Modeling the dynamics of genes and excitable membranes

神经系统的主要功能是以导致适应性行为的方式处理信息，为了实现这一点，神经元的兴奋性及其突触连接的强度需要不断调节。在分析了神经系统的一个神经元后， 多年来，我们有可能问它携带了什么信息，以及它如何促成这种可塑性。在这一点上，计算方法可以极大地帮助整合积累的数据，以解释系统的不同组件如何相互作用。通过计算， 补充实验，提高对神经元可塑性所需的关键遗传调控系统的动力学的理解，以及这种遗传系统和膜电流之间预期的相互作用。 两个不同层次的组织将被建模。在分子水平上，一个详细的模型将开发的基因调控系统，利用CREB和相关的转录因子。从哺乳动物和无脊椎动物的实验中得知，这个系统对突触可塑性和长期记忆的形成很重要。在单个神经元的生物电特性的水平上，有大量的实验证据表明离子通道密度通过电活动进行调节。广泛特征化的神经元R15将作为 一个模型，用它来计算调查这种反馈的后果。一个电导为基础的模型R15将通过增加耦合项CREB遗传模型，以提供一个合理的描述基因表达对电行为的影响，并描述从电活动的反馈，通过钙内流，基因表达。有了这个组合模型，和参数值来自实验或文献，我们还将研究是否已知的CREB调节的动力学特性可以提供一种机制，在特定的刺激频率的最佳转录，这样的机制可以帮助解释实验，已经证明了最佳的刺激频率在无脊椎动物的长期记忆形成。最后，关注这些系统有望进一步实现我们初步研究的目标--确定基因的特定观察行为是如何产生的， 基因调控系统的一般组织原则。

The main function of the nervous system is to process information in ways that lead to adaptive behavior, and to accomplish this, the excitability of neurons and the strength of their synaptic connections need to be modulated continual. After a neuron of neural system has been analyzed for years, it becomes possible to ask what information it carries and how it contributes to this plasticity. At this point, computational approaches can greatly assist integrating accumulated data to explain how different components of a system interact. This proposal will, via computation supplemented with experiments, improve the understanding of the dynamics of a key genetic regulatory system necessary for neuronal plasticity, and of the reciprocal interactions that could be expected between such genetic systems and membrane currents. Two distinct levels of organization will be modeled. At the molecular level, a detailed model will be developed for the genetic regulatory system that utilizes CREB and related transcription factors. This system is known from experiments with mammals and invertebrates to be important for synaptic plasticity and long-term memory formation. At the level of the bioelectrical properties of a single neuron, there is abundant experimental evidence for regulation of ion channel densities by electrical activity. The extensively characterized neuron R15 of Aplysia will serve as a model with which to computationally investigate the consequences of this feedback. A conductance-based model of R15 will be improved by adding coupling terms to the CREB genetic model to provide a plausible description of the effects of gene expression on electrical behavior and to describe feedback from electrical activity, via calcium influx, to gene expression. With this combined model, and parameter values derived from experiment or from the literature, we will also investigate whether known kinetic properties of CREB regulation could provide a mechanism for optimal transcription at specific stimulus frequencies-such a mechanism Could help explain experiments that have demonstrated optimal stimulus frequencies for long-term memory formation in invertebrates. Finally, focusing on these systems is expected to further the aim of our Preliminary Studies-to determine how specific observed behaviors of genes arise from general organizational principles of genetic regulatory systems.