神经元机制，特别是对高度注意需求的反应，仍然知之甚少。为了研究节奏同步在SA dFPN中的作用，我们记录了在低注意负荷和高注意负荷下执行5-Choice系列反应时间任务（5-CSRTT）的雪貂的局部场电位和单单元活动。在高注意力负荷下，dFPN表现出明显的状态转移，这与动物的行为变化相对应。在目标刺激开始之前，动物从以额叶θ波振荡和dFPN θ波连接为特征的静止状态过渡到与感觉加工相关的主动探索状态。这种转变是通过抑制抑制性α振荡和增加顶叶皮层的兴奋性θ和γ振荡来指示的。我们进一步表明，dFPN theta连接可以预测高注意力负荷下的性能波动。总之，这些结果表明维持SA的行为策略与dFPN中的神经元状态动力学密切相关。重要的是，这些发现确定了FPN内的节律同步是注意力中断的新治疗策略的潜在神经靶点。

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引用次数: 0

Whole-brain effective connectivity of the sensorimotor system using 7 T fMRI with electrical microstimulation in non-human primates 使用7 T功能磁共振成像与电微刺激在非人类灵长类动物的感觉运动系统的全脑有效连接

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-07-01 Epub Date: 2025-04-23 DOI: 10.1016/j.pneurobio.2025.102760

Min-Jun Han , Younghyun Oh , Yejin Ann , Sangyun Kang , Eunha Baeg , Seok Jun Hong , Hansem Sohn , Seong-Gi Kim

The sensorimotor system is a crucial interface between the brain and the environment, and it is endowed with multiple computational mechanisms that enable efficient behaviors. For example, predictive processing via an efference copy of a motor command has been proposed as one of the key computations used to compensate for the sensory consequence of movement. However, the neural pathways underlying this process remain unclear, particularly regarding whether the M1-to-S1 pathway plays a dominant role in predictive processing and how its influence compares to that of other pathways. In this study, we present a causally inferable input–output map of the sensorimotor effective connectivity that we made by combining ultrahigh-field functional MRI, electrical microstimulation of the S1/M1 cortex, and dynamic causal modeling for the whole sensorimotor network in anesthetized primates. We investigated how motor signals from M1 are transmitted to S1 at the circuit level, either via direct cortico-cortical projections or indirectly via subcortical structures such as the thalamus. Across different stimulation conditions, we observed a robust asymmetric connectivity from M1 to S1 that was also the most prominent output from M1. In the thalamus, we identified distinct activations: M1 stimulation showed connections to the anterior part of ventral thalamic nuclei, whereas S1 was linked to the more posterior regions of the ventral thalamic nuclei. These findings suggest that the cortico-cortical projection from M1 to S1, rather than the cortico-thalamic loop, plays a dominant role in transmitting movement-related information. Together, our detailed dissection of the sensorimotor circuitry underscores the importance of M1-to-S1 connectivity in sensorimotor coordination.

感觉运动系统是大脑和环境之间的关键接口，它被赋予了多种计算机制，使有效的行为。例如，通过对运动指令的复制进行预测处理被认为是用来补偿运动的感觉后果的关键计算之一。然而，这一过程背后的神经通路尚不清楚，特别是M1-to-S1通路是否在预测加工中起主导作用，以及它与其他通路的影响如何。在这项研究中，我们提出了一个因果推理的感觉运动有效连接的输入-输出图，我们结合了超强场功能MRI， S1/M1皮层的电微刺激，以及对麻醉灵长类动物整个感觉运动网络的动态因果建模。我们研究了M1的运动信号是如何在回路水平上通过皮质-皮层直接投射或间接通过皮层下结构（如丘脑）传递到S1的。在不同的增产条件下，我们观察到M1到S1之间存在强大的不对称连通性，这也是M1最突出的输出。在丘脑中，我们发现了不同的激活：M1刺激显示与丘脑腹侧核的前部相连，而S1与丘脑腹侧核的后部相连。这些发现表明，从M1到S1的皮质-皮质投射，而不是皮质-丘脑回路，在传递运动相关信息中起主导作用。总之，我们对感觉运动电路的详细剖析强调了m1到s1连接在感觉运动协调中的重要性。

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引用次数: 0

Awake reactivation of cortical memory traces predicts subsequent memory retrieval 清醒时皮层记忆痕迹的再激活预示着随后的记忆提取。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-07-01 Epub Date: 2025-05-15 DOI: 10.1016/j.pneurobio.2025.102778

Wei Duan , Pingping Lu , Zhansheng Xu , Jing Wang , Yue Lu , Mengyang Wang , Ken A. Paller , Nikolai Axmacher , Liang Wang

