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Elucidating the interaction between stretch and stiffness using an agent-based spring network model of progressive pulmonary fibrosis 利用基于代理的渐进性肺纤维化弹簧网络模型阐明伸展与僵硬之间的相互作用
Pub Date : 2024-05-22 DOI: 10.3389/fnetp.2024.1396383
Joseph K. Hall, Jason H. T. Bates, Ramaswamy Krishnan, Jae Hun Kim, Yuqing Deng, K. Lutchen, B. Suki
Pulmonary fibrosis is a deadly disease that involves the dysregulation of fibroblasts and myofibroblasts, which are mechanosensitive. Previous computational models have succeeded in modeling stiffness-mediated fibroblasts behaviors; however, these models have neglected to consider stretch-mediated behaviors, especially stretch-sensitive channels and the stretch-mediated release of latent TGF-β. Here, we develop and explore an agent-based model and spring network model hybrid that is capable of recapitulating both stiffness and stretch. Using the model, we evaluate the role of mechanical signaling in homeostasis and disease progression during self-healing and fibrosis, respectively. We develop the model such that there is a fibrotic threshold near which the network tends towards instability and fibrosis or below which the network tends to heal. The healing response is due to the stretch signal, whereas the fibrotic response occurs when the stiffness signal overpowers the stretch signal, creating a positive feedback loop. We also find that by changing the proportional weights of the stretch and stiffness signals, we observe heterogeneity in pathological network structure similar to that seen in human IPF tissue. The system also shows emergent behavior and bifurcations: whether the network will heal or turn fibrotic depends on the initial network organization of the damage, clearly demonstrating structure’s pivotal role in healing or fibrosis of the overall network. In summary, these results strongly suggest that the mechanical signaling present in the lungs combined with network effects contribute to both homeostasis and disease progression.
肺纤维化是一种致命疾病,涉及对机械敏感的成纤维细胞和肌成纤维细胞的失调。以前的计算模型成功地模拟了硬度介导的成纤维细胞行为,但这些模型忽略了拉伸介导的行为,尤其是拉伸敏感通道和拉伸介导的潜伏 TGF-β 释放。在这里,我们开发并探索了一种基于代理的模型和弹簧网络模型的混合模型,该模型能够再现僵硬和拉伸。利用该模型,我们分别评估了自我修复和纤维化过程中机械信号在平衡和疾病进展中的作用。我们建立的模型存在一个纤维化阈值,在该阈值附近,网络趋向于不稳定和纤维化,而在该阈值以下,网络趋向于愈合。自愈反应是由拉伸信号引起的,而纤维化反应则发生在刚度信号超过拉伸信号时,这就形成了一个正反馈回路。我们还发现,通过改变拉伸和僵硬信号的比例权重,我们可以观察到病理网络结构的异质性,这与人类 IPF 组织中的情况类似。该系统还显示出突发性行为和分岔:网络是愈合还是纤维化取决于损伤的初始网络组织,这清楚地表明了结构在整个网络的愈合或纤维化中的关键作用。总之,这些结果有力地表明,肺部存在的机械信号与网络效应相结合,有助于平衡和疾病的发展。
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引用次数: 0
Editorial: Reviews in networks in the brain system 社论:大脑系统网络评论
Pub Date : 2024-05-21 DOI: 10.3389/fnetp.2024.1403698
Cristina Masoller, Klaus Lehnertz, Marc Goodfellow, Dimitris Kugiumtzis, Michal Zochowski
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引用次数: 0
Testing dynamic correlations and nonlinearity in bivariate time series through information measures and surrogate data analysis 通过信息度量和代用数据分析测试双变量时间序列中的动态相关性和非线性
Pub Date : 2024-05-21 DOI: 10.3389/fnetp.2024.1385421
Hélder Pinto, Ivan Lazic, Y. Antonacci, R. Pernice, Danlei Gu, Chiara Barà, L. Faes, Ana Paula Rocha
The increasing availability of time series data depicting the evolution of physical system properties has prompted the development of methods focused on extracting insights into the system behavior over time, discerning whether it stems from deterministic or stochastic dynamical systems. Surrogate data testing plays a crucial role in this process by facilitating robust statistical assessments. This ensures that the observed results are not mere occurrences by chance, but genuinely reflect the inherent characteristics of the underlying system. The initial