Neurons that drive forward movement charted in the zebrafish brain

Study may help to better understand how motor circuits go wrong in Parkinson’s

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A zebrafish is shown swimming in an illustration.

Researchers have built a map of how neurons wire up in the zebrafish brain to propel forward and steer movement, something people with Parkinson’s disease may have trouble with.

As movement begins to be initiated, a region at the base of the brain known as the mesencephalic locomotor region (MLR) is activated and signals a group of nearby command neurons called V2a reticulospinal neurons.

“These neurons control the finer details of movement, such as starting, stopping, and changing direction,” Claire Wyart, PhD, one of the study’s co-senior authors at the Paris Brain Institute in France, said in a press release. “In a way, they give steering instructions!”

While the study was done in zebrafish, “motor circuits in vertebrate species are conserved,” the researchers wrote, so the map may help understand how these circuits can go wrong in Parkinson’s and how to repair them. The study, “The mesencephalic locomotor region recruits V2a reticulospinal neurons to drive forward locomotion in larval zebrafish,” was published in Nature Neuroscience.

Parkinson’s causes motor symptoms such as tremor, slowness of movement, stiffness, and difficulty maintaining balance. People with the disease may also experience freezing, where they can’t move their muscles, even if they try.

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The mechanisms of movement in zebrafish

Locomotion, or movement from one place to another, involves the activity of reticulospinal neurons in the brain stem, a region at the base of the brain, that relay signals between the brain and spinal cord.

As command neurons, like push buttons that control actions, they “have a crucial role in starting, maintaining, and stopping locomotion, as well as in adjusting posture and steering,” the researchers wrote.

The MLR, also on the brain stem, is critical for movement.

“Because the role of the MLR is conserved in many vertebrate species, we assume that it is an ancient region in their evolution — essential for initiating walking, running, flying, or swimming,” said Martin Carbo-Tano, PhD, one of the study’s co-first authors and a postdoctoral fellow at Paris Brain Institute.

While the MLR promotes locomotion by activating reticulospinal neurons, “until now, we didn’t know how this region transmits information to the reticulospinal neurons,” Carbo-Tano said. “This prevented us from gaining a global view of the mechanisms that enable the vertebrae to set themselves in motion and, therefore, from pointing out possible anomalies in this fascinating machinery.”

This gap was mainly due to the fact that brain stem neurons aren’t easily accessible and it’s difficult to monitor their activity in a moving animal. Using a zebrafish, an animal model commonly used in research, made this possible.

Larval (young) zebrafish are transparent, letting the researchers spot the connections where signals get passed between the neurons during locomotion using fluorescent tags.

In the zebrafish brain, the mesencephalic locomotor region contains an average of 110 neurons, nearly a third (30.8%) of which became active as they swim. Of these, about 22 neurons become more active with the vigor of the session, both when the zebrafish swam freely and in response to a visual cue.

“We observed that neurons in the mesencephalic locomotor region are stimulated when the animal moves spontaneously, but also in response to a visual stimulus,” Wyart said.

Using a thin wire or electrode to directly stimulate the MLR, the researchers saw that different electrical frequencies resulted in different swimming frequencies. Moreover, the animals swam for the whole duration of the stimulus (2 or 4 seconds), while spontaneous swims “only lasted for a few hundreds of milliseconds,” the researchers wrote.

“Quadrupeds can adopt different gaits, such as walking, trotting, or galloping,” Carbo-Tano said. “We think that MLR has a role to play in this intensification of movement, which we have observed in zebrafish.”

The MLR neurons cconnected with both the cell bodies and nerve projections of a subpopulation of reticulospinal neurons called V2a.

Using a microscope to record high-speed images of neuronal activity, the researchers saw that V2a reticulospinal neurons strongly connected with MLR were active when the zebrafish swam forward or steered. The weakly connected ones controlled how long and how often the forward movement happened.

“Our study identified the MLR in larval zebrafish and mapped the downstream command circuits involved in forward locomotion,” the researchers wrote, noting their finding “represents an essential step for future research on supraspinal [above the spinal cord] motor control.”