Throughout the period of this grant we have used computer simulations to gain insight into the relative contributions of morphology and ionic channels to the functioning of single nerve cells. We have developed a program, NEURON, (available on PC's and Unix workstations) to simulate individual and networks of neurons with complex branching morphology, multiple channel types, inhomogeneous channel distribution, and restricted extracellular space. A good example of its use is in the interpretation of experimental results on failure and recovery of action potential propagation due to partial demyelination and new node formation in multiple sclerosis. We plan to continue the refinement of our present computer software in order to make the task of nerve cell simulation much less intimidating for non-specialists in numerical methods - and much less infuriating to sophisticated modelers who too often find that a small but novel request requires a serious and unforeseen investment in computer programming. The neuron simulation software will be extended in several directions, the most important ones being: (1) Increased numerical method robustness in the presence of changing ionic concentration including longitudinal diffusion. (2) Increased functionality of the new graphical interface for management of and maintaining conceptual control over complex simulations. (3) Increased compatibility (through the use of filters) with other simulation programs to promote sharing, reuse, verification of, and building upon each others simulations. (4) Vastly increased leveraging of the power of NEURON by utilizing an interoperability protocol (CORBA) that will allow embedding of NEURON components within other analysis packages (and vice versa) in a distributed fashion across a network. We plan to use the NEURON program to carry out simulations on models of stylized neurons and models of synaptic transmission. As a consequence of the principal investigator's move to Yale there will be much closer ties to some of the experimentalists using NEURON to model their systems. The resulting personal collaborations will enhance those researcher's usage of NEURON and feed back into ways of improving NEURON's effectiveness as a practical research tool.
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