process involves formulating a null hypothesis, which is tested using surrogate data in cases where assumptions about the underlying distributions are absent. A discriminating statistic is then computed for both the original data and each surrogate data set. Significantly deviating values between the original data and the surrogate data ensemble lead to the rejection of the null hypothesis. In this work, we present various surrogate methods designed to assess specific statistical properties in random processes. Specifically, we introduce methods for evaluating the presence of autodependencies and nonlinear dynamics within individual processes, using Information Storage as a discriminating statistic. Additionally, methods are introduced for detecting coupling and nonlinearities in bivariate processes, employing the Mutual Information Rate for this purpose. The surrogate methods introduced are first tested through simulations involving univariate and bivariate processes exhibiting both linear and nonlinear dynamics. Then, they are applied to physiological time series of Heart Period (RR intervals) and respiratory flow (RESP) variability measured during spontaneous and paced breathing. Simulations demonstrated that the proposed methods effectively identify essential dynamical features of stochastic systems. The real data application showed that paced breathing, at low breathing rate, increases the predictability of the individual dynamics of RR and RESP and dampens nonlinearity in their coupled dynamics.
描述物理系统特性演变的时间序列数据越来越多,这促使人们开发出各种方法,重点是深入了解系统随时间变化的行为,分辨它是源于确定性动态系统还是随机动态系统。代用数据测试通过促进稳健的统计评估,在这一过程中发挥着至关重要的作用。这可以确保观察到的结果并非偶然发生,而是真正反映了底层系统的固有特征。最初的过程包括提出一个零假设,并在不存在基本分布假设的情况下使用代用数据进行检验。然后对原始数据和每个代用数据集计算判别统计量。原始数据和代用数据集合之间的显著偏差值会导致拒绝零假设。在这项工作中,我们介绍了各种旨在评估随机过程中特定统计属性的代用方法。具体来说,我们介绍了评估单个过程中是否存在自依赖性和非线性动态的方法,并将信息存储作为一种判别统计量。此外,我们还介绍了检测双变量过程中耦合性和非线性的方法,并为此使用了互信息率。介绍的代用方法首先通过涉及单变量和双变量过程的模拟进行测试,这些过程既有线性动态过程,也有非线性动态过程。然后,将其应用于在自主呼吸和起搏呼吸过程中测量的心脏周期(RR 间隔)和呼吸流量(RESP)变异性的生理时间序列。模拟结果表明,所提出的方法能有效识别随机系统的基本动态特征。实际数据应用表明,低呼吸频率下的节律呼吸提高了 RR 和 RESP 各自动态的可预测性,并抑制了它们耦合动态的非线性。
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引用次数: 0
Complexity synchronization in living matter: a mini review 生命物质的复杂性同步化:小型综述
Pub Date : 2024-05-20 DOI: 10.3389/fnetp.2024.1379892
B. J. West
Fractal time series have been argued to be ubiquitous in human physiology and some of the implications of that ubiquity are quite remarkable. One consequence of the omnipresent fractality is complexity synchronization (CS) observed in the interactions among simultaneously recorded physiologic time series discussed herein. This new kind of synchronization has been revealed in the interaction triad of organ-networks (ONs) consisting of the mutually interacting time series generated by the brain (electroencephalograms, EEGs), heart (electrocardiograms, ECGs), and lungs (Respiration). The scaled time series from each member of the triad look nothing like one another and yet they bear a deeply recorded synchronization invisible to the naked eye. The theory of scaling statistics is used to explain the source of the CS observed in the information exchange among these multifractal time series. The multifractal dimension (MFD) of each time series is a measure of the time-dependent complexity of that time series, and it is the matching of the MFD time series that provides the synchronization referred to as CS. The CS is one manifestation of the hypothesis given by a “Law of Multifractal Dimension Synchronization” (LMFDS) which is supported by data. Therefore, the review aspects of this paper are chosen to make the extended range of the LMFDS hypothesis sufficiently reasonable to warrant further empirical testing.
