Olivares Erick, Salgado Simón, Maidana Jean Paul, Herrera Gaspar, Campos Matías, Madrid Rodolfo, Orio Patricio
Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile.
Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.
PLoS One. 2015 Oct 1;10(10):e0139314. doi: 10.1371/journal.pone.0139314. eCollection 2015.
Cold-sensitive nerve terminals (CSNTs) encode steady temperatures with regular, rhythmic temperature-dependent firing patterns that range from irregular tonic firing to regular bursting (static response). During abrupt temperature changes, CSNTs show a dynamic response, transiently increasing their firing frequency as temperature decreases and silencing when the temperature increases (dynamic response). To date, mathematical models that simulate the static response are based on two depolarizing/repolarizing pairs of membrane ionic conductance (slow and fast kinetics). However, these models fail to reproduce the dynamic response of CSNTs to rapid changes in temperature and notoriously they lack a specific cold-activated conductance such as the TRPM8 channel. We developed a model that includes TRPM8 as a temperature-dependent conductance with a calcium-dependent desensitization. We show by computer simulations that it appropriately reproduces the dynamic response of CSNTs from mouse cornea, while preserving their static response behavior. In this model, the TRPM8 conductance is essential to display a dynamic response. In agreement with experimental results, TRPM8 is also needed for the ongoing activity in the absence of stimulus (i.e. neutral skin temperature). Free parameters of the model were adjusted by an evolutionary optimization algorithm, allowing us to find different solutions. We present a family of possible parameters that reproduce the behavior of CSNTs under different temperature protocols. The detection of temperature gradients is associated to a homeostatic mechanism supported by the calcium-dependent desensitization.
冷敏神经末梢（CSNTs）通过规则的、有节奏的、依赖温度的放电模式来编码稳定的温度，这种模式范围从不规则的紧张性放电到规则的爆发性放电（静态反应）。在温度突然变化期间，CSNTs表现出动态反应，随着温度降低其放电频率短暂增加，而在温度升高时则停止放电（动态反应）。迄今为止，模拟静态反应的数学模型基于两对去极化/复极化的膜离子电导（慢动力学和快动力学）。然而，这些模型无法再现CSNTs对温度快速变化的动态反应，而且它们明显缺乏一种特定的冷激活电导，如TRPM8通道。我们开发了一个模型，该模型将TRPM8作为一种依赖温度的电导，并具有钙依赖性脱敏作用。我们通过计算机模拟表明，它能恰当地再现小鼠角膜CSNTs的动态反应，同时保留其静态反应行为。在这个模型中，TRPM8电导对于显示动态反应至关重要。与实验结果一致，在没有刺激（即中性皮肤温度）的情况下，持续的活动也需要TRPM8。该模型的自由参数通过进化优化算法进行调整，使我们能够找到不同的解决方案。我们提出了一组可能的参数，它们能再现CSNTs在不同温度方案下的行为。温度梯度的检测与一种由钙依赖性脱敏支持的稳态机制相关。
