Carnegie Mellon Ph.D. candidate proposes a unified hypothesis behind skilled motor actions

Ongoing research at Carnegie Mellon’s Yttri Lab, led by Ph.D. candidate Mark A. Nicholas, could lead to new understanding of the neural activity behind skilled motor activities. On Feb. 9, Nicholas presented his work at the weekly Department of Biological Sciences Research Club Seminar.

“Individual areas of the brain work together to produce things such as thoughts, perception, and movement," Nicholas said. "The neurons in the motor cortex send direct projections to the motor output areas, such as the brainstem, cerebellum, and spine to direct skilled motor actions. The striatum of the basal ganglia is another part of the brain which works with the motor cortex to produce skilled movements.”

So far, the field of neuroscience has conflicting hypotheses about the brain regions responsible for skilled movement. Some scientists believe that the motor cortex is necessary for learning and executing motor functions, while others believe that the striatum is more pivotal.

A 2015 study from Harvard University concluded that the motor cortex was required for learning a motor skill, but not for the execution of it. This was based on an experiment in which rats were trained to learn a precise motor sequence in exchange for a reward, and after they reached peak performance, their motor cortices were inhibited. The rats were able to perform at the same level as before manipulation, which led the scientists at Harvard to reach a conclusion about the motor cortex’s importance during skill acquisition but not execution.

Meanwhile, another study led by scientists at the Janelia Research Campus (at Howard Hughes Medical Institute) concluded that the motor cortex was required for the execution of skilled motor actions. The scientists used optogenetics (the use of light to control specific cell types) to inhibit the function of the cortex after training the mice to reach and grab a food pellet in a task. As a result, the mice were unable to perform the trained task they had learned before, but were able to execute untrained forelimb movements.

Nicholas stated that the difference in methodology of both of these studies could be related to the differences in conclusions regarding motor cortex function.

On the other hand, prior studies from the Yttri Lab demonstrated the importance of the striatum in selective or voluntary actions. Specific direct pathway (D1) and indirect pathway (D2) cells in the striatum were activated via optogenetics during the fastest third of the movements, after the mice were trained in a specific task. The results pointed towards increased movement velocity after bilateral activation of D1 neurons, and decreased movement velocity after bilateral activation of D2 neurons. In addition, the researchers at the Yttri Lab found the opposite results when stimulating on the slowest third of reaches and concluded that the plasticity of the striatum was dependent on activity and reward. This suggests that the striatum is responsible for gain modulation, which are reward-related changes within the neural connections of the striatum.

Nicholas’s unified hypothesis states that the motor cortex is responsible for the generation of motor commands, while the striatum (the input nucleus of the basal ganglia) is responsible for the gain modulation related to those motor commands.

In Nicholas’s study at the Yttri lab, mice were trained to push a joystick to a certain distance. When the mice successfully pushed the joystick past the threshold distance, they received a reward. In addition, mice learned to wait for a fixed interval of three seconds between push attempts. Due to the high spatial-temporal resolution of the system used, Nicholas and his team were able to get the reach kinematics, like distance and speed, of each attempt as well.

Nicholas and his team hypothesized that removing motor cortex function would negatively impact behavioral performance and alter kinematic representation.

Task performance dropped in mice who did not maintain motor cortex function; they were almost unable to perform the task past the threshold distance, if at all. It took nearly seven days of task repetition for the mice to reach near-original ability.

Moreover, Nicholas and his team recorded movement-related striatal activity every day in the mice without motor cortex function and found a decrease in reach-related signals in the striatum. This meant that as the mice were able to push the joystick, this movement was not reflected nor produced in the striatum. Based on the recovery of behavior in the absence of striatal representation, the researchers were able to conclude the loss of gain modulation.

To provide a negative control for the experiment, Nicholas and his team included an additional sample of mice with inhibited parietal cortex function. Their performance and striatal activity were not impacted, which proved that only the motor cortex and striatum were the areas of importance.