By Kelly Rae Chi

Duke brain scientists are shaking up their field’s understanding of a part of the brain called the basal ganglia that’s sort of a crossroads for many important functions.

A simplified map of the pathways domamine and serotonin travel to the basal ganglia, the snail-shaped structure in the middle of the human brain.

A simplified map of the pathways dopamine (blue) and serotonin travel to the basal ganglia, the snail-shaped structure in the middle of the human brain.

Basal ganglia signaling is involved in movement, learning, language, attention, and motivation.  But this centrality also makes it  challenging to figure out how it works, said Henry Yin,  an assistant professor of psychology and neuroscience at Duke, and a member of the Duke Institute for Brain Sciences.

As healthy mice collected food pellets delivered into a cup once per minute every minute for two hours. Yin’s team was recording the electrical activity of  neurons projecting to and from the basal ganglia.

Henry Yin is an assistant professor in Psychology and Neuroscience.

Henry Yin is an assistant professor in Psychology and Neuroscience.

Naturally, the mice picked up food less often as they became full and some of the cells that use dopamine to signal reward showed less activity.

But other dopamine cells became more active.

In a paper describing these experiments , Yin’s group proposed that the cells’ activity reflected not reward but what the animals are physically doing.

This was new and Yin became curious. Was there a direct relationship between movement and dopamine activity?

Using a different experimental setup with cameras and pressure pads, Yin’s group quantified mouse movements while recording neural activity. “What happens is that whenever there’s movement, (there are phases of) dopamine activity,” Yin said to a room full of fellow neuroscientists during a recent seminar at Duke.

Putting the mice on top of a “shaker,” a piece of lab equipment  normally used to gently shake tubes and dishes full of liquids,  they found individual dopamine neurons responded to specific directions the mouse was tilted on the shaker. The same was true for nearby neurons that signal using GABA, an inhibitory chemical in the brain.

Using additional methods for tracking motions of freely moving mice, the group has discovered specific sub-populations of neurons that respond to different aspects of movement, especially movement speed and acceleration.

The researchers have also created transgenic mice whose dopamine neurons can be stimulated using light. Turning on these neurons makes the mice move.

Yin is working on publishing these results, but he said there’s a lot of resistance in the field.  His work appears to be directly challenging the dogma that  dopamine is linked to reward. He says it might actually be involved in generating movements.

“Let’s say you’re drinking coffee and that’s a reward,” Yin said. “I record your neural activity, and it’s correlated with coffee. You might say it’s a coffee neuron. But that’s not true unless you can measure the movement kinematics and rule out other possible correlations. What we’re seeing is that, with no exceptions, the phasic activity of DA neurons is always correlated with movement.”

Yin’s work also challenges theories about why people with Parkinson’s disease, whose dopamine cells degenerate, often have trouble initiating movement, or they move more slowly than they mean to.

“If you’re a doctor, a neurologist, what you study is the rate model. That’s the textbook description,” Yin said. The gist of the rate model is that the basal ganglia is constantly putting the “brakes” on behavior, and when its neurons settle down, that allows for movement.  Parkinson’s patients can’t initiate movements, it’s thought, because their basal ganglia output (more specifically, the rate of firing in the inhibitory output neurons) is too high, producing excessive braking.

In contrast, according to Yin’s work, at least four different types of basal ganglia output neurons are adjusting behavior dynamically and continuously, to shape the speed and direction of movement.

When the activity of these neurons is constant, it reflects a stable posture, Yin said.  So he argues that the problem with Parkinson’s patients is not that their basal ganglia output is too high, but that this output is stuck in firing mode. The downstream brain areas required for postural control don’t get the right commands.

Nicole Calakos is an associate professor of neurology.

Nicole Calakos is an associate professor of neurology.

“Henry’s studies are really exciting because we’ve thought about this circuitry in one way for a very long time and his findings really cast a new light on those interpretations,” said Nicole Calakos,  M.D., Ph.D., an associate professor of neurology. “I treat patients with Parkinson’s disease and other diseases that involve this circuitry. It is interesting to consider this alternate view to explain the problems my patients face in doing their day-to-day activities.”

Calakos’ own research focuses on how learning alters signal processing by the basal ganglia, and how the signaling goes awry in brain diseases such as obsessive-compulsive disorder. Duke researchers are finding compelling links between different behavioral states and specific long-lasting patterns of activity in the basal ganglia.