For more than a century, scientists have known that while the commands that initiate movement come from the brain, the neurons that control locomotion once movement is underway reside within the spinal cord. Studies in mice by scientists at Columbia University have now found that one type of neuron, called ventral spinocerebellar tract neurons (VSCTs), is both necessary and sufficient for regulating this type of movement.
The researchers found that when just these cells were chemically silenced in freely moving adult mice, the animals could no longer move properly. Once the effects of the drugs had worn off, the mice could move normally again. The investigators suggest that their study results could help point to new therapeutic strategies for treating trauma or diseases that impact movement.
“We hope that our findings will open up new avenues toward understanding how complex behaviors like locomotion come about and give us new insight into the mechanisms and biological principles that control this essential behavior,” said George Mentis, PhD, associate professor of pathology and cell biology in the department of neurology at Columbia University. “It’s also possible that our findings will lead to new ideas for therapeutic avenues, whether they involve treatments for spinal cord injury or neurodegenerative diseases that affect movement and motor control.”
Mentis, together with Columbia University colleagues and collaborators at University College London, reported on their findings in Cell, in a paper titled, “Control of mammalian locomotion by ventral spinocerebellar tract neurons.”
Locomotion is an essential animal behavior that is critical for survival, the authors wrote. “Overground locomotion is defined as the alternating, rhythmic motor activity between opposing limbs, as well as between antagonistic muscles of the same limb.” Walking is generally a natural movement. We don’t have to think before putting one foot in front of the other. But how is this coordinated?
“As one might expect, it’s the brain that initiates locomotion,” commented Mentis, who investigates the circuits that control walking with an eye toward finding new treatments for patients with ALS, SMA, and spinal cord injuries. “But it doesn’t coordinate it.”
Instead, coordination of our many walking muscles is handled by neurons in the spinal cord. It’s a complex job: With precise timing, these neurons must send signals so the left and right leg alternate their activity—left, right, left, right—and so flexor and extensor muscles in each leg contract in an alternating fashion.
Most scientists thought that such a complex task could only be handled by complex neuronal circuits, with contributions from different types of neurons. This assembly of circuits, called the central pattern generator, seemed to run the show. “Although sensory feedback and supraspinal commands are important for modulating locomotion, a network of spinal interneurons—known as the central pattern generator (CPG)—is thought to be responsible for the genesis of locomotor activity without relying on sensory or descending inputs,” the researchers continued. However, they pointed out, “It is unknown whether multiple or a single neuronal type is responsible for the control of mammalian locomotion.”
VSCTs were discovered in the 1940s, but researchers have long believed that their main function was to relay messages about neuronal activity from the spinal cord to the cerebellum. The newly reported study showed that instead, they control locomotor behavior both during development and in adulthood.
“These findings were a huge surprise,” Mentis said. “One of the key discoveries in our study was that apart from their connection to the cerebellum, these neurons make connections with other spinal neurons that are also involved in locomotor behavior via their axon collaterals.”
Mentis and colleagues carried out several novel experimental approaches. The team applied optogenetics, using LED light to regulate certain proteins that were expressed selectively in VSCTs, to either activate or suppress the neuronal activity. Another set of experiments used chemogenetic techniques to activate or suppress synthetic ligands expressed artificially in these neurons, controlling their activity.
Leveraging the ability of intact spinal cords from newborn mice to function in a dish, the researchers showed that activation of VSCTs by light induced locomotor behavior. When VSCT activity was suppressed by light or by drugs, ongoing locomotor behavior was halted. “… we show that VSCTs are contacted by MN axon collaterals during early development via both chemical and electrical synapses. The nature of these contacts is both chemical via excitatory synapses, as well as electrical through gap junctions.”
In vivo studies in addition confirmed that freely moving adult mice stopped moving when the activity of VSCT was suppressed by injecting an inhibitory drug. Normal movement then returned when drug activity stopped. Locomotor behavior was also tested by the ability of mice to swim. Mice were unable to swim and simply floated in the water when VSCTs were silenced. In all of these models and experiments, the researchers demonstrated that VSCTs alone were both necessary and sufficient for controlling locomotor activity—activating them was enough to induce activity while suppressing them was enough to stop it. “These findings identify VSCTs as critical components for mammalian locomotion and provide a paradigm shift in our understanding of neural control of complex behaviors,” the team commented.
Mentis acknowledges that there are limitations to conducting this type of research in mice, including the fact that while humans are bipedal, mice are quadrupedal; thus, their locomotion could be regulated in a different way. But he notes that other research on neurodegenerative diseases and processes in mice has led to clinical trials in human patients, suggesting that the murine findings are also likely to be applicable to humans.
The study results may have important implications for the development of new therapies for people with spinal cord injuries or motor disorders. “For example, it may not be enough to reconnect the brain and the spinal cord in people with severed spinal cords,” Mentis commented. “Our findings suggest that you would also have to restore proper activity in the ventral spinocerebellar tract neurons to ensure that the central pattern generator is working properly. Everything has to be tightly balanced between exciting certain neurons and inhibiting others. If this balance is compromised, you won’t have coordinated movement.”
For their next steps, the team plans to identify and map precisely the neuronal circuits that VSCTs make with motor neurons and other spinal neurons. They also would like to identify select genetic markers and uncover potential subpopulations of VSCTs and explore their role in different modes of locomotion. Finally, they plan to explore how the function of VSCTs is altered in the context of pathology and neurodegenerative diseases.
“Our findings identify an unexpected function for VSCTs as key controllers of mammalian locomotion and demonstrate that a single neuronal type is essential for such behavior, fundamentally changing the way we think complex behaviors are produced,” the team stated. They claim the discovery that these VSCTs are necessary and sufficient for locomotor behavior, and represent core components of the locomotor CPG “… provides the conceptual foundation for developing therapeutic approaches for patients suffering from spinal cord injury and motor disorders.”