Penn neuroscientist solves motor control mystery

Whether it is in a recital hall, operating room, or on a football field, the difference between “good” and “great” often comes down to fine motor control. Even for more mundane activities, the brain must orchestrate complicated combinations of nerve signals to accomplish any given task. In order to learn those skills, the brain needs a feedback system to tell it if its muscle-controlling neurons, known as Purkinje cells, make a mistake. Without one, the brain could never adapt and improve.

Neuroscientists have known about the neurons responsible for delivering these feedback signals—called climbing fibers—for decades, but have been wrestling with a paradox since their discovery. These climbing fibers send signals when there is an error to report, but also do so spontaneously, about once a second. There did not seem to be any way for an individual Purkinje cell to tell the difference between the kind of signal that needed to be acted upon and the kind that could be safely ignored. Some other brain mechanism must have been in play.

A new study led by Javier Medina, an assistant professor in the Department of Psychology in the School of Arts & Sciences, has demonstrated that these cells can make this distinction on their own, laying the foundation for new research on how fine motor control can be improved with practice.

In their study, the researchers had mice walk on treadmills while their heads were kept stationary. This allowed the researchers to blow random puffs of air at their faces, causing them to blink. Unexpected stimuli like this causes climbing fibers to signal to their corresponding Purkinje cells, so Medina and his colleagues used a non-invasive technique to monitor those neurons during the experiment.

The technique—two-photon microscopy—uses an infrared laser and a reflective dye to look deep into living tissue, providing information on both structure and chemical composition. Neural signals are transmitted within neurons by changing calcium concentrations, so the researchers used this technique to measure the amount of calcium contained within the Purkinje cells in real time. This allowed them to compare how the neurons responded to spontaneous climbing fiber activations with the “true” signals they received when the mice blinked.

“What we have found is that the Purkinje cell fills with more calcium when its corresponding climbing fiber sends a signal associated with that kind of sensory input, rather than a spontaneous one,” Medina says. “This was a bit of a surprise for us because climbing fibers had been thought of as ‘all or nothing’ for more than 50 years now.”

The exact mechanism by which these climbing fiber signals produce different responses in their corresponding Purkinje cells remains elusive, but future research in this field will underpin the fundamentals of how the brain learns from mistakes.