The Hodgkin–Huxley model (or "conductance-based model") is a mathematical model (a type of scientific model) that describes how action potentials in neurons are initiated and propagated. It is a set of nonlinear differential equations that approximates the electrical characteristics of excitable cells such as neurons and cardiac myocytes.
Alan Lloyd Hodgkin and Andrew Huxley described the model in 1952 to explain the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon. They received the 1963 Nobel Prize in Physiology or Medicine for this work.
The typical Hodgkin–Huxley model treats each component of an excitable cell as an electrical element (as shown in the figure). The lipid bilayer is represented as a capacitance (Cm). Voltage-gated ion channels are represented by electrical conductances (gn, where n is the specific ion channel) that depend on both voltage and time. Leak channels are represented by linear conductances (gL). The electrochemical gradients driving the flow of ions are represented by voltage sources (En) whose voltages are determined by the ratio of the intra- and extracellular concentrations of the ionic species of interest. Finally, ion pumps are represented by current sources (Ip). The difference between the membrane potential and the resting potential is typically called "Vm".
Mathematically, the current flowing through the lipid bilayer is written as
and the current through a given ion channel is
where is the reversal potential of the i-th ion channel. Thus, for a cell with sodium and potassium channels, the total current through the membrane is given by:
where I is the total membrane current per unit area, Cm is the membrane capacitance per unit area, gK and gNa are the potassium and sodium conductances per unit area, respectively, VK and VNa are the potassium and sodium reversal potentials, respectively, and gl and Vl are the leak conductance per unit area and leak reversal potential, respectively. The time dependent elements of this equation are Vm, gNa, and gK, where the last two conductances depend explicitly on voltage as well.
Ionic current characterization
In voltage-gated ion channels, the channel conductance gi is a function of both time and voltage (gn(t, V) in the figure), while in leak channels gi is a constant (gL in the figure). The current generated by ion pumps is dependent on the ionic species specific to that pump. The following sections will describe these formulations in more detail.
Voltage-gated ion channels
Using a series of voltage clamp experiments and by varying extracellular sodium and potassium concentrations, Hodgkin and Huxley developed a model in which the properties of an excitable cell are described by a set of four ordinary differential equations. Together with the equation for the total current mentioned above, these are:
where I is the current per unit area, and and are rate constants for the i-th ion channel, which depend on voltage but not time. is the maximal value of the conductance. n, m, and h are dimensionless quantities between 0 and 1 that are associated with potassium channel activation, sodium channel activation, and sodium channel inactivation, respectively. For , and take the form
and , and are the steady state values for activation and inactivation, respectively, and are usually represented by Boltzmann equations as functions of .
In order to characterize voltage-gated channels, the equations are fit to voltage clamp data. For a derivation of the Hodgkin–Huxley equations under voltage-clamp, see. Briefly, when the membrane potential is held at a constant value (i.e., voltage-clamp), for each value of the membrane potential the nonlinear gating equations reduce to linear differential equations of the form:
Thus, for every value of membrane potential the sodium and potassium currents can be described by
In order to arrive at the complete solution for a propagated action potential, one must write the current term I on the left-hand side of the first differential equation in terms of V, so that the equation becomes an equation for voltage alone. The relation between I and V can be derived from cable theory and is given by
where a is the radius of the axon, R is the specific resistance of the axoplasm, and x is the position along the nerve fiber. Substitution of this expression for I transforms the original set of equations into a set of partial differential equations, because the voltage becomes a function of both x and t.
While the original experiments treated only sodium and potassium channels, the Hodgkin Huxley model can also be extended to account for other species of ion channels.
Leak channels account for the natural permeability of the membrane to ions and take the form of the equation for voltage-gated channels, where the conductance is a constant.
Pumps and exchangers
The membrane potential depends upon the maintenance of ionic concentration gradients across it. The maintenance of these concentration gradients requires active transport of ionic species. The sodium-potassium and sodium-calcium exchangers are the best known of these. Some of the basic properties of the Na/Ca exchanger have already been well-established: the stoichiometry of exchange is 3 Na+:1 Ca2+ and the exchanger is electrogenic and voltage-sensitive. The Na/K exchanger has also been described in detail.
Improvements and alternative models
The Hodgkin–Huxley model is regarded as one of the great achievements of 20th-century biophysics. Nevertheless, modern Hodgkin–Huxley-type models have been extended in several important ways:
- Additional ion channel populations have been incorporated based on experimental data.
- Models often incorporate highly complex geometries of dendrites and axons, often based on microscopy data.
- Stochastic models of ion-channel behavior, leading to stochastic hybrid systems
Several simplified neuronal models have also been developed (such as the Fitzhugh-Nagumo model), facilitating efficient large-scale simulation of groups of neurons, as well as mathematical insight into dynamics of action potential generation. Another new model, the Soliton model, explains why an action potential traveling along an axon results in a slight local thickening and outward displacement of the membrane. It also accounts for a slight increase in temperature, followed by a decrease in temperature, during an action potential.
- Hodgkin, A. L.; Huxley, A. F. (1952). "A quantitative description of membrane current and its application to conduction and excitation in nerve". The Journal of physiology 117 (4): 500–544. PMC 1392413. PMID 12991237.
- Hodgkin, A.L., and Huxley, A.F., "A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. (1952) 177, 500-544
- Gray, Daniel Johnston; Wu, Samuel Miao-Sin (1997). Foundations of cellular neurophysiology (3rd. ed.). Cambridge, Mass. [u.a.]: MIT Press. ISBN 9780262100533.
- Marquardt, D. W. (1963). "An Algorithm for Least-Squares Estimation of Nonlinear Parameters". Journal of the Society for Industrial and Applied Mathematics 11 (2): 431–000. doi:10.1137/0111030.
- Levenberg, K (1944). "A method for the solution of certain non-linear problems in least squares". Qu. App. Maths. 2: 164.
- Hille, Bertil (2001). Ion channels of excitable membranes (3. ed. ed.). Sunderland, Mass.: Sinauer. ISBN 9780878933211.
- Pakdaman, K (2010). "Fluid limit theorems for stochastic hybrid systems with applications to neuron models". Adv.Appl.Proba 43..
- Interactive Java applet of the HH model Parameters of the model can be changed as well as excitation parameters and phase space plottings of all the variables is possible.
- Direct link to Hodgkin-Huxley model and a Description in BioModels Database
- Direct link to Hodgkin-Huxley paper #1 via PubMedCentral
- Direct link to Hodgkin-Huxley paper #2 via PubMedCentral
- Direct link to Hodgkin-Huxley paper #3 via PubMedCentral
- Direct link to Hodgkin-Huxley paper #4 via PubMedCentral
- Direct link to Hodgkin-Huxley paper #5 via PubMedCentral
- Neural Impulses: The Action Potential In Action by Garrett Neske, The Wolfram Demonstrations Project
- Interactive Hodgkin-Huxley model by Shimon Marom, The Wolfram Demonstrations Project
- ModelDB A computational neuroscience source code database containing 4 versions (in different simulators) of the original Hodgkin–Huxley model and hundreds of models that apply the Hodgkin–Huxley model to other channels in many electrically excitable cell types.
- Several articles about the stochastic version of the model and its link with the original one.