Brief periods of rest after learning facilitate consolidation of new memories. Memory reactivation and hippocampal-cortical dialogue have been proposed as candidate mechanisms supporting consolidation. However, the study of these mechanisms has mostly concerned sleep-based consolidation. Whether and how awake reactivation can selectively consolidate cortical memory traces to guide subsequent behavior requires more human electrophysiological evidence. This study addressed these issues by utilizing intracranial electroencephalography (iEEG) recordings from 11 patients with drug-resistant epilepsy, who learned a set of object-location associations. Using representational similarity analysis, we found that, among the multiple cortical memory traces of object-location associations for the same object generated through several rounds of learning, the association corresponding to memory traces with stronger cortical activation during wakeful rest was more likely to be retrieved later. Awake reactivation of cortical memory trace was accompanied by increased hippocampal ripple rates and enhanced theta-band hippocampal-cortical communication, with hippocampal interactions with cortical regions within the default mode network preceding cortical reactivation. Together, these results suggest that awake reactivation of cortical memory trace during post-learning rest supports memory consolidation, predicting subsequent recall.

学习后短暂的休息有助于巩固新记忆。记忆再激活和海马体-皮层对话被认为是支持巩固的候选机制。然而，对这些机制的研究主要涉及基于睡眠的巩固。清醒再激活是否以及如何选择性地巩固皮层记忆痕迹以指导后续行为需要更多的人类电生理证据。本研究通过利用11例耐药癫痫患者的颅内脑电图（iEEG）记录来解决这些问题，这些患者学习了一组物体定位关联。通过表征相似性分析，我们发现，在通过多轮学习产生的对同一物体的物体定位关联的多个皮层记忆痕迹中，在清醒休息时皮层激活较强的记忆痕迹对应的关联更有可能在随后被检索。皮层记忆痕迹的清醒再激活伴随着海马纹波率的增加和海马-皮层通讯的增强，在皮层再激活之前，海马与默认模式网络内的皮层区域相互作用。总之，这些结果表明，在学习后休息期间皮层记忆痕迹的清醒再激活支持记忆巩固，预测随后的回忆。

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引用次数: 0

EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2 MDGA2负向调节EphB2受体酪氨酸激酶介导的兴奋性突触功能

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-07-01 Epub Date: 2025-05-01 DOI: 10.1016/j.pneurobio.2025.102772

Hyeonho Kim , Younghyeon Jeon , Seunghye Kim , Yuxuan Guo , Dongwook Kim , Gyubin Jang , Julia Brasch , Ji Won Um , Jaewon Ko

MDGA2 is an excitatory synapse-specific suppressor that uses distinct extracellular mechanisms to negatively regulate various postsynaptic properties. Here, we identify EphB2, an excitatory synapse-specific receptor tyrosine kinase, as a new binding partner for MDGA2. The first three immunoglobulin domains of MDGA2 undergo cis-binding to the ligand-binding domain of EphB2, enabling MDGA2 to compete with Ephrin-B1 for binding to EphB2. Moreover, EphB2 forms complexes with MDGA2 and GluN2B-containing NMDA receptors (NMDARs) in mouse brains. MDGA2 deletion promotes formation of the EphB2/Ephrin-B1 complex but does not alter the surface expression levels and Ephrin-stimulated activation of EphB2 receptors and downstream GluN2B-containing NMDARs in cultured neurons. AlphaFold-based molecular replacement experiments reveal that MDGA2 must bind EphB2 to suppress spontaneous synaptic transmission and NMDAR-mediated, but not AMPAR-mediated, postsynaptic responses at excitatory synapses in cultured neurons. These results collectively suggest that MDGA2 is a versatile factor that suppresses distinct excitatory postsynaptic properties via different transsynaptic pathways.

MDGA2是一种兴奋性突触特异性抑制因子，使用不同的细胞外机制负性调节各种突触后特性。在这里，我们发现EphB2，一种兴奋性突触特异性受体酪氨酸激酶，作为MDGA2的新结合伙伴。MDGA2的前三个免疫球蛋白域与EphB2的配体结合域进行顺式结合，使MDGA2与Ephrin-B1竞争EphB2的结合。此外，EphB2在小鼠脑内与含有MDGA2和glun2b的NMDA受体（NMDARs）形成复合物。MDGA2缺失促进EphB2/Ephrin-B1复合物的形成，但不改变培养神经元中EphB2受体的表面表达水平和ephrin刺激的EphB2受体和下游含glun2b的NMDARs的激活。基于alphafold的分子替代实验表明，MDGA2必须结合EphB2才能抑制神经元兴奋性突触的自发突触传递和nmdar介导的突触后反应，而不是ampar介导的突触后反应。这些结果共同表明MDGA2是一个多用途因子，通过不同的跨突触途径抑制不同的兴奋性突触后特性。

