Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer’s disease

理解tau蛋白、淀粉样蛋白与神经网络在阿尔茨海默病时空进展中的复杂相互作用

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. 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.

神经退行性疾病中淀粉样蛋白和tau蛋白的相互作用是阿尔茨海默病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，但在人类受试者中，它们的因果方向和模式（局部、远程或网络介导）仍不清楚。本研究的目的是比较编码不同跨物种耦合的数学反应 - 扩散模型，以确定哪些相互作用是模型成功的关键。尽管网络传播模型捕捉到了人类受试者中tau蛋白和淀粉样蛋白的时空演变，但包含从淀粉样蛋白到tau蛋白单向聚集相互作用的模型表现最佳。

REF: Raj A, Torok J, Ranasinghe K. Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer's disease. Prog Neurobiol. 2025;249:102750. doi:10.1016/j.pneurobio.2025.102750 PMID: 40107380

Expanding the stimulus domain: Co-occurrence of motion and body-category selectivity in the macaque ventral STS

扩展刺激领域：猕猴腹侧上颞沟中运动选择性与身体类别选择性的共现

The primate Superior Temporal Sulcus (STS) plays a pivotal role in the recognition of bodies and their actions, which is essential for survival and social interaction with conspecifics. Here, we show that, surprisingly, a sizable proportion of macaque middle ventral STS units are selective for static bodies and random dot motion. They show a faithful representation of random dot motion direction, with motion directions differing by 180 degrees being represented distinctly, although responding more strongly to complex optic flow patterns. This aligns with an fMRI experiment in which we show that the mid-STS body patch, defined by a greater activation to static bodies compared to faces and objects, is also more strongly activated by moving random dot patterns compared to static ones, especially when including complex optic flow patterns. More anterior ventral STS body-selective units demonstrate a less pronounced random dot motion selectivity and this is mainly for complex optic flow patterns. Moreover, middle STS units, but rarely those of the anterior STS, respond selectively to dynamic dot patterns in which body parts are visible solely through motion, and their preference correlates with those for videos of acting monkeys. Overall, these findings highlight an association between body and motion processing in the macaque ventral STS, which might result from the co-occurrence of body features and motion during the observation of bodily actions.

灵长类动物的上颞沟（STS）在识别身体及其动作方面起着关键作用，这对于生存和与同类进行社交互动至关重要。在这里，我们惊讶地发现，猕猴中腹侧上颞沟的相当一部分神经元对静态身体和随机点运动具有选择性。它们能如实表征随机点运动的方向，相差180度的运动方向能被清晰区分，不过对复杂的光流模式反应更强。这与一项功能性磁共振成像（fMRI）实验结果相符，在该实验中我们发现，与面部和物体相比，对静态身体有更强激活的中STS身体区，与静态随机点图案相比，对动态随机点图案的激活也更强，尤其是当包含复杂光流模式时。更靠前的腹侧STS身体选择性神经元对随机点运动的选择性不太明显，且主要针对复杂光流模式。此外，中STS的神经元，但前STS的神经元很少，会选择性地对仅通过运动才能看到身体部位的动态点图案做出反应，并且它们的偏好与对猴子动作视频的偏好相关。总体而言，这些发现凸显了猕猴腹侧STS中身体处理和运动处理之间的关联，这可能是由于在观察身体动作时身体特征和运动同时出现所致。

REF: Bognár A, Nejad GG, Rens G, Raman R, Vogels R. Expanding the stimulus domain: Co-occurrence of motion and body-category selectivity in the macaque ventral STS. Prog Neurobiol. 2025;249:102769. doi:10.1016/j.pneurobio.2025.102769 PMID: 40254177

Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's disease mouse model

运动前皮质兴奋性的调节可减轻帕金森病小鼠模型的行为和电生理异常

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.

丘脑底核（STN）在抑制优势反应倾向方面起着至关重要的作用。在停止信号反应期间，支配STN的前额叶区域活动增加，对这些神经元进行光遗传学激活可抑制正在进行的行为。对STN进行高频电刺激能有效治疗帕金森病（PD）的运动症状，但其潜在的环路机制仍不清楚。在此，我们研究了在PD小鼠模型中投射到STN的运动前区（M2）神经元的参与情况，以及靶向STN的深部脑刺激（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爆发式放电和同步振荡。值得注意的是，模拟DBS - STN期间的逆向激活，对投射到STN的M2神经元进行高频刺激可缓解运动症状和过度兴奋。这些变化归因于通过使超极化激活的内向电流（Ih）正常化而降低了放电频率与电流的关系。PD模型小鼠的M2神经元表现出Ih增加，而高频刺激可逆转这一现象。此外，向M2区注入HCN通道阻滞剂ZD7288可重现高频刺激的效果。总之，我们的研究揭示了在PD小鼠模型中，通过M2 - STN突触存在过度兴奋和抑制性运动控制。DBS - STN期间M2神经元的逆向兴奋可减轻这种抑制，从而改善运动障碍。这些发现为深入了解深部脑刺激治疗PD的环路水平动力学提供了依据，表明M2 - STN突触可能成为未来治疗策略的潜在靶点。

