Fresh insights into the development of voluntary movement

Researchers at Duke University have succeeded in mapping brain cells that are directly connected to the motor neurons responsible for whisker movement in mice. The scientists, whose work has been published in the journal Neuron, believe that their findings represent an important step forward for several potential medical applications, including those concerned with the restoration of movement in people who have suffered paralysis from brain injuries.

In collaboration with researchers from the University of Chicago, Baylor College of Medicine, the Max Planck Institute and Pfizer Inc, the Duke Medicine team set out to gain a better understanding of rodent motor-control circuits with the potential to shed new light on the way in which human brains develop.

The researchers, whose work has been funded by the National Institutes of Health (NIH) and the Duke Institute for Brain Science (DIBS), focused on how newborn mice develop the capacity to perform an action known as ‘whisking’ – a process whereby the animals brush their whiskers back and forth in a sweeping pattern to detect and discriminate objects in the dark. In order to learn about how whisker control takes place, the scientists exploited the rabies virus’s ability to spread throughout connected nerve cells. By introducing a disabled form of the virus capable of expressing a fluorescent protein, the team was able to trace its journey through a network of brain cells directly connected to the motor neurons responsible for whisker movement.

To find out more about what the scientists discovered and how their results could prove useful within the field of human medicine, I spoke to lead investigator Dr Fan Wang, Associate Professor of Cell Biology and member of DIBS. I began by asking why she and her colleagues selected the rabies virus as the most appropriate tool to map the brain cells in question.

"Rabies is a classic tool that is often utilised by those wishing to trace neurological connections," Dr Wang replied. "In terms of mapping, the advantage of the rabies virus is its ability to ‘jump’. Rabies is successful in killing animals because it continuously spreads. However, it is actually possible to control its jumping. By preventing the virus from jumping more than once, we were able to trace specific motor neurons. This approach allowed us to observe the direct connections between brain cells and the motor neurons responsible for whisker movement."

By introducing the fluorescent rabies virus into the brains of infant mice, the researchers were able to track whisker-control development with stunning clarity.

"We saw the entire distribution of the neural network," Dr Wang explained. "By checking the maps generated on different days, we were able to catalogue the developmental changes that were taking place within the mouse’s brain. These maps were really bright because the virus had been engineered to express fluorescent proteins. There was no need for us to do any staining; the connections were clearly visible within our images. The result was a beautifully labelled, step-by-step map of the neural network’s development."

I went on to ask Dr Wang whether or not these results were in keeping with her initial hypothesis. As she explained, whilst the findings did not contradict any of her expectations, she uncovered more than she had bargained for.

"I had no idea that the neural network was so complex," she said. "I had only expected to find a few groups, so as you might imagine, I was extremely surprised to discover gazillions of connections. In fact, I was worried that I wouldn’t be able to see any changes whatsoever because of the complexity of the network. Fortunately, this did not turn out to be the case."

During the course of their research, Dr Wang and her colleagues discovered that as whisking capabilities develop, motor neurons receive a new set of inputs from the LPGi region of the brainstem. This region, it seems, plays an important role in the synchronisation of certain voluntary movements.

"We still don’t know much about the functional role of the LPGi region," conceded Dr Wang. "However, we do know that there are lots of connections in that region. I think that we have actually filled somewhat of a missing link by recognising that the neurons in this region can project actions bilaterally; they can coordinate movements on the left and on the right. In most cases, cortical motor neurons don’t connect directly to motor neurons. In humans, for example, the extreme fingertips have direct cortical motor-neuron control, which is why our fingers are particularly good at manipulating objects. The motor neurons responsible for speech also have direct input. However, the majority of others do not. In light of this, one of our most interesting discoveries is the fact that the LPGi neurons receive extensive direct cortical input, making this region an extremely effective relay station. As these neurons are excitatory, they are able to relay cortical commands and thus facilitate voluntary movement."

The researchers decided to investigate whisker control because of its similarity with the way in which human babies utilise their fingers. It is hoped that an improved understanding of how such capabilities develop in mice will help scientists to restore motor control in injured humans in the future. In light of this, I asked Dr Wang to what extent her findings are likely to translate to the human brain.

"That’s a good question," she answered. "I would love to know whether or not humans also exhibit the neurological traits that we have identified. Personally, I think that there is a transferable theme whereby new capabilities develop in mice and in humans in a similar fashion. Of course, I have no evidence in regard to humans; this is merely speculative. Even so, I am very excited by the prospect of conducting further investigations with mice. It will be interesting to see whether or not we can manipulate their neural functions and inhibit the development of voluntary movement. In turn, somebody might decide to perform related human studies in the future."

Finally, I asked what types of medical application might result from an improved understanding of the way in which mice develop the capability to make voluntary movements.

"It is possible to endlessly trace circuits," Dr Wang replied. "Eventually of course, it would be nice to have a library containing all of the interconnected circuits that control voluntary movement. I think that such a tool would prove particularly useful within the field of medicine; it would help us to better understand why motor control deteriorates in patients who suffer certain injuries. We could learn about compensatory pathways with the potential to be exploited. After all, brains never have only one, direct pathway between two locations. There are always multiple loops of connections. Conceivably, therefore, our results could facilitate researchers working to compensate for the debilitating effects of movement disorders.

"Also, in one of our previous studies, we conducted reports on several brain regions with the intention of using our results in collaboration with other researchers," concluded Dr Wang. "There is some stunning work taking place within the emerging field of brain-machine interfaces, and we hope to collaborate with scientists working within this discipline. Together, we could set about developing some really advanced prostheses that will enable patients with brain and spinal injuries to walk again. This is one of our long-term goals."