A new Northwestern Medicine study has demonstrated how dopamine modulates the activity of a specific group of neurons in the striatum, according to findings published in Neuron. These results could shed light on neurological conditions including Parkinson’s disease and addiction, according to Mark Bevan, PhD, professor of Physiology and senior author of the study.
Dopamine’s role in the brain has been intensely studied for decades, but its influence on neurons in the striatum — the main site of dopamine release in the brain — has remained enigmatic, according to Asha Lahiri, a doctoral student in the Northwestern Interdepartmental Neuroscience Program, a member of the Bevan laboratory and first author of the study.
“As a field, we had mostly converged on the view that dopamine should have vaguely positive effects on the excitability of D1 receptor-expressing striatal neurons, but we had absolutely no idea of the dynamics, strength or consistency of the effect,” Lahiri said.
Lahiri, along with Bevan, used a novel combination of experimental approaches that finally resolved this long-standing mystery.
“These are the first experiments that have linked the activity of dopaminergic neurons to dynamic modulation of movement-promoting striatal neurons,” Bevan said. “Furthermore, this modulation is distinct from what was previously reported using classic pharmacological approaches.”
Most dopamine neurons are located in the basal ganglia, a brain region important for goal-directed and habitual movement. To initiate movement, other brain regions such as the cortex give a command to move and the basal ganglia commits to that behavior if it is determined to be biologically beneficial — for example, seeking food or social interaction.
“Recent studies, some of which were done at Northwestern, have suggested that dopamine neurons are tracking these commands and increasing the vigor of the associated movements in real time,” Bevan said. “However, until now the cellular mechanisms underlying that regulation had not been demonstrated.”
Studying the cellular actions of dopamine had proved to be very difficult, according to Bevan. Previously applied experimental techniques disrupted both the normal activity of striatal neurons and their responsiveness to dopamine, but Lahiri and Bevan utilized a seldom-used approach to preserve dopaminergic modulation.
The technique, called “perforated patch-clamp recording,” uses a glass probe to deliver an antibiotic called gramicidin to neurons, opening tiny pores in their membranes that scientists can use to measure electrical activity.
“Although one has electrical access, these pores are so small that large, complex proteins and signaling machinery are retained within the cell,” Bevan said.
This technique is not new, but is difficult and time consuming, according to Lahiri.
“These experiments take a lot out of you,” Lahiri said. “The days are extremely long and demanding, progress is slow, and some days you get really unlucky and end up with nothing. But I always knew that what we were doing, and the way we were doing it, was essential to really nail down the cellular mechanisms of dopaminergic modulation.”
In addition to perforated patch-clamp recording, Lahiri and Bevan used a technique known as “optogenetics” to selectively stimulate dopaminergic neurons using light.
During these experiments, the investigators discovered that in response to native dopamine release, the electrical activity of movement-promoting striatal neurons increased within hundreds of milliseconds and remained elevated for several minutes.
“This effect has never been seen before,” Bevan said. “It means the dopaminergic neurons can make these cells more sensitive to incoming motor commands, and it does so quickly and persistently.”
The long-lasting nature of modulation was especially surprising, according to Bevan.
“It may represent a mechanism that promotes repetition of rewarding behaviors,” Bevan said
Another possibility is that there are other undiscovered mechanisms that counteract persistent modulation, according to Bevan.
“In the intact brain, things could be much more complex,” Bevan said. “There are other neuromodulators in the striatum, such as acetylcholine, that might limit dopamine’s effects.”
In the future, Bevan’s lab plans to run analogous experiments using combinations of classic and modern circuit-interrogation approaches to understand how naturalistic dopaminergic signals regulate the activity of striatal neurons in health and disease.
This study was funded by National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) grants P50 NS047085, R37 NS041280 and F31 NS100357.