REF: Choi IS, Kim J, Choi JH, Kim EM, Choi JW, Rah JC. Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's disease mouse model. Prog Neurobiol. 2025;249:102761. doi:10.1016/j.pneurobio.2025.102761 PMID: 40258455

Glycine-gated extrasynaptic NMDARs activated during glutamate spillover drive burst firing in nigral dopamine neurons

谷氨酸外溢期间激活的甘氨酸门控突触外N - 甲基 - D - 天冬氨酸受体（NMDARs）驱动黑质多巴胺能神经元产生爆发式放电

Burst firing in substantia nigra pars compacta dopamine neurons is a critical biomarker temporally associated to movement initiation. This phasic change is generated by the tonic activation of NMDARs but the respective role of synaptic versus extrasynaptic NMDARs in the ignition of a burst and what is their level of activation remains unknown. Using ex vivo electrophysiological recordings from adolescent rats, we demonstrate that extrasynaptic NMDARs are the primary driver of burst firing. This pool of receptors is recruited during intense synaptic activity via spillover of glutamate and require the binding of NMDAR co-agonist glycine for full activation. Basal synaptic transmission activating only synaptic NMDARs with the support of D-serine is insufficient to generate a burst. Notably, both synaptic and extrasynaptic NMDARs share the same subunit composition but are regulated by distinct co-agonists. Location of NMDARs and regionalization of co-agonists but not NMDAR subunit composition underly burst generation and may serve as a guideline in understanding the physiological role of dopamine in signaling movement.

黑质致密部多巴胺能神经元的爆发式放电是与运动启动在时间上相关的关键生物标志物。这种阶段性变化是由N - 甲基 - D - 天冬氨酸受体（NMDARs）的持续性激活所引发的，但突触和突触外NMDARs在触发爆发式放电中各自的作用以及它们的激活水平仍不清楚。通过对青春期大鼠进行离体电生理记录，我们发现突触外NMDARs是爆发式放电的主要驱动因素。在强烈的突触活动期间，这部分受体可通过谷氨酸的弥散而被募集，并且其完全激活需要NMDAR的共激动剂甘氨酸结合。仅在D - 丝氨酸支持下激活突触NMDARs的基础突触传递不足以引发爆发式放电。值得注意的是，突触和突触外NMDARs具有相同的亚基组成，但受不同的共激动剂调节。NMDARs的位置和共激动剂的区域化而非NMDAR亚基组成是爆发式放电产生的基础，这可能为理解多巴胺在运动信号传导中的生理作用提供指导。

REF: Ringlet S, Motta Z, Vandries L, et al. Glycine-gated extrasynaptic NMDARs activated during glutamate spillover drive burst firing in nigral dopamine neurons. Prog Neurobiol. 2025;249:102773. doi:10.1016/j.pneurobio.2025.102773 PMID: 40294743

Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention

癫痫中由突触传递和容积传递介导的神经元网络致命性相互作用为预防提供了思路

Neuronal network interactions are important in normal brain physiology and also in brain disorders. Many mesoscopic networks, including the auditory and respiratory network, mediate a single brain function. Macroscopic networks, including the locomotor network, central autonomic network (CAN), and many seizure networks involve interactions among multiple mesoscopic networks. Network interactions are mediated by neuroactive substances, acting via synaptic transmission, which mediate rapid interactions between networks. Slower, but vitally important network interactions, are mediated by volume transmission. Changes in the interactions between networks, mediated by neuroactive substances, can significantly alter network function and interactions. The acoustic startle response involves interactions between auditory and locomotor networks, and also includes brainstem reticular formation (BRF) nuclei, which participate in many different networks. In the fear-potentiated startle paradigm this network interacts positively with the amygdala, induced by conditioning. Seizure networks can interact negatively with the respiratory network, which becomes lethal in sudden unexpected death in epilepsy (SUDEP), a tragic emergent property of the seizure network. SUDEP models that exhibit audiogenic seizures (AGSz) involve interactions between the auditory and locomotor networks with BRF nuclei. In the DBA/1 mouse SUDEP model the AGSz network interacts negatively with the respiratory network, resulting in postictal apnea. The apnea is lethal unless the CAN is able to initiate autoresuscitation. These network interactions involve synaptic transmission, mediated by GABA and glutamate and volume transmission mediated by adenosine, CO2 and serotonin. Altering these interaction mechanisms may prevent SUDEP. These epilepsy network interactions illustrate the complex mechanisms that can occur among neuronal networks.

