Neural Circuits and Motor Control: A Q&A with Eiman Azim

WHEN YOU REACH FOR A GLASS on a high shelf or grab your cell phone as it slips from your grasp, a symphony of nerve cell impulses conducted by the brain launches the muscles in your limbs to complete these tasks – often without a second thought. Scientists in Thomas Jessell's laboratory at Columbia University's Kavli Institute for Brain Science recently published two papers in separate issues of the journal Nature in which they identified two distinct groups of neurons responsible for these actions. The first group is excitatory neurons needed to make accurate and precise movements, while the second group is inhibitory neurons necessary for achieving smooth movement of the limbs. Taken together, these findings confirm long-standing theories about how the brain controls fine movement, and lays the groundwork for improving our understanding of motor control in humans.

The Kavli Foundation asked Eiman Azim, first author of the paper that identified the excitatory neurons and a contributing author on the second paper, about his research and what it may mean for understanding movement in humans.

THE KAVLI FOUNDATION (TKF): What excites you about this research?

EIMAN AZIM: When we catch a ball or throw a dart, we usually don’t think twice about the intricate neural circuits that drive such impressive and precise movements. Somehow we are able to coordinate the activity of dozens of muscles to propel our hand to a very specific point in space. Mouse genetics gives us the ability to delve into and disentangle the individual neural pathways in the brain and spinal cord that make these movements possible. I’m very excited to find out how far these reductionist approaches will take us and see what new questions will arise.

TKF: Your findings seem to be telling us that the nervous system has a built-in redundancy: one pathway carries information to the limbs, which controls motor movement, while a copy of this pathway projects to the brain. Is this an accurate description? Is this redundancy replicated in other parts of the nervous system?

AZIM: These pathways are redundant in that the same messages are sent along two axonal branches that travel in different directions. Yet in a functional sense, these pathways are not redundant – the copies that these neurons transmit are uniquely suited to overcome some of the limitations inherent in our motor system. When we move our arm, sensory feedback from our muscles informs us of the outcome of our movements, allowing us to refine and correct our behaviors. Yet this feedback takes time to get from the periphery back to the spinal cord and brain, making it of limited use during very rapid skilled movements. A system that conveys copies of outgoing motor commands internally can act as a “shortcut,” keeping our brain aware of ongoing motor output, and enabling us to correct movements online. Axon branching and bifurcation is extremely common in the nervous system, suggesting that the conveyance of internal copies is a widespread and fundamental strategy across motor pathways.

TKF: In this study, your group found that eliminating specific cells in the spinal cord called propriospinal neurons (PNs) in mice impaired their ability to reach for an object. Are there conditions in humans in which PNs malfunction?

AZIM: We don’t yet know if there are specific disorders that affect PNs. However, spinal cord injury and neurodegenerative diseases that impact motor pathways are likely to affect PNs and the neurons with which they communicate. Interestingly, there is some evidence that after incomplete spinal cord injury, PN connections can rewire and provide a “bridge” around the injury site, contributing to motor recovery. Essential to our understanding of the therapeutic relevance of PNs is a better understanding of their basic organization and function during movement.

TKF: Optogenetics -- the use of light to control the activation of neurons -- is emerging as a valuable tool for studying the brain and nervous system. What did optogenetics enable you to do in this study that would have been difficult or impossible to do without it?

AZIM: Optogenetics was instrumental in allowing us to explore the function of the PN internal copy pathway. Because copy circuits are by their nature intimately associated with motor output pathways, classical approaches such as electrical stimulation have had difficulty isolating such copies experimentally since activation of the copy branch would also activate the motor branch. By shining light on the PN internal copy axon branch, we were able to activate this pathway selectively while leaving the motor output branch untouched. This allowed us to decalibrate internal copy from motor output and ask questions about how the PN copy pathway affects movement.

TKF: What do your findings in mice tell us about motor control in humans?

AZIM: Rodent and primate reaching movements exhibit remarkably equivalent limb extension, flexion and rotation movements. Similarly, central features of PN anatomy, and motor circuit connectivity more generally, are shared between species, suggesting that fundamental aspects of how PN copy pathways are used to rapidly update forelimb movements in mice will apply to humans. Yet humans have evolved an impressive amount of skill and dexterity that mice do not have, especially in movements of the hand and digits. By exploring the basic building blocks of skilled motor control that are shared across species, we can also infer which changes might have enabled species-specific adaptations during evolution.

TKF: How did you get interested in studying motor control and the spinal cord?

AZIM: Since I first began neuroscience research, I have been interested in linking neural circuits to behavior. This is a challenging task, requiring technical and conceptual links between molecular, cellular, circuit and behavioral levels of analysis. Motor control and the spinal cord in particular are well suited to these kinds of questions – the activity of genetically defined spinal circuits is directly linked to observable and readily quantifiable output, through the activation of muscles, providing a very rich system for exploring the neural basis of behavior.

— Joseph Bonner