PICTURE
William Holmes, Assistant Professor
Ph.D. University of California, Los Angeles

Computational Neuroscience


The goal of my research is to develop mathematical and computational models of individual neurons of the hippocampus that will be appropriate for use in network models. The immediate focus is to develop highly detailed models of dentate granule cells that describe appropriately how computation and synaptic modification occur in these cells. These highly detailed models must satisfy the constraints imposed by experimental data including conditions leading to long-term potentiation (LTP) and long-term depression (LTD).

Modeling work is proceeding on molecular, synaptic and neuron levels. On the molecular level, a model of a dendritic spine is being extended to include calcium binding to calmodulin and calmodulin binding and trapping by CaM-kinase II with the hope of being able to express the essence of these biochemical reactions in a synaptic modification rule. On the synaptic level, diffusion models of the synaptic cleft have been developed to determine more accurate descriptions of NMDA and AMPA conductances for use in neuron level models. On the neuron level, detailed morphology is being used in simulations to determine the range of computational possibilities of neurons as constrained by the spatial and temporal distribution of synaptic and non-synaptic conductances. Methods are being developed to determine appropriate parameter values for the conductances.

Holmes, W.R. and Levy, W.B (1997) Quantifying the role of inhibition in associative long-term potentiation in dentate granule cells with computational models. J. Neurophysiol. 78:103-116.

Holmes, W.R. (1996) Modeling the effects of ambient glutamate on NMDA and non-NMDA conductances. In: Computational Neuroscience. J.M. Bower, ed. Academic Press: San Diego, pp. 83-88.

Holmes, W.R. (1995) Modeling the effects of diffusion and uptake on NMDA and non-NMDA receptor saturation. Biophys. J. 69(5):1734-1747.

Holmes, W.R. and Levy, W.B. (1994) Temporal requirement for associative LTP in the dentate. Dependence on modeled Rm and Ri values. In: Computation in Neurons and Neural Systems. F. Eeckman (ed.) Kluwer Press, Boston. pp 299-304.

Holmes, W.R. and Rall, W. (1992) Estimating the electrotonic structure of neurons with compartmental models. J. Neurophysiol. 68:1438-1452.

Holmes, W.R. (1992) Computer simulations of individual neurons. In: Methods in Neurosciences, vol. 10, Computers and Computations in the Neurosciences. P.M. Conn, ed. Academic Press: San Diego, pp. 503-525.

Holmes, W.R. and Rall, W. (1992) Electrotonic models of neuronal dendrites and single neuron computation. In: Single Neuron Computation, T. McKenna, J. Davis and S.F. Zornetzer, eds, Academic Press: Boston, pp. 725.

Holmes, W.R. (1990) Is the function of dendritic spines to concentrate calcium? Brain Res. 519:338-342.

Holmes, W.R. and Levy, W.B. (1990) Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes. J. Neurophysiol. 63:1148-1168.