神经网络相互作用在正常大脑生理以及脑部疾病中都很重要。许多介观网络，包括听觉网络和呼吸网络，介导单一的大脑功能。宏观网络，包括运动网络、中枢自主神经网络（CAN）和许多癫痫发作网络，涉及多个介观网络之间的相互作用。网络相互作用由神经活性物质介导，通过突触传递发挥作用，介导网络之间的快速相互作用。较慢但至关重要的网络相互作用则由容积传递介导。由神经活性物质介导的网络间相互作用的改变，可显著改变网络功能和相互作用。听觉惊跳反射涉及听觉网络和运动网络之间的相互作用，还包括脑干网状结构（BRF）核，这些核参与了许多不同的网络。在恐惧增强惊跳范式中，该网络在条件作用诱导下与杏仁核产生正向相互作用。癫痫发作网络可与呼吸网络产生负向相互作用，在癫痫猝死综合征（SUDEP）中这种相互作用会致命，这是癫痫发作网络的一种悲剧性涌现特性。表现出声源性癫痫发作（AGSz）的SUDEP模型涉及听觉和运动网络与BRF核之间的相互作用。在DBA/1小鼠SUDEP模型中，AGSz网络与呼吸网络产生负向相互作用，导致发作后呼吸暂停。除非CAN能够启动自主复苏，否则这种呼吸暂停会致命。这些网络相互作用涉及由γ-氨基丁酸（GABA）和谷氨酸介导的突触传递，以及由腺苷、二氧化碳和血清素介导的容积传递。改变这些相互作用机制可能预防SUDEP。这些癫痫网络相互作用阐明了神经元网络之间可能出现的复杂机制。

REF: Faingold CL. Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention. Prog Neurobiol. 2025;249:102770. doi:10.1016/j.pneurobio.2025.102770 PMID: 40258456

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

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）是一大类神经发育障碍性疾病，其特征包括重复行为和社交互动困难。值得注意的是，自闭症谱系障碍患者甚至在其他核心症状出现之前就已表现出明显的运动技能损伤。这些技能对于日常活动（如沟通、模仿和探索）至关重要，对自闭症谱系障碍患者而言意义重大。本综述旨在通过阐述与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，为理解运动技能损伤提供新的见解，主要依据的是特征明确的基因小鼠模型研究，并为未来的治疗干预提出潜在靶点。我们还将探讨与小脑和大脑特定脑区发育相关的潜在致病异常，以及关键神经元连接通路的结构和功能破坏。有必要开展更多利用流行病学数据、临床观察和动物研究方法的研究，以加深我们对运动技能学习对儿童成长、发育和社会融合影响的理解。最后，我们的综述提出了未来治疗干预的潜在靶点。

REF: Duan J, Zeng D, Wu T, et al. Neural connections and molecular mechanisms underlying motor skill deficits in genetic models of autism spectrum disorders. Prog Neurobiol. 2025;249:102759. doi:10.1016/j.pneurobio.2025.102759 PMID: 40254176

Slumber under pressure: REM sleep and stress response

压力下的睡眠：快速眼动睡眠与应激反应

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.

睡眠是一种反应性降低且大脑活动独特的状态，在整个动物界都至关重要。本综述探讨了快速眼动睡眠（REM睡眠）在适应压力方面的潜在适应性功能，强调了其在记忆巩固、情绪调节和威胁处理中的作用。我们进一步探究了将应激反应与REM睡眠联系起来的潜在神经机制。通过整合当前研究结果，我们提出REM睡眠使动物能够在安全的离线状态下“预演”或模拟对危险的反应，同时保持情绪平衡。环境因素，如被捕食风险和社会动态，进一步影响REM睡眠。这种调节可能通过优化动物的应激反应，同时满足其生理需求来提高生存率。深入了解REM睡眠在动物中的作用，可能有助于理解在现代压力源和睡眠干扰背景下的人类睡眠。本综述还探讨了压力、免疫、睡眠干扰（尤其是涉及REM睡眠的干扰）之间的复杂相互作用及其进化基础。

REF: Schaefke B, Li J, Zhao B, Wang L, Tseng YT. Slumber under pressure: REM sleep and stress response. Prog Neurobiol. 2025;249:102771. doi:10.1016/j.pneurobio.2025.102771 PMID: 40273975