COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 175
iological characteristics of the neural system of interest. GENESIS reflects the modeling perspective that spatial
organization and structure are important for understanding neural function. GENESIS is organized around
neurons constructed out of components such as compartments (short sections of cellular membrane) and
variable conductance ion channels that receive inputs, perform calculations on them, and then generate
outputs. Neurons in turn can be linked to form neural circuits. GENESIS originally was used largely for realistic
simulations of cortical networks and of the cerebellar Purkinje cell and, more recently, to interconnect cell
and network properties to biochemical signaling pathways.NEURON is similar to GENESIS in many ways, but contains optimizations that enable it to run very fast on
networks in which cable properties play a crucial role, that involve system sizes ranging from parts of single
cells to small numbers of cells, and that involve complex branched connections. Furthermore, the perfor-
mance of NEURON degrades very slowly with increasing complexity of morphology and membrane mecha-
nisms, and it has been applied to very large network models (10^4 cells with six compartments each and a total
of 10^6 synapses in the network. Using a high-level language known as NMODL, NEURON has also been
extended to investigate new kinds of membrane channels. The morphology and membrane properties of
neurons are defined with an object-oriented interpreter, allowing for voltage control, manipulation of current
stimuli, and other biological parameters.SOURCES: For more information, see http://www.mcell.cnl.salk.edu; J.R. Stiles and T.M. Bartol, Jr., “Monte Carlo Methods for Simulating
Realistic Synaptic Microphysiology Using MCell,” pp. 87-127 in Computational Neuroscience: Realistic Modeling for Experimentalists, E. de
Shutter, ed., Boca Raton, FL, CRC Press, 2000; J.R. Stiles, T.M. Bartol, Jr., E.E. Salpeter, M.M. Salpeter, T.J. Sejnowski, “Synaptic Variability:
New Insights from Reconstructions and Monte Carlo Simulations with MCell,” pp. 681-731 in Synapses, W.M. Cowan, T.C. Sudhof, C.F.
Sudhof, eds., Johns Hopkins University Press, Baltimore, 2001; J.M. Bower, D. Beeman, and M. Hucka, “The GENESIS Simulation System,”
The Handbook of Brain Theory and Neural Networks, Second Edition, M.A. Arbib, ed., MIT Press, Cambridge, MA, 2003, pp. 475-478,
available at http://www.genesis-sim.org/GENESIS/hbtn2e-bower-etal/hbtn2e-bower-etal.html; M.L. Hines and N.T. Carnevale, “The NEU-
RON Simulation Environment,” Neural Computation 9(6):1179-1209, 1997, available at http://www.neuron.yale.edu/neuron/papers/nc97/
nsimenv.pdf.5.4.5.3 Muscular Control
Muscles are controlled by action potentials—brief, rapid depolarizations of membranes in nerves
and muscles. The timing of action potentials transmitted from motor neurons coordinates the contrac-
tion of the muscles they innervate. Rhythmic activity of the nervous system often takes the form of
complex bursting oscillations in which intervals of action potential firing and quiescent intervals of
membrane activity alternate. The relative timing of action potentials generated by different neurons is a
key ingredient in the function of the nervous system.
Changes in the electrical potential of membranes are mediated by ion channels that selectively
permit the flow of ions such as sodium, calcium, and potassium across the membrane. Individual
channels are protein complexes containing membrane-spanning pores that open and close randomly at
rates that depend on many factors. Cellular and network models of membrane potential represent these
systems as electrical circuits in which voltage gated channels function as “nonlinear” resistors whose
conductance depends on membrane potential. Information is transmitted from one neuron to another
through synapses where action potentials trigger the release of neurotransmitters that bind to channels
of adjacent cells, stimulating changes in the ionic currents of these cells. (The action potential is the basic
neuronal signaling “packet” of ionic flow through a cell membrane.)
The most basic model of this mechanism is the Hodgkin-Huxley model, which refers to a set of
differential equations that describe the action potential.^102 Specifically, the Hodgkin-Huxley equations
(^102) A.L. Hodgkin and A.F. Huxley, “A Quantitative Description of Membrane Current and Its Application to Conduction and
Excitation in Nerve,” Journal of Physiology 117(4):500-544, 1952.