Daniel P Chapman, Stefano Vicini, Mark P Burns, Rebekah Evans
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Here, we generated in silico models of CA1 pyramidal neurons from current clamp data of control mice and mice that sustained HFHI. We use a directed evolution algorithm with a crowding penalty to generate a large and unbiased population of plausible models for each group that approximated the experimental features. The HFHI neuron model population showed decreased voltage gated sodium conductance and a general increase in potassium channel conductance. We used partial least squares regression analysis to identify combinations of channels that may account for CA1 hypoexcitability after HFHI. The hypoexcitability phenotype in models was linked to A- and M-type potassium channels in combination, but not by any single channel correlations. 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The HFHI neuron model population showed decreased voltage gated sodium conductance and a general increase in potassium channel conductance. We used partial least squares regression analysis to identify combinations of channels that may account for CA1 hypoexcitability after HFHI. The hypoexcitability phenotype in models was linked to A- and M-type potassium channels in combination, but not by any single channel correlations. 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引用次数: 0
摘要
创伤性脑损伤(TBI)和重复性头部撞击可导致多种神经系统症状。尽管重复性头部撞击和创伤性脑损伤是世界上最常见的神经系统疾病,但没有任何治疗方法获得美国食品及药物管理局的批准。单个神经元建模允许研究人员根据实验数据推断单个神经元的细胞变化。我们最近鉴定了一种高频头部撞击(HFHI)模型,其认知障碍表型与 CA1 神经元兴奋性下降和突触变化有关。虽然突触变化已在体内进行了研究,但重复性头部撞击后兴奋性降低的原因和潜在治疗目标尚不清楚。在这里,我们从对照组小鼠和持续性高频头痛小鼠的电流钳数据中生成了 CA1 锥体神经元的硅学模型。我们使用了一种带有拥挤惩罚的定向进化算法,为每组小鼠生成了大量无偏的近似实验特征的可信模型。HFHI 神经元模型群显示电压门控钠电导降低,钾通道电导普遍升高。我们使用偏最小二乘法回归分析来确定可能导致 CA1 在 HFHI 后兴奋性降低的通道组合。模型中的低兴奋表型与 A 型和 M 型钾通道组合有关,但与任何单一通道无关。我们提供了一组对照和高频手震条件下的 CA1 锥体神经元开放存取模型,可用于预测药物干预对创伤性脑损伤模型的影响。
Single Neuron Modeling Identifies Potassium Channel Modulation as Potential Target for Repetitive Head Impacts.
Traumatic brain injury (TBI) and repetitive head impacts can result in a wide range of neurological symptoms. Despite being the most common neurological disorder in the world, repeat head impacts and TBI do not have any FDA-approved treatments. Single neuron modeling allows researchers to extrapolate cellular changes in individual neurons based on experimental data. We recently characterized a model of high frequency head impact (HFHI) with a phenotype of cognitive deficits associated with decreases in neuronal excitability of CA1 neurons and synaptic changes. While the synaptic changes have been interrogated in vivo, the cause and potential therapeutic targets of hypoexcitability following repetitive head impacts are unknown. Here, we generated in silico models of CA1 pyramidal neurons from current clamp data of control mice and mice that sustained HFHI. We use a directed evolution algorithm with a crowding penalty to generate a large and unbiased population of plausible models for each group that approximated the experimental features. The HFHI neuron model population showed decreased voltage gated sodium conductance and a general increase in potassium channel conductance. We used partial least squares regression analysis to identify combinations of channels that may account for CA1 hypoexcitability after HFHI. The hypoexcitability phenotype in models was linked to A- and M-type potassium channels in combination, but not by any single channel correlations. We provide an open access set of CA1 pyramidal neuron models for both control and HFHI conditions that can be used to predict the effects of pharmacological interventions in TBI models.
期刊介绍:
Neuroinformatics publishes original articles and reviews with an emphasis on data structure and software tools related to analysis, modeling, integration, and sharing in all areas of neuroscience research. The editors particularly invite contributions on: (1) Theory and methodology, including discussions on ontologies, modeling approaches, database design, and meta-analyses; (2) Descriptions of developed databases and software tools, and of the methods for their distribution; (3) Relevant experimental results, such as reports accompanie by the release of massive data sets; (4) Computational simulations of models integrating and organizing complex data; and (5) Neuroengineering approaches, including hardware, robotics, and information theory studies.