A squid

The Most Famous Paper In Neuroscience

Perhaps the most important paper in neuroscience is called: “A quantitative description of membrane current and its application to conduction and excitation in nerve”. At the time of writing, the article has over 30,000 citations.

Written in the Journal of Physiology in 1952 by Alan Hodgkin and Andrew Huxley, the paper presents a mathematical model of action potentials in an axon.

It, along with their wider work in neurophysiology, earned the authors the Nobel Prize in Physiology and Medicine in 1963. But what does it say and what’s the history? Here, we explore one of the most famous papers in neuroscience.

Squids in 1939

In 1939, Alan Hodgkin, who had spent the previous summer studying squid giant axons in the USA, invited Andrew Huxley, a recent graduate in physiology from Cambridge, to join him in Plymouth to investigate nerve conduction.

With Hodgkin’s prior experience with squid axons, and Huxley’s fresh perspective, the two neuroscientists tried using mercury droplets to measure viscosity of cytoplasm within the axon of a squid. However, they were unsuccessful.

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Nonetheless, their setback was not fruitless. Inspired, they came up with the idea of inserting a fine capillary electrode into a nerve fibre to record membrane potential. This yielded mankind’s first intracellular action potential recordings.

Despite this promising start, the outbreak of World War II halted their research; the researchers had to contribute to the war effort, of course. As such, their findings, published in Nature in October 1939, marked the end of their initial, pre-war collaboration. These findings were already groundbreaking.

Voltage clamping in 1947

After seven years of war, during which the two scientists gained valuable insights from their non-academic endeavours, Hodgkin and Huxley reconvened. What they were about to do was measure, more precisely than ever before, the voltage potential of a squid axon.

Although it is called a “giant axon” it is, at its largest, 1.5mm in diameter. Typically, squid axons are half a millimeter in diameter. Giant for an axon; small in reality. The axon is associated with a squid’s propulsion system.

To measure this voltage potential, Hodgkin and Huxley would need to adopt voltage clamping.

What is voltage clamping?

Voltage clamping allows scientists to control the voltage across an axon membrane. The reason neuroscientists want to do this is that during an action potential, the voltage across the cell membrane is changing in time and space. This makes measuring the voltage across an axon incredibly difficult.

Voltage clamping solves this problem, by measuring the voltage potential across the cell membrane using one electrode, and then passing a current through the axon using another electrode. This current is designed to change with the changing potential so that the voltage is clamped at a certain value. Voltage clamping stops the voltage from changing.

In this way, what was really measured by early adopters of voltage clamping was the amount of current required to maintain the desired voltage potential.

Hodgkin and Huxley were not the first

Hodgkin and Huxley were certainly not the first to use voltage clamping on a squid’s giant axon. They are not even cited as its inventors!

However, they had discussed the idea prior to the war’s end, and they contributed significantly to the implementation of voltage-clamping by the end of 1949. Specifically, they introduced a second electrode, which solved problems associated with electrode polarization.

This dual electrode approach enabled Hodgkin and Huxley to directly record the ionic currents across a squid’s axon without altering its voltage potential. As such, they could investigate the voltage sensitivity and kinetics of the underlying ion channels.

We should note that, post-war, Hodgkin and Huxley were aided in some experiments by Bernard Katz.

The Hodgkin-Huxley model in 1952

After all of this, then, what is the famous paper all about?

The article was in fact a summary of four previous papers where the authors used voltage clamping, and other tools, to investigate the electrical activity of action potentials in a squid giant axon.

The paper is split into three parts. In part 1, the authors discuss their previous experimental results. In part 2, the authors present a mathematical description of the current in an axon during a voltage clamp. In the final part, the authors describe how they use their mathematical descriptions to predict the behaviour of the squid giant axon.

What is the Hodgkin-Huxley model

One of the reasons the paper is so popular, is that it presents, in part 2, what is known as the Hodgkin-Huxley model. The model describes the mechanisms underlying the generation and propagation of action potentials in excitable cells, particularly in neurons.

The model consists of a system of ordinary differential equations that describe how ion currents change across a neuron’s membrane. Specifically, it considers how the currents of sodium (Na+), potassium (K+), capacitance and leak contribute to changes in membrane potential.

Without going into took much detail, by summing each of these currents iteratively, one can derive the time course of an action potential with high precision. This is remarkable given the number of factors the Hodgkin-Huxley model omits.

Despite its simplicity, the model provides a robust framework for understanding the electrical behaviour of neurons and has served as the foundation for subsequent computational models of neuronal activity. Most importantly, it has advanced our understanding of the principles governing electrical signalling in the nervous system.

In fact, without such solid research into neuronal firing dynamics it is questionable whether we would have had such great progress in the artificial neural networks that now make news headlines almost daily. Such counterfactuals we will never know.

The techniques employed by Hodgkin and Huxley and many other early neuroscientists were highly invasive procedures. Still today, amazing technological breakthroughs allow scientists to measure molecular changes in vitro.

However, we can measure neuronal firing patterns non-invasively too using EEG. Small, mobile EEG amplifiers, like Mentalab Explore+, make this easier than every. They allow participants to move around and relax without obstructive wires that tether them to a stationary amplifier.

Much of what is written in this article was taken from the wonderful perspective by Schwiening (2012). Do take a look for more!

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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 physiology117(4), 500–544. https://doi.org/10.1113/jphysiol.1952.sp004764

Schwiening, C. J. (2012). A brief historical perspective: Hodgkin and Huxley. The Journal of Physiology, 590 (11), (pp. 2571–2575). Wiley. https://doi.org/10.1113/jphysiol.2012.230458