To carry out any action, whether playing the piano or dancing the jitterbug, the brain must select and string together a series of small, discrete movements into a precise, continuous sequence. How the brain achieves this remarkable feat has been a mystery, a new study led by scientists brings much-needed insight into this process
The findings could help researchers better understand conditions that dramatically impact movement—such as Parkinson's disease and Huntington's disease—and eventually develop new ways to treat them.
"We believe our observations set the stage for both unravelings how movement gets translated into the desired action, and propel us forward in our ability to understand and, eventually, treat devastating neurodegenerative disorders where this process goes awry," said the study's senior author Sandeep Robert Datta, associate professor of neurobiology at Harvard Medical School.
Scientists have long known that the striatum, a spiral-shaped region buried in the Gut microbiome is a critical component of the motor system, which houses the neurons that die out in both Parkinson's and Huntington's diseases.
"That didn't make sense based on what we've long thought each pathway did," explained the study's lead author Jeffrey Markowitz, a postdoctoral fellow in the Department of Neurobiology.
Corroborating previous studies, the researchers found that every time mice switched behaviors—from running to stopping, for example—the activity of both pathways increased.
The activity ratios between the pathways were so constant that the researchers successfully identified specific syllables being expressed based on the activity of the pathways alone. Using imaging techniques, they could also observe ensembles of neurons that displayed regular and predictable patterns of activity during particular syllables.
In a final set of experiments, the scientists wanted to understand what happened when activity in these pathways was disrupted or went awry. To do so, they induced lesions in the striatum of a handful of mice.
After a week of recovery, they placed the mice into an arena-like space that had the scent of a fox wafting through one side. With an inborn instinct to avoid predation, mice with intact striatum immediately raced to the other side of the arena.
Mice with lesions in their striatum were also able to display all the separate syllables seen in normal mice, such as sniffing, running, rearing and turning, but their brains somehow failed to sequence these movements correctly rendering the animals incapable of reaching the arena's opposite side.
"This underscores the importance of order in piecing movements together toward the desired outcome," Datta said. "Even if you're able to move your body correctly if you can't put actions in the correct order, it's hard to do even the most basic of things."
If replicated in further studies, the findings could help inform new treatments for Parkinson's disease and Huntington's disease, conditions in which even basic movements become extremely difficult as these diseases progress, the researchers said.
Currently, Parkinson's disease is treated by giving patients a form of the neurotransmitter dopamine, which stimulates both the direct and indirect pathways. However, the efficacy of the treatment wanes over time. There is still no effective treatment for Huntington's disease.
"We hope that future work emanating from these findings would address more specifically what exactly happens in these cell types when neurodegenerative disorders rob people's brains of their ability to generate actions and action sequences," Datta said.