分形时间序列在人类生理学中被认为是无处不在的,而这种无处不在所带来的一些影响是非常显著的。本文讨论的同时记录的生理时间序列之间的相互作用中观察到的复杂性同步(CS)就是分形无处不在的结果之一。大脑(脑电图)、心脏(心电图)和肺部(呼吸)产生的相互影响的时间序列组成的器官网络(ON)的相互作用三元组揭示了这种新型同步。来自三元组每个成员的缩放时间序列看起来彼此完全不同,但它们却具有肉眼无法看到的深度同步记录。缩放统计理论被用来解释在这些多分形时间序列之间的信息交换中观察到的 CS 的来源。每个时间序列的多分形维度(MFD)是衡量该时间序列随时间变化的复杂性的指标,而正是多分形维度时间序列的匹配提供了被称为 CS 的同步性。CS 是 "多分形维度同步定律"(LMFDS)假设的一种表现形式,该假设得到了数据的支持。因此,本文的综述内容选择使 LMFDS 假设的扩展范围足够合理,值得进一步实证检验。
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引用次数: 0
A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology 急性肺损伤和呼吸机诱发肺损伤的无标度模型:受地震学启发的网络理论方法
Pub Date : 2024-05-01 DOI: 10.3389/fnetp.2024.1392701
Drew C. Gottman, Bradford J. Smith
Introduction Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes. Methods Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as ‘nodes’ in the network and ‘edges’ quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events. Results Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across ‘injury’ pixels. Overall accuracy across ‘injury’, ‘air’, and ‘other’ pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a ‘rich-get-richer’ phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks. Conclusion The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury ‘hubs’ that are consistent with a ‘rich-get-richer’ dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury ‘hubs’ to reduce the impact of VILI in ARDS management.
引言 急性呼吸窘迫综合征(ARDS)是一项重大的临床挑战,呼吸机诱发的肺损伤(VILI)是挽救生命的机械通气引起的严重并发症。了解 VILI 的空间和时间动态可为减轻肺损伤和改善预后的治疗策略提供依据。方法 使用 Ilastik 对最初健康的小鼠和接受第二次 VILI 的肺灌洗损伤小鼠的组织切片进行分割,以确定肺损伤区域。采用无标度网络方法评估损伤区域之间的相关性,将损伤区域表示为网络中的 "节点","边 "量化节点之间的相关程度。还进行了模拟时间序列分析,以模拟损伤事件的时间序列。结果 自动分割识别出不同的肺部区域,与人工评分结果一致,"损伤 "像素的灵敏度为 78%,特异度为 85%。损伤"、"空气 "和 "其他 "像素的总体准确率为 81%。损伤区域的大小呈幂律分布,表明肺损伤的分布存在 "越丰富越严重 "的现象。网络分析揭示了损伤相关性的无规模分布,突出了损伤中心,可作为治疗干预的焦点。模拟时间序列分析进一步支持了初始损伤后二次损伤事件的概念,其模式与地震学研究中观察到的余震模式相似。结论 受伤区域的大小分布凸显了急性肺损伤和呼吸机诱发肺损伤在空间上的异质性。网络理论的应用表明,损伤 "中心 "的出现符合 "富者愈富 "的动态。模拟时间序列分析表明,肺部损伤事件的发展可能遵循类似于地震学中余震发展的时空模式,为损伤分布和传播机制提供了新的见解。这两种现象都表明,针对这些损伤 "枢纽 "的干预措施有可能在 ARDS 的治疗中减少 VILI 的影响。
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引用次数: 0
A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology. 急性和呼吸机诱发肺损伤的无标度模型:受地震学启发的网络理论方法。
Pub Date : 2024-05-01 eCollection Date: 2024-01-01 DOI: 10.3389/fnetp.2024.1392701
Drew C Gottman, Bradford J Smith

Introduction: Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes.

