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.
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