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引用次数: 0

Slumber under pressure: REM sleep and stress response 压力下的睡眠：快速眼动睡眠和应激反应

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-01 Epub Date: 2025-04-22 DOI: 10.1016/j.pneurobio.2025.102771

Bernhard Schaefke , Jingfei Li , Binghao Zhao , Liping Wang , Yu-Ting Tseng

Sleep, a state of reduced responsiveness and distinct brain activity, is crucial across the animal kingdom. This review explores the potential adaptive functions of REM sleep in adapting to stress, emphasizing its role in memory consolidation, emotional regulation, and threat processing. We further explore the underlying neural mechanisms linking stress responses to REM sleep. By synthesizing current findings, we propose that REM sleep allows animals to "rehearse" or simulate responses to danger in a secure, offline state, while also maintaining emotional balance. Environmental factors, such as predation risk and social dynamics, further influence REM sleep. This modulation may enhance survival by optimizing stress responses while fulfilling physiological needs in animals. Insights into REM sleep's role in animals may shed light on human sleep in the context of modern stressors and sleep disruptions. This review also explores the complex interplay between stress, immunity, sleep disruptions—particularly involving REM sleep—and their evolutionary underpinnings.

睡眠是一种反应能力降低、大脑活动明显的状态，在动物王国中至关重要。本文探讨了快速眼动睡眠在适应压力方面的潜在适应功能，强调了其在记忆巩固、情绪调节和威胁处理方面的作用。我们进一步探讨了应激反应与快速眼动睡眠之间的潜在神经机制。通过综合目前的研究结果，我们提出快速眼动睡眠允许动物在安全的离线状态下“排练”或模拟对危险的反应，同时也保持情绪平衡。环境因素，如捕食风险和社会动态，进一步影响快速眼动睡眠。这种调节可以通过优化应激反应来提高动物的存活率，同时满足动物的生理需求。对动物快速眼动睡眠作用的深入了解，可能会在现代压力源和睡眠中断的背景下，为人类睡眠提供启示。这篇综述还探讨了压力、免疫力、睡眠中断（特别是涉及快速眼动睡眠）及其进化基础之间复杂的相互作用。

引用次数: 0

Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's disease mouse model 运动前皮层兴奋性的调节减轻了帕金森病小鼠模型的行为和电生理异常

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-01 Epub Date: 2025-04-19 DOI: 10.1016/j.pneurobio.2025.102761

In Sun Choi , Jinmo Kim , Joon Ho Choi , Eun-Mee Kim , Ji-Woong Choi , Jong-Cheol Rah

The subthalamic nucleus (STN) plays a crucial role in suppressing prepotent response tendency. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and the optogenetic activation of these neurons suppresses ongoing behavior. High-frequency electrical stimulation of the STN effectively treats the motor symptoms of Parkinson's disease (PD), yet its underlying circuit mechanisms remain unclear. Here, we investigated the involvement of STN-projecting premotor (M2) neurons in PD mouse models and the impact of deep brain stimulation targeting the STN (DBS-STN). We found that the M2 neurons exhibited enhanced burst firing and synchronous oscillations in the PD mouse model. Remarkably, high-frequency stimulation of STN-projecting M2 neurons, simulating antidromic activation during DBS-STN relieved motor symptoms and hyperexcitability. These changes were attributed to reduced firing frequency vs. current relationship through normalized hyperpolarization-activated inward current (Ih). The M2 neurons in the PD model mouse displayed increased Ih, which was reversed by high-frequency stimulation. Additionally, the infusion of ZD7288, an HCN channel blocker, into the M2 replicated the effects of high-frequency stimulation. In conclusion, our study reveals excessive excitability and suppressive motor control through M2-STN synapses in a PD mouse model. Antidromic excitation of M2 neurons during DBS-STN alleviates this suppression, thereby improving motor impairment. These findings provide insights into the circuit-level dynamics underlying deep brain stimulation's therapeutic effects in PD, suggesting that M2-STN synapses could serve as potential targets for future therapeutic strategies.

丘脑下核（STN）在抑制性早熟反应倾向中起重要作用。在停止信号反应期间，支配STN的前额叶区域表现出增加的活性，并且这些神经元的光遗传激活抑制了正在进行的行为。高频电刺激STN有效治疗帕金森病（PD）的运动症状，但其潜在的电路机制尚不清楚。在此，我们研究了PD小鼠模型中STN投射前运动（M2）神经元的参与以及针对STN的脑深部刺激（DBS-STN）的影响。我们发现，在PD小鼠模型中，M2神经元表现出增强的突发放电和同步振荡。值得注意的是，模拟DBS-STN过程中反向激活的stn投射M2神经元的高频刺激可缓解运动症状和高兴奋性。这些变化归因于通过标准化超极化激活的内向电流（Ih）降低了放电频率与电流的关系。PD模型小鼠M2神经元Ih升高，高频刺激可逆转Ih升高。此外，将HCN通道阻滞剂ZD7288注入M2可复制高频刺激的效果。总之，我们的研究揭示了PD小鼠模型通过M2-STN突触过度兴奋性和抑制性运动控制。DBS-STN时M2神经元的反向兴奋可缓解这种抑制，从而改善运动损伤。这些发现为深部脑刺激对PD治疗作用的回路水平动力学提供了见解，表明M2-STN突触可以作为未来治疗策略的潜在靶点。