Methods: Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as 'nodes' in the network and 'edges' quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events.

Results: Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across 'injury' pixels. Overall accuracy across 'injury', 'air', and 'other' pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a 'rich-get-richer' phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks.

Conclusion: The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury 'hubs' that are consistent with a 'rich-get-richer' dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury 'hubs' to reduce the impact of VILI in ARDS management.

简介急性呼吸窘迫综合征(ARDS)是一项重大的临床挑战,呼吸机诱发的肺损伤(VILI)是挽救生命的机械通气所引起的严重并发症。方法:用 Ilastik 对最初健康的小鼠和接受第二次呼吸机诱发肺损伤的肺灌洗损伤小鼠的组织切片进行分割,以确定肺损伤区域。采用无标度网络方法评估损伤区域之间的相关性,将损伤区域表示为网络中的 "节点","边 "量化节点之间的相关程度。进行了模拟时间序列分析,以模拟损伤事件的时间序列:结果:自动分割识别出的不同肺部区域与人工评分结果一致,"损伤 "像素的灵敏度为 78%,特异度为 85%。损伤"、"空气 "和 "其他 "像素的总体准确率为 81%。损伤区域的大小呈幂律分布,表明肺损伤的分布存在 "越丰富越严重 "的现象。网络分析揭示了损伤相关性的无规模分布,突出了损伤中心,可作为治疗干预的焦点。模拟时间序列分析进一步支持了初始损伤后二次损伤事件的概念,其模式与地震学研究中观察到的余震模式相似:结论:损伤区域的大小分布凸显了急性肺损伤和呼吸机诱发肺损伤在空间上的异质性。网络理论的应用表明,损伤 "中心 "的出现符合 "富者愈富 "的动态。模拟时间序列分析表明,肺部损伤事件的发展可能遵循类似于地震学中余震发展的时空模式,为损伤分布和传播机制提供了新的见解。这两种现象都表明,针对这些损伤 "枢纽 "的干预措施有可能在 ARDS 的治疗中减少 VILI 的影响。
{"title":"A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology.","authors":"Drew C Gottman, Bradford J Smith","doi":"10.3389/fnetp.2024.1392701","DOIUrl":"https://doi.org/10.3389/fnetp.2024.1392701","url":null,"abstract":"<p><strong>Introduction: </strong>Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes.</p><p><strong>Methods: </strong>Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as 'nodes' in the network and 'edges' quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events.</p><p><strong>Results: </strong>Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across 'injury' pixels. Overall accuracy across 'injury', 'air', and 'other' pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a 'rich-get-richer' phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks.</p><p><strong>Conclusion: </strong>The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury 'hubs' that are consistent with a 'rich-get-richer' dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury 'hubs' to reduce the impact of VILI in ARDS management.</p>","PeriodicalId":73092,"journal":{"name":"Frontiers in network physiology","volume":"4 ","pages":"1392701"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140960390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Model-based closed-loop control of thalamic deep brain stimulation. 基于模型的丘脑深部脑刺激闭环控制。
Pub Date : 2024-04-08 eCollection Date: 2024-01-01 DOI: 10.3389/fnetp.2024.1356653
Yupeng Tian, Srikar Saradhi, Edward Bello, Matthew D Johnson, Gabriele D'Eleuterio, Milos R Popovic, Milad Lankarany

Introduction: Closed-loop control of deep brain stimulation (DBS) is beneficial for effective and automatic treatment of various neurological disorders like Parkinson's disease (PD) and essential tremor (ET). Manual (open-loop) DBS programming solely based on clinical observations relies on neurologists' expertise and patients' experience. Continuous stimulation in open-loop DBS may decrease battery life and cause side effects. On the contrary, a closed-loop DBS system uses a feedback biomarker/signal to track worsening (or improving) of patients' symptoms and offers several advantages compared to the open-loop DBS system. Existing closed-loop DBS control systems do not incorporate physiological mechanisms underlying DBS or symptoms, e.g., how DBS modulates dynamics of synaptic plasticity. Methods: In this work, we propose a computational framework for development of a model-based DBS controller where a neural model can describe the relationship between DBS and neural activity and a polynomial-based approximation can estimate the relationship between neural and behavioral activities. A controller is used in our model in a quasi-real-time manner to find DBS patterns that significantly reduce the worsening of symptoms. By using the proposed computational framework, these DBS patterns can be tested clinically by predicting the effect of DBS before delivering it to the patient. We applied this framework to the problem of finding optimal DBS frequencies for essential tremor given electromyography (EMG) recordings solely. Building on our recent network model of ventral intermediate nuclei (Vim), the main surgical target of the tremor, in response to DBS, we developed neural model simulation in which physiological mechanisms underlying Vim-DBS are linked to symptomatic changes in EMG signals. By using a proportional-integral-derivative (PID) controller, we showed that a closed-loop system can track EMG signals and adjust the stimulation frequency of Vim-DBS so that the power of EMG reaches a desired control target. Results and discussion: We demonstrated that the model-based DBS frequency aligns well with that used in clinical studies. Our model-based closed-loop system is adaptable to different control targets and can potentially be used for different diseases and personalized systems.

