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As a graduate student conducting basic science research, Matthew Baker, Ph.D., focused over the last few years on one mysterious process of the brain — specifically, what takes place in cases of addiction. His mentor, molecular pharmacologist Doo-Sup Choi, Ph.D., leads a research team that aims to understand the molecular and cellular mechanisms of drug and alcohol addiction with the goal of identifying treatments.

Three years ago, Dr. Baker's graduate thesis project took a turn when he read an article in a medical journal describing an approach that could zero in on and delete a specific neural circuit. His idea was to apply the approach to the region of the brain known as the external globus pallidus, or GPe, which relays information between two brain regions. The GPe was known to be active in motor function but had only recently been linked to the process of how the brain chooses an action to seek a reward or addictive drug.

He and Seungwoo Kang, Ph.D., a research associate who also was working in Dr. Choi's lab, conducted experiments and identified a neural circuit from the GPe that extended to a specific area of the dorsal striatum, a brain region associated with addiction. With that information, Dr. Baker and Dr. Choi began to formulate a plan to investigate whether the circuit played a role in addictive behavior.

"It was a courageous idea," says Dr. Choi. "Not many people had tried this approach of deleting a circuit, and not in this area. We agreed to go there."

The research team, which included collaborators from Korea Advanced Institute of Science and Technology, revealed a specific group of neurons within the GPe that are connected to addictive behaviors. "Our work identified a new function of this neural circuit," says Dr. Baker, who graduated in May from Mayo Clinic Graduate School of Biomedical Sciences and is the first author of the article in Nature Communications. (Dr. Kang, now at Medical College of Georgia, is co-first author of the paper.) Ultimately, the researchers hope the discovery will inform new treatment strategies that reduce habitual and compulsive drug and alcohol use.

Neurons that keep behaviors in check

The studies, looking at mouse models, identified a subgroup of GPe neurons — arkypallidal neurons — as playing a role in addictive behaviors. Arkypallidal neurons comprise only 25% of the neurons in the GPe and extend to the dorsal striatum, which is known to regulate goal-directed and habitual behavior. The study involved using a genetic calcium sensor that fluoresces with light when neurons activate. The fluorescence is then detected with fiber optics and captured as data with more than 30 frames per second. "Over 30 minutes, that becomes an enormous amount of very useful information," Dr. Choi says. With computational models and machine learning techniques, the research team was able to use the activation patterns to predict compulsive reward-seeking behaviors.

The team found that arkypallidal neurons were more active during habitual behavior — for instance, a routine action with no apparent reward — than during goal-oriented behavior, the type of planned action likely to yield a payoff. As part of a feedback circuit that relays information between the GPe and the dorsal striatum, the neurons were associated with suppressing the types of actions that occur in compulsive reward-seeking. What's more, the team found that dysfunctional arkypallidal neurons resulted in increased addictive behavior patterns.

All of the information suggests that it may be possible to target the GPe, and the arkypallidal neurons in particular, to reduce compulsive behavior, says Dr. Choi. A medication or neuromodulation approach that activates arkypallidal neurons may help reduce habitual and compulsive reward-seeking. "Our preclinical studies have further implications in fields such as pharmacology, psychiatry, neurology and neurosurgery," he notes, adding that his team will be collaborating with clinical investigators to confirm the role of arkypallidal neurons in humans.

Ideas that make unique science possible

The findings are another step in the drug and alcohol addiction research program that Dr. Choi directs. His laboratory uses a combination of genetics, pharmacology, proteomics, metabolomics, brain imaging and behavior studies to address the complexity of addiction. His team will continue to investigate arkypallidal neurons, determining whether they convey information to other neurons in the dorsal striatum, particularly a set of neurons that are sensitive to dopamine and may respond to dopaminergic drugs.

Importantly, Dr. Choi credits the current findings to the outside-the-box thinking that kicked off the exploration of the GPe. "It was this new idea that made this unique science possible," he says.

The study was funded in part by donations to advance addiction research, including the Samuel C. Johnson Program for Genomics of Addiction Program at Mayo Clinic. Additional funding came from the Ulm Family Foundation and the National Institutes of Health.

For Dr. Baker, the studies have helped direct the next step of his research. He is continuing his training at Mayo Clinic as a postdoctoral research fellow with neurosurgeon Kai Miller, M.D., Ph.D., whose studies include neuromodulation. "I'm excited to have the opportunity to study similar brain circuits in the basal ganglia, such as those related to motor control, and to learn about approaches such as neurostimulation to address other complex neurological disorders,” he says.

—Kate Ledger

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