Rachel Sharp
Reagan Bullins watched intently as a mouse navigated a behavioral task in her lab. As the mouse moved, she used specialized equipment to activate specific neurons – something that usually disrupts natural movement patterns. But then, she saw something surprising. Instead of worsening the mouse’s performance, the brain stimulation she applied seemed to help the mouse move more accurately and consistently. More surprising still: the mouse maintained these skill gains long after the experiment concluded.
“Usually when we perturb neurons, skilled behavior gets disrupted,” explains Bullins, a graduate researcher in Adam Hantman’s lab at The University of North Carolina at Chapel Hill. “But what’s really interesting about these neurons is that when we activated them, it actually resulted in better skilled behavior. The movements became less variable over trials.”
The cells Bullins is referring to are called NDNF (Neuron-derived Neurotropic Factor) neurons, named for the growth protein, called neurotrophic factor, that they produce. Though they make up only a small fraction of neurons in the outermost layer of the brain’s cortex, they appear to play a crucial role in coordinating complex movements. Their location in the cortex’s uppermost layer (Layer 1) allows them to integrate both sensory information about the environment and motor commands that impact movement.
“What’s interesting about Layer 1 is it receives a lot of sensory inputs that are necessary to carry out skilled movement,” Bullins says. “As you’re about to interact with your world, you’re integrating sensory information with motor information to prepare how to respond. These NDNF neurons are uniquely positioned to have a role in control over both sensory information coming into Layer 1 and motor output neurons in Layer 5.”
Until now, these neurons have only been studied in the visual cortex—the brain region responsible for processing sight—where researchers found they play a role in visual learning. Their newfound role in coordinating movement opens up exciting new possibilities for understanding how we learn and refine physical skills.
To study these neurons in action, Bullins and her lab needed to get closer than traditional microscopes allow. Using two-photon microscopy, they can watch the neurons firing in real time during complex behavioral tasks. The team can also selectively activate or suppress the NDNF neurons using light-sensitive proteins, a technique called optogenetics.
Through these experiments, they’ve found that NDNF neurons are highly active during movement. But the most exciting discovery came when they stimulated the neurons during these skilled-movement tasks. Not only did the movements become more consistent, but these improvements lasted even after the stimulation ended.
This persistence is particularly intriguing because NDNF neurons are hard at work during early childhood when the brain is especially plastic and adaptable. “When we’re kids, we have increased levels of plasticity,” Bullins notes. “These neurons being highly expressed during that development period points to the possibility that they do have a role in plasticity. So activating these neurons in adulthood may be a potential way to increase plasticity again.” Plasticity in the brain refers to its ability to adapt, reorganize, grow new networks of connection, or dissolve unneeded ones, as a function of learning and experience. As Bullins notes, our brains are highly plastic during childhood, where the massive volume of new experiences requires near-constant re-writing of connections. This plasticity decreases as we enter adulthood, but promoting increased plasticity can be crucial for recovery from brain or motor injury.
The potential role these neurons play in plasticity raises exciting possibilities for treating conditions affecting movement, like stroke. After a stroke, there’s a short critical window during which the brain shows increased plasticity and potential for recovery. As Bullins notes, if NDNF neurons could be harnessed to extend or enhance this plasticity, it could improve rehabilitation outcomes. “The stimulation of these cell types had a long-lasting effect on the behavior, which makes them an interesting target for plasticity or even for use in a disease model of stroke.”
Many questions remain: Could these neurons help restore movement after injury? “If we activate these cells during learning, does this lead to faster learning? Does it lead to more consistent behaviors faster?” Bullins wonders. “Would this be a way to increase plasticity and thus increase learning rates?”
As Bullins emphasizes, they’re still in the early stages of understanding these mysterious neurons. “We can’t make any statements about what it means yet, but it was really interesting to see these effects,” she says. As these neurons continue to reveal their surprising influence on movement and learning, they offer a promising new avenue for understanding—and potentially enhancing—the brain’s natural capacity for recovery.
Peer Editors: Tiffany Peters & Elizabeth Abrash