导言:脑深部刺激(DBS)的闭环控制有利于对帕金森病(PD)和本质性震颤(ET)等各种神经系统疾病进行有效的自动治疗。手动(开环)DBS 编程完全基于临床观察,依赖于神经科医生的专业知识和患者的经验。开环 DBS 的持续刺激可能会缩短电池寿命并导致副作用。相反,闭环 DBS 系统使用反馈生物标志物/信号来跟踪患者症状的恶化(或改善)情况,与开环 DBS 系统相比具有多项优势。现有的闭环 DBS 控制系统没有纳入 DBS 或症状的生理机制,例如 DBS 如何调节突触可塑性的动态。方法:在这项工作中,我们提出了开发基于模型的 DBS 控制器的计算框架,其中神经模型可以描述 DBS 和神经活动之间的关系,而基于多项式的近似值可以估计神经和行为活动之间的关系。在我们的模型中,控制器以准实时的方式用于寻找能显著减轻症状恶化的 DBS 模式。通过使用所提出的计算框架,这些 DBS 模式可以在为患者提供 DBS 之前通过预测 DBS 的效果进行临床测试。我们将这一框架应用于仅根据肌电图(EMG)记录寻找治疗本质性震颤的最佳 DBS 频率的问题。腹侧中间核(Vim)是震颤的主要手术靶点,基于我们最近建立的网络模型,我们开发了神经模型模拟,其中 Vim-DBS 的生理机制与 EMG 信号的症状变化相关联。通过使用比例-积分-派生(PID)控制器,我们证明闭环系统可以跟踪肌电信号并调节 Vim-DBS 的刺激频率,从而使肌电图的功率达到预期的控制目标。结果与讨论我们证明,基于模型的 DBS 频率与临床研究中使用的频率非常一致。我们基于模型的闭环系统可以适应不同的控制目标,并有可能用于不同的疾病和个性化系统。
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引用次数: 0
Biophysical modulation and robustness of itinerant complexity in neuronal networks. 神经元网络中巡回复杂性的生物物理调节和稳健性。
Pub Date : 2024-03-07 eCollection Date: 2024-01-01 DOI: 10.3389/fnetp.2024.1302499
Siva Venkadesh, Asmir Shaikh, Heman Shakeri, Ernest Barreto, John Darrell Van Horn

Transient synchronization of bursting activity in neuronal networks, which occurs in patterns of metastable itinerant phase relationships between neurons, is a notable feature of network dynamics observed in vivo. However, the mechanisms that contribute to this dynamical complexity in neuronal circuits are not well understood. Local circuits in cortical regions consist of populations of neurons with diverse intrinsic oscillatory features. In this study, we numerically show that the phenomenon of transient synchronization, also referred to as metastability, can emerge in an inhibitory neuronal population when the neurons' intrinsic fast-spiking dynamics are appropriately modulated by slower inputs from an excitatory neuronal population. Using a compact model of a mesoscopic-scale network consisting of excitatory pyramidal and inhibitory fast-spiking neurons, our work demonstrates a relationship between the frequency of pyramidal population oscillations and the features of emergent metastability in the inhibitory population. In addition, we introduce a method to characterize collective transitions in metastable networks. Finally, we discuss potential applications of this study in mechanistically understanding cortical network dynamics.

