Profile: Greg Stuart

Greg Stuart has pioneered methods for measuring neuronal signals in the brain to a degree and complexity never before achieved. He will speak at next week’s Australian Neuroscience Society annual meeting.

The human brain is made up of around 80 billion individual nerve cells or neurons, each of which receives thousands to hundreds of thousands of electrical inputs from other nerve cells at any one time.

These inputs are being received both in time and space. They arrive at the nerve cell membrane continuously in millisecond barrages (time component), received across processes of the cell called dendrites (space component).

In the dendrites, the signals undergo quite complex computations that ultimately modify the rate of nerve impulse generation. So, the ultimate output from the processing is a nerve impulse or action potential.

Professor Greg Stuart’s research seeks to understand exactly how individual neurons in the brain process all that incoming information to generate an output.

When Stuart, now at the John Curtin School of Medical Research at ANU, first started university, he wanted to be an electrical engineer, having always been fascinated with how things worked.

However, the reality of lectures didn’t match up to what he was looking for and after falling into science, he discovered an interest in physiology.

“It was sort of like engineering of the body,” he says. His interests eventually settled on the master controller of all working things in the body – the brain.

Stuart’s first foray into neuroscience research during his postgraduate studies found him looking at nerve signals in the periphery of the body, such as in muscles, and how they are transmitted to the brain in terms of the distance that the neural impulse has to travel.

Wanting to then explore how the peripherally generated information is processed once it reaches the brain, he moved into the cortex, which he considers the ultimate processing part of the brain. And that is what he has concentrated on for many years.

“Unfortunately, the capacity to look at signal processing in any detail at that time was very limited,” he says. This was something that had always frustrated Stuart’s PhD supervisor, Dr Stephen Redman, who had for a long time sought to understand signal processing in neuronal dendrites. Redman’s frustration rubbed off on his students, and particularly on Stuart.

During his subsequent postdoc in Germany, Stuart set about trying to overcome this technical hurdle in the field, with landmark success. Not only was he involved in developing novel techniques that enabled direct and unprecedented recording of dendritic activity, but by using these techniques Stuart also discovered the process of neuronal back-propagation, whereby nerve impulses actively propagate back to the site of synaptic input.

The new dendritic recordings enabled by Stuart’s work basically confirmed what many people had suspected for a long time.

Previously, scientists wanting to study dendritic signalling had to take indirect recordings from larger, more accessible parts of the neuron such as the cell body, and interpret from them what might be happening in the dendrites.

“This always required developing a lot of models and assumptions, but it was the only way to do it,” he says. So, these new recording techniques were really quite an important advance in the field of dendritic physiology and in neuroscience more generally.

The first paper from the technically based work was originally planned to just describe the novel techniques, which Stuart and colleagues realised would ultimately yield a plethora of new information about neural processing.

However, with the findings on dendritic back-propagation, the paper was published in Nature in 1997, and Stuart’s name was firmly etched on the neuroscience map.

---PB--- Action potentials

At the Australian Neuroscience Society conference being held in Canberra next week, Stuart will give an overview of his work to date and then present some recent findings.

“One of the things we are focusing on at the moment involves processing in another part of the neuron called the axon, which is the main output pathway of neurons,” he says.

“It is there that these output signals or action potentials are generated, and it is also where a lot of signal processing goes on.”

Like dendrites, the axon is quite small, so previous work on signal processing in the axon has again relied technically on indirect signal recording and interpretation from the cell body.

Already, Stuart’s results on the axon, published last year in Neuron and elsewhere, have thrown up a whole new way of looking at things.

“Previously we all thought of the axon as just an all-or-none generator or switch, with all the more complex computations going on either in the dendrites or in the cell body.

“But instead of the axon simply being a motor that either initiates an output or it doesn’t, it turns out that a very specialised region of the axon called the axon initial segment (AIS) is jam-packed full of proteins that are really important for electrical signalling in nerves and there is a whole lot more going on there than we thought.”

Inactivation of the AIS changed the strength and distribution of signal output, rather than just whether it was on or off. Stuart’s data indicated a new functional role for this axonal region, suggesting that it is critical for regulating the presynaptic signal and thereby the release of nerve impulses at synapses within the brain cortex.

“It changes thinking on the computational role of axons in neuronal processing,” he says.

Thus, the techniques developed years ago for making direct electrical recordings from dendrites are now allowing Stuart and his colleagues to analyse the same sorts of things in the axon – which proteins are there, what their properties are, what they are doing – and already their findings are breaking new ground.

“I think that this feature of densely packed proteins in the AIS will turn out to be critical for modulating the outputs of nerve cells in the brain, and not only for the already known function of generating or modulating inputs.

“So the axon probably functions as much more than just a switch, and this is really quite surprising – it is not what we were looking for at all.”

The results on axonal processing are largely preliminary and quite hypothetical at this stage, but Stuart thinks they will turn out to be true even though the exact significance of the findings and the mechanisms involved are not clear yet.

In fact, at the giant American Society for Neuroscience conference in the US, others reported another protein that is also at high density in the AIS.

“It is one the field had not even considered would be at this site, so I think this focus will provide very interesting information, although of course there is still much more to do.”