This article was published in The Guardian, May 1, 2015. Ahmed El Hady is presenting his work on May 5th, at AUB.
Two researchers from Princeton University have developed a theoretical model describing the nervous impulse as an electromechanical wave that travels along nerve fibres, explaining curious experimental observations and challenging basic assumptions about how the brain works.
The mechanism of the nervous impulse was made clear in a series of experiments carried out by Alan Hodgkin and Andrew Huxley from the late 1930s onwards. They prepared segments of giant squid axon, placed them in salt water solution, and then impaled them with microelectrodes, with which they could both inject electrical current into the fibre and record its voltage. This enabled them to control the voltage across the membrane and also measure the movements of current responsible for producing the impulse.
Resting nerve cells have a lower concentration of sodium ions, and a higher concentration of potassium ions, than the spaces surrounding them, so that the inside of the membrane is negatively charged with respect to the outside. This transmembrane voltage is called the resting potential; most nerve cells have a resting potential of about -70 millivolts.
Hodgkin and Huxley discovered that the nervous impulse is caused by the flow of sodium ions into the cell, followed almost immediately by the flow of potassium ions out. The ions move in and out through channel proteins that traverse the membrane, and open briefly in response to changes in membrane voltage, allowing first one ion species in, then the other out, in just one thousandth of a second. The influx of sodium ions reverses the transmembrane voltage, but then the potassium ion efflux quickly reverts it to its resting state. Hence, neuroscientists refer to nervous impulses as action potentials.
As these charges move along the membrane, they activate sodium channels in adjacent regions, carrying the impulse along the axon towards the nerve terminal. Upon arriving at the terminal, they cause synaptic vesicles to fuse with the terminal membrane and release neurotransmitter molecules into the synapse, relaying the signal to another cell, which then produces its own impulses.
Hodgkin and Huxley developed a mathematical model describing how nervous impulses are produced and propagated along the nerve fibre. They published their work in a series of classic 1952 papers, and were later awarded the 1963 Nobel Prize in Physiology or Medicine for their work. Their technique for recording the movement of ionic currents across nerve cell membranes (called voltage-clamping) is still used widely by electrophysiologists today.
The Hodgkin-Huxley model remains highly influential, but since its publication other researchers have noticed that nervous impulses are accompanied by various mechanical perturbations of the axon fibre. Some have observed small rapid changes in axon diameter and pressure, while others have recorded changes in fibres’ optical properties but, failing to see how or why this might happen, dismissed the observations as meaningless by-products of the nervous impulse, or as experimental artefacts.
The nervous impulse (action potential, AP) and accompanying action wave (AW) together make up an electromechanical pulse that travels along the axon. The nervous impulse (action potential, AP) and accompanying action wave (AW) together make up an electromechanical pulse that travels along the axon.
The new model, developed by Ahmed El Hady and Benjamin Machta, is based on data about biophysical parameters such as axon diameter, elasticity of the nerve cell membrane, and density and viscosity of the axoplasm (the cytoplasm inside the axon), gleaned from other experiments.
It states that initiation of a nervous impulse displaces the membrane inwards just behind it. This triggers an accelerating mechanical wave that precedes the impulse as it is propagated along the axon and constricts the fibre as it moves, causing tiny ripples in both the axoplasm and the fluid outside the cell.
“We call them action waves,” says El Hady, “and we think they are driven by action potentials. They’re a bit like the surface waves you get when you throw a stone into water – the stone is like a travelling electrical wave that induces this mechanical displacement of the membrane.”
Before moving to Princeton, El Hady and his colleagues had been using state-of-the-art super-resolution microscopy to examine the actin cytoskeleton, a dynamic network of filamentous proteins, in live neurons. Recently, a team of researchers in China showed that in axons the cytoskeleton is arranged as a series of concentric rings, and El Hady suspects that action waves may be produced by the successive constriction of these rings.
White matter might matter much more than we thought
The action wave is purely theoretical, existing only as equations describing the mechanical changes that occur at the nerve cell membrane as a nervous impulse passes along it. Recently, several research groups have independently reported the surprise finding that ultrasonic stimulation can induce nervous impulses, suggesting that the electrical and mechanical properties of the membrane do indeed interact. Sodium channels are modulated by membrane mechanics, and may therefore mediate this interaction.
El Hady and Machta have used the model to make predictions that are consistent with others’ research findings, and are now planning to test it experimentally themselves. “The next step will be to see how these actin rings are moving,” says El Hady, “and we also want to vibrate neurons with fine piezoelectric elements to see if we can elicit an electrical response.”
They believe action waves are required for propagating impulses along nerve fibres and for carrying information, and are also planning experiments involving artificial constriction of axons, to see if this hinders the movement of impulses. They also argue that the waves contribute information processing, too, perhaps by helping to position synaptic vesicles at the nerve terminal, prime ion channels for the incoming electrical impulse, or help to synchronise their opening and closing.
“Our main aim is to make people think about this,” says El Hady, “and ultimately we hope more people will come on board to do experiments that test the model.”
Reference: El Hady, A. & Machta, B. B. (2015). Mechanical surface waves accompany action potential propagation. Nat. Comm. DOI: 10.1038/ncomms7697
Photo credit: Hokusai, published by The Guardian