Terrestrial animals move around for a variety of reasons, and the majority of that movement falls somewhere along a spectrum that ranges from wandering aimlessly to running for your life.
“There’s what we’ll call ‘simple exploration,’” said Christopher Del Negro, neuroscientist and professor of applied science at William & Mary. “It’s doing things like looking for food, looking for a mate. You’re just going around and looking for stuff. It's low-intensity locomotion. Then there’s high-intensity locomotion, and that’s more along the lines of ‘there's a predator looming over me and I'm about to get killed.’”
The difference sounds simple enough, but parsing the neural nuances of low- and high-intensity locomotion is a crucial step in understanding, and eventually curing, movement disorders like Parkinson’s disease, explained Del Negro.
“Think about the brain as an hourglass,” he said. “The top of the brain has volition. It wants to make a movement. At the bottom, you have the spinal cord circuits that are in charge of execution. They carry out the movement. The skinny part of the hourglass is the midbrain -- and that's the part we're focused on.”
Del Negro and a team that includes undergraduate and graduate students, post-docs, senior scientists and faculty are working to better understand the largely unexplored circuits of the midbrain. The instruments in the lab were designed and built by W&M Makerspaces students and staff.
“This is breakthrough material we’re working on,” Del Negro said. “We’re on the cusp of something really important.”
The job of the midbrain is to inhibit unwanted movements and to facilitate wanted movements, Del Negro explained. With Parkinson’s, the midbrain stops functioning like it should and patients lose their ability to engage in voluntary locomotion. Patients also experience tremors, which are the failure to stop unwanted movements.
“There is no circumventing the midbrain,” said Del Negro. “Whether you’re startled or just sauntering around — anything that top, cauliflower-like part of your brain wants to do — it has to go through the midbrain pathway to do it. It’s like the brain’s Hampton Roads Bridge Tunnel. No matter what, you’re gonna have to go through it.”
In order to study the neuroscience of the midbrain circuits, Del Negro turned to the Kiehn Lab at the University of Copenhagen, the world’s foremost experts in locomotor circuitries in mammals. He went on sabbatical to work in the lab in 2018. Then, in 2019, Del Negro was awarded a grant from the National Institutes of Health to further his partnership with the lab by collecting data there throughout the summer of 2020.
Along came COVID-19 and the world went on lockdown. Del Negro was grounded and his research at a standstill. As the pandemic raged on, the clock on his grant funding was ticking. That’s when W&M Makerspaces Director Jonathan Frey made the mountain come to Muhammad.
“We needed to have a laboratory where we could assess both low-intensity and high-intensity forms of locomotion,” Del Negro said. “I went to Jonathan and told him I couldn’t get to Denmark to do these experiments, so I just floated the idea of building a lab here. He and his students immediately kicked into gear – and a month later, we had a fully equipped behavior locomotion lab for less than it would have cost me to go to Denmark.”
Frey, who has bachelor’s and master’s degrees in electrical engineering, said the locomotion lab became a passion project for him, Small Hall Machine Shop Director Will Henninger and several students over the winter break. They designed and built four apparatuses to generate a range of high and low intensity locomotion in mice: an open field test, a hole board, a corridor and a precision treadmill. Each apparatus is outfitted with a slow-motion camera to capture the movement, which is then analyzed using artificial intelligence.
Designing for mice presented its own unique challenges, Frey explained. He learned that mice are incredible jumpers – and can reach heights of almost a foot, or roughly the wall height on an early hole board prototype.
“One thing I was not prepared for was how often mice poop when they’re in motion,” Frey said. “It’s amazing. We’re talking like once every five seconds. That’s one problem I never envisioned myself having to engineer my way out of.”
Del Negro is quick to credit his current research program to Frey’s ingenuity.
“Without the Makerspace and its director, this lab wouldn’t exist,” Del Negro said. “Scientists like me, who don’t have Jonathan’s expertise, have to go out and buy equipment, which is extremely expensive and hard to find. It’s not like Peloton is out there selling mouse treadmills. Without their work and dedication, this research would not be happening.”
For students like Mai Ishikawa, a second-semester freshman at W&M, the experience of getting in on the ground floor of the new lab has been invaluable. She plans to become a pediatric physician and spends her spare time volunteering as a scribe at a local health clinic.
“I’m so grateful to everyone who made this lab a reality,” she said. “It’s such an incredible opportunity for students like me to be at the forefront of groundbreaking research like this – research that will hopefully pave the way for clinical applications in the future.”