Timing of acetylcholine release determines if dopamine promotes movement or learning

Scientists have long-studied the role of dopamine, a chemical in the brain that helps control learning and movement, in order to better understand Parkinson’s disease, schizophrenia, and depression-afflictions caused, in part, by a disruption or alteration of dopamine activity.

In a study of laboratory rats, New York University neuroscientists have uncovered a new dynamic in dopamine function: the timing of the interaction of two neurotransmitters-dopamine and acetylcholine-determines whether or not dopamine is effective in guiding learning or effective movement. 

“This study addresses the single-largest question in the dopamine field, which is how to reconcile its dual roles in learning and motor control,” says Christine Constantinople, a professor in NYU’s Center for Neural Science and the senior author of the research, which appears in the journal Nature Neuroscience. “Dopamine can both help learning by reinforcing behaviors that lead to rewarding outcomes or invigorate upcoming movements-depending on when acetylcholine is released. 

“Our research shows that whether anything is learned from dopamine or whether dopamine promotes movement vigor comes down to the timing of acetylcholine release-a difference of a matter of tens of milliseconds, or about the blink of an eye.”

Dopamine is known to help with both learning and in controlling movement. With learning, dopamine reinforces behaviors that have been rewarding in the past by promoting synaptic plasticity-the ability of the brain to change in order to learn. Notably, certain motor disorders, such as Parkinson’s disease, are due to the loss of certain dopamine neurons-though the specifics of what brings about this affliction are unclear. A major challenge for scientists, then, has been to better understand how a single neurotransmitter, dopamine, can support both reward-based learning and motor control.

In the Nature Neuroscience work, the researchers sought to better illuminate this dynamic by focusing on dopamine and another neurotransmitter, acetylcholine, which aids in muscle contraction, memory, and learning. 

Their study of laboratory rats simultaneously measured dopamine and acetylcholine while the animals performed a decision-making task that involved both learning and moving: finding a reward (a source of water) after learning the significance of sound cues, which indicated the water’s amount and location. The scientists hypothesized that varying acetylcholine-dopamine interactions would prompt either learning (the amount of future water rewards) or purposeful movement toward it.

The results showed that the timing of acetylcholine release determined whether dopamine promoted learning (i.e., predicted future behavior and changed neural dynamics) or moving (i.e., preceded and predicted the nature of movements). In many cases, the difference in timing was a matter of tens of milliseconds. 

The scientists say the process is akin to a see-saw’s movement. When dopamine was concurrent with a reduction in acetylcholine release, it promoted learning; when it coincided with a burst of acetylcholine -or increase in acetylcholine release-it predicted the vigor of upcoming movements.

When neurons such as dopamine and acetylcholine malfunction, they can contribute to Parkinson’s disease as well as schizophrenia and depression. Therefore, a greater understanding of the mechanisms by which they coordinate different aspects of behavior holds promise for revealing novel therapeutic targets for these disorders.” 

Christine Constantinople, professor in NYU’s Center for Neural Science 

The paper’s other authors included NYU postdoctoral fellows Hee Jae Jang and Carla Golden and Royall McMahon Ward, an NYU research technician at the time of the study and now a doctoral student at Northwestern University. 

This work was supported by grants from the National Institutes of Health (DP2MH126376, R01MH136272) and an Alfred P. Sloan Research Fellowship.