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引用次数: 0

Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer’s disease 了解tau、淀粉样蛋白和网络在阿尔茨海默病时空进展中的复杂相互作用。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-01 Epub Date: 2025-03-17 DOI: 10.1016/j.pneurobio.2025.102750

Ashish Raj , Justin Torok , Kamalini Ranasinghe

Introduction

The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success.

Methods

We tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI.

Results

Although network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best.

Discussion

This mathematical exposition of the “pas de deux” of co-evolving proteins provides quantitative, whole-brain support to the concept of amyloid-facilitated-tauopathy rather than the classic amyloid-cascade or pure-tau hypotheses, and helps explain certain known but poorly understood aspects of AD.

淀粉样蛋白和tau蛋白在神经退行性疾病中的相互作用是AD病理生理学的核心特征。虽然实验研究指出了各种相互作用机制，但它们的因果方向和模式（本地、远程或网络介导）在人类受试者中仍然未知。本研究的目的是比较数学反应-扩散模型编码不同的跨物种耦合，以确定哪些相互作用是模型成功的关键。方法：我们在ADNI的公开数据上测试了网络传播、聚集和淀粉样蛋白-tau相互作用的竞争性数学模型。结果：尽管网络传播模型捕获了人类受试者中tau和淀粉样蛋白的时空演化，但包括淀粉样蛋白-tau蛋白单向聚集相互作用的模型表现最好。讨论：这种对共同进化蛋白的“双人跳”的数学阐述为淀粉样蛋白促进性tau病的概念提供了定量的全脑支持，而不是经典的淀粉样蛋白级联或纯tau假设，并有助于解释AD的某些已知但知之甚少的方面。

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引用次数: 0

Neural connections and molecular mechanisms underlying motor skill deficits in genetic models of autism spectrum disorders 自闭症谱系障碍遗传模型中运动技能缺陷的神经连接和分子机制

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-01 Epub Date: 2025-04-18 DOI: 10.1016/j.pneurobio.2025.102759

Jingwen Duan , Deyang Zeng , Tong Wu , Zhenzhao Luo , Geng Jingwen , Wei Tan , Yan Zeng

Autism spectrum disorders (ASDs) comprise a broad category of neurodevelopmental disorders that include repetitive behaviors and difficulties in social interactions. Notably, individuals with ASDs exhibit significant impairments in motor skills even prior to the manifestation of other core symptoms. These skills are crucial for daily activities, such as communication, imitation, and exploration, and hold significant importance for individuals with ASDs. This review seeks to offer new insights into the understanding of motor skill impairments by delineating the pathological mechanisms underlying motor skill learning impairments associated with gene mutations in Fmr1, Chd8, Shank3, BTBR, 16p11.2, and Mecp2, predominantly drawing from well-characterized genetic mouse model studies and proposing potential targets for future therapeutic interventions. We further discuss the underlying pathogenic abnormalities associated with the development of specific brain regions within the cerebellum and cerebrum, as well as disruptions in the structure and function of critical neuronal connectivity pathways. Additional research utilizing epidemiological data, clinical observations, and animal research methodologies is warranted to enhance our understanding of the effect of motor skill learning on the growth, development, and social integration of children. Ultimately, our review suggests potential targets for future therapeutic interventions.

自闭症谱系障碍（ASDs）包括一大类神经发育障碍，包括重复性行为和社会互动困难。值得注意的是，asd患者甚至在其他核心症状出现之前就表现出了运动技能的显著损伤。这些技能对于日常活动至关重要，比如沟通、模仿和探索，对自闭症患者来说非常重要。本综述旨在通过描述与Fmr1、Chd8、Shank3、BTBR、16p11.2和Mecp2基因突变相关的运动技能学习障碍的病理机制，为理解运动技能障碍提供新的见解，主要来自于具有良好特征的遗传小鼠模型研究，并提出未来治疗干预的潜在目标。我们进一步讨论了与小脑和大脑内特定大脑区域发育相关的潜在致病性异常，以及关键神经元连接通路结构和功能的破坏。利用流行病学数据、临床观察和动物研究方法的进一步研究是有必要的，以增强我们对运动技能学习对儿童生长、发育和社会融合的影响的理解。最后，我们的综述提出了未来治疗干预的潜在目标。

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