From steering a car to swinging a tennis racket, we learn to perform all kinds of skillful movements throughout our lives. You might think that this learning is implemented only by neurons, but a new study by researchers at The Picower Institute for Learning and Memory at MIT shows the essential role of another type of brain cell: astrocytes.
Just as teams of elite athletes train together with coaching staffs, ensembles of neurons in the brain’s motor cortex depend on nearby astrocytes to help them learn to encode when and how to move and the optimal timing and trajectory of a movement, the study shows. Describing a series of experiments on mice, the new paper in Journal of Neuroscience reveals two specific ways in which astrocytes directly influence motor learning by maintaining an optimal molecular balance in which neuronal ensembles can properly improve movement performance.
“This finding is part of a series of work from our lab and other labs elevating the importance of astrocytes in neural coding and thus behavior,” said senior author Mriganka Sur, Professor of Neuroscience at The Picower Institute and the Department of Brain of MIT. and Cognitive Sciences. “This shows that while population coding of behaviors is a neuronal function, we need to include astrocytes as partners with it.”
Picower Institute postdoc Jennifer Shih and former Sur Lab postdocs Chloe Delepine and Keji Li are co-lead authors of the paper.
“This research highlights the complexity of astrocytes and the importance of astrocyte-neuron interactions in fine-tuning brain function by providing concrete evidence of these mechanisms in the motor cortex,” Delepine said.
Messing with engine mastery
The team gave their mice a simple motor task to master. When presented with a tone, the mice had to reach and press a lever within five seconds. The rodents showed that they could learn the task within a few days and master it within a few weeks. Not only did they perform the task more accurately, but their reactions were quickened and the trajectory of reaching and pushing became smoother and more even.
In some of the mice, however, the team used precise molecular interventions to disrupt two specific functions of astrocytes in the motor cortex. In some mice, they disrupted astrocytes’ ability to take up the neurotransmitter glutamate, a chemical that stimulates nerve activity when taken up at connections called synapses. In other mice, they overactivated astrocyte calcium signals, which affected how they functioned. In both ways, the interventions disrupted the normal process by which neurons would form or change their connections with each other, a process called “plasticity” that enables learning.
Each of the interventions affected the mice’s performance. The first (a knockdown of the glutamate transporter GLT1) did not affect whether or how quickly the mice pressed the lever. On the contrary, it disturbed the smoothness of the movement. GLT1-disrupted mice remained erratic and shaky, as if unable to improve their technique. Mice that underwent the second intervention (activation of Gq signaling) showed deficits not only in the smoothness of their movement trajectory but also in their understanding of when to press the lever and their speed to do so.
The team dug deeper into how these deficits arose. Using a two-photon microscope, they monitored neural activity in the motor cortex in unlesioned mice and mice treated with each intervention. Compared to what was seen in normal mice, the GLT1-disrupted mice showed less correlated activity between neurons. Mice with Gq activation showed exaggerated correlated activity compared to normal mice.
“The data suggest that an optimal level of neural correlation is required for the emergence of functional neural ensembles that guide task performance,” the authors wrote. “It is the meaningful associations that convey information that drive motor learning despite the sheer magnitude of potentially non-specific associations.”
The team dug even deeper. They carefully isolated astrocytes from the motor cortex of mice, including some that were not trained in the motor task as well as those that were trained, including mice that were unlesioned and mice that underwent each intervention. In all of these purified astrocyte samples, they then sequenced the RNA to assess how they differed in their gene expression. They found that in trained versus untrained mice, astrocytes showed greater expression of GLT1-related genes. In mice where they intervened they saw reduced expression. This evidence further suggests that the glutamate transport process is indeed fundamental to motor task training.
“Here we show that astrocytes play an important role in allowing neurons to encode information correctly, both learning and performing a movement for example,” said Sur.
Pierre Gaudeaux is a co-author of the paper. The research was funded by the National Institutes of Health, the Simons Foundation, and the JPB Foundation.