神经元网络中爆发活动的瞬时同步是体内观察到的网络动力学的一个显著特点,它以神经元之间可移动的巡回相位关系模式出现。然而,神经元网络中这种动态复杂性的形成机制还不甚明了。大脑皮层区域的局部回路由具有不同内在振荡特征的神经元群组成。在这项研究中,我们用数值方法证明,当抑制性神经元群的固有快速尖峰动态受到来自兴奋性神经元群的较慢输入的适当调节时,抑制性神经元群中就会出现瞬时同步现象,这种现象也被称为可迁移性。我们的研究使用了一个由兴奋性锥体神经元和抑制性快速尖峰神经元组成的介观尺度网络的紧凑模型,证明了锥体神经元群振荡频率与抑制性神经元群中出现的可迁移性特征之间的关系。此外,我们还介绍了一种表征可代谢网络中集体转换的方法。最后,我们讨论了这项研究在从机理上理解皮层网络动力学方面的潜在应用。
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引用次数: 0
Tissue lipidomic profiling supports a mechanistic role of the prostaglandin E2 pathway for albuminuria development in glomerular hyperfiltration 组织脂质体分析支持前列腺素 E2 通路在肾小球高滤过性白蛋白尿形成中的机理作用
Pub Date : 2023-12-22 DOI: 10.3389/fnetp.2023.1271042
Debora Kaiser-Graf, Angela Schulz, Eva Mangelsen, Michael Rothe, Juliane Bolbrinker, Reinhold Kreutz
Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. The Munich Wistar Frömter (MWF) rat is a non-diabetic model of chronic kidney disease (CKD) with GH due to inherited low nephron number resulting in spontaneous albuminuria and podocyte injury. In MWF rats, we identified prostaglandin (PG) E2 (PGE2) signaling as a potential causative mechanism of albuminuria in GH.Method: For evaluation of the renal PGE2 metabolic pathway, time-course lipidomic analysis of PGE2 and its downstream metabolites 15-keto-PGE2 and 13-14-dihydro-15-keto-PGE2 was conducted in urine, plasma and kidney tissues of MWF rats and albuminuria-resistant spontaneously hypertensive rats (SHR) by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS).Results: Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE2 and 15-keto-PGE2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE2 levels. Glomerular metabolic ratios of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were significantly lower, while metabolic ratios of prostaglandin reductases (PTGRs) were significantly higher in MWF rats with manifested albuminuria compared to SHR, respectively.Conclusion: Our data reveal glomerular dysregulation of the PGE2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE2 degradation. This study provides first insights into dynamic changes of the PGE2 pathway that support a role of glomerular PGE2 metabolism and signaling for early albuminuria manifestation in GH.
背景:肾小球高滤过(GH)是高血压患者白蛋白尿发生的重要机制。慕尼黑Wistar Frömter(MWF)大鼠是一种非糖尿病慢性肾病(CKD)模型,由于遗传性肾小球数量少导致自发性白蛋白尿和荚膜细胞损伤,因而患有GH。在 MWF 大鼠中,我们发现前列腺素(PG)E2(PGE2)信号传导是 GH 白蛋白尿的潜在致病机制:为了评估肾脏 PGE2 代谢途径,我们采用液相色谱电喷雾串联质谱法(LC/ESI-MS/MS)对 MWF 大鼠和白蛋白尿耐药自发性高血压大鼠(SHR)的尿液、血浆和肾组织中的 PGE2 及其下游代谢产物 15-酮-PGE2 和 13-14 二氢-15-酮-PGE2 进行了时程脂质体分析:结果:脂质组分析表明,血浆 PGs 在白蛋白尿发展过程中未出现失调,而与白蛋白尿耐药 SHR 相比,MWF 肾小球中的 PGE2 和 15-keto-PGE2 水平显著升高。总体而言,肾小球中PGE2的平均水平比相应的15-酮-PGE2水平高出150倍。与 SHR 相比,表现出白蛋白尿的 MWF 大鼠肾小球中 15-羟基前列腺素脱氢酶(15-PGDH)的代谢比率明显较低,而前列腺素还原酶(PTGRs)的代谢比率则明显较高:我们的数据揭示了在 GH 白蛋白尿的发生过程中肾小球 PGE2 代谢失调,至少部分原因是 PGE2 降解减少。这项研究首次揭示了 PGE2 通路的动态变化,支持肾小球 PGE2 代谢和信号在 GH 早期白蛋白尿表现中的作用。
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引用次数: 0
Reaction of the endogenous regulatory mechanisms to early weekday wakeups: a review of its popular explanations in light of model-based simulations 内源性调节机制对工作日早起的反应:根据模型模拟回顾其流行解释
Pub Date : 2023-12-15 DOI: 10.3389/fnetp.2023.1285658
Arcady A. Putilov
Introduction: Several widely held explanations of the mechanisms underlying the responses of endogenous sleep–wake-regulating processes to early weekday wakeups have been proposed. Here, they were briefly reviewed and validated against simulations based on the rhythmostatic version of a two-process model of sleep–wake regulation.Methods: Simulated sleep times on weekdays and weekends were compared with the times averaged over 1,048 samples with either earlier or later weekday risetimes. In total, 74 paired samples were collected before and during lockdown, and 93 paired samples were collected during early and later school start times.Results: The counterintuitive predictions of the simulations included the following: 1) only one night of ad lib sleep is sufficient to restore the endogenously determined sleep times after 1 day/5 days of larger/smaller reduction/extension of the sleep/wake phase of the circadian sleep–wake cycle; 2) sleep loss on weekdays is irrecoverable; 3) irrespective of the amount of such deadweight loss, sleep on weekends is not prolonged; and 4) the control of the circadian clocks over the sleep–wake cyclicity is not disrupted throughout the week.Discussion: The following popular explanations of the gaps between weekends and weekdays in sleep timing and duration were not supported by these simulations: 1) early weekday wakeups cause “social jetlag,” viewed as the weekend and weekday (back and forth) shifts of the sleep phase relative to the unchanged phase of the circadian clocks, and 2) early weekday wakeups cause an accumulation of “sleep debt paid back” on weekends, or, in other terms, people can “catch-up” or “compensate” sleep on weekends.
导言:对于内源性睡眠-觉醒调节过程对工作日早醒的反应机制,人们提出了几种广为流传的解释。在此,我们对这些解释进行了简要回顾,并根据睡眠-觉醒调节双过程模型的节律性版本进行了模拟验证:方法:将工作日和周末的模拟睡眠时间与 1,048 个样本中工作日早起或晚起的平均时间进行比较。共收集了 74 个在停课前和停课期间的配对样本,以及 93 个在较早和较晚开学时间的配对样本:模拟的反直觉预测包括以下几点:1)在昼夜节律睡眠-觉醒周期的睡眠-觉醒阶段经过 1 天/5 天较大幅度/较小幅度的减少/延长之后,只有一个晚上的自由睡眠才足以恢复内生决定的睡眠时间;2)工作日的睡眠损失是不可恢复的;3)无论这种自重损失有多少,周末的睡眠时间都不会延长;4)昼夜节律钟对睡眠-觉醒周期性的控制在整个一周内都不会中断:以下关于周末与工作日在睡眠时间和持续时间上的差距的流行解释并没有得到这些模拟的支持:1)工作日早醒会导致 "社会时差",即周末和工作日(前后)睡眠阶段相对于昼夜节律钟不变阶段的移动;2)工作日早醒会导致周末 "睡眠债务偿还 "的积累,或者换句话说,人们可以在周末 "补觉 "或 "补偿 "睡眠。
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Frontiers in network physiology
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