Summary: New discoveries about dopamine-sensitive neurons in the striatum reshape understanding of how the brain updates learned actions and suggest fresh directions for treating Parkinson’s disease, Tourette syndrome and other basal ganglia disorders.
Source: University of New South Wales
Scientists at UNSW Sydney’s Decision Neuroscience Lab have reported a major advance in how brain circuits influence behavior, challenging a 30-year-old model.
Researchers led by Dr Miriam Matamales and Dr Jay Bertran-Gonzalez, together with Neuroscience Lab Director Scientia Professor Bernard Balleine, have published new experimental evidence showing that the two principal classes of striatal neurons interact locally within the striatum during goal-directed learning. These findings, reported in Science, may change how scientists and clinicians think about voluntary action, learning and the treatment of basal ganglia disorders such as Parkinson’s disease, Huntington’s disease, dystonia, Tourette syndrome and obsessive-compulsive disorder.
To study how the striatum updates behavior, the team recorded activity across large territories of the striatum while mice learned new actions that produced a food reward. They focused on the two main populations of spiny projection neurons (SPNs) that express different dopamine receptor subtypes: D1-SPNs and D2-SPNs. For decades, D1- and D2-neurons were believed to act largely independently—D1 neurons promoting action initiation and D2 neurons inhibiting action. The UNSW experiments reveal a different picture: an extensive, dynamic interaction in which D2-SPNs locally modulate D1-SPN activity to update previously learned behaviors.
Lightbulb moment
Dr Matamales gives a simple real-world example to illustrate the process: you enter a dark room, flick the switch and nothing happens. The action—flicking the switch—was previously associated with a rewarding outcome, and that expectation must be revised when the bulb is blown. The brain must stop defaulting to the old response to avoid wasting energy. The researchers show that this updating—extinction learning and the suppression of outdated action tendencies—relies on a local interaction between D2- and D1-neurons within the striatum.
Professor Balleine clarifies that this mechanism does not erase the original learning; rather, it temporarily suspends or reshapes it while a new, context-appropriate response is encoded. “D1-neurons support acquiring and maintaining ongoing behaviors,” he says, “while D2-neurons are engaged when those behaviors need updating. Crucially, this regulatory interaction occurs in the striatum itself—not only in downstream motor centers as previously thought.”
Rethinking brain health
This revised view of striatal circuitry has important implications for clinical neuroscience. The authors argue that current models of basal ganglia function, widely used to guide treatment strategies, are incomplete because they overlook the local D2-to-D1 transmodulation that reshapes goal-directed behavior.
“Our research suggests that the whole theory of basal ganglia function that people have been working with in order to try and treat diseases of various kinds, is seriously incomplete,” Professor Balleine says.
Dr Bertran-Gonzalez notes that many basal ganglia disorders emerge slowly over years and often involve inappropriate or uncontrolled actions—movements or behaviors that should have been inhibited but were not. Such symptoms could reflect impaired learning or defective updating within the striatum, rather than—or in addition to—pure motor output failure. He proposes that therapies should not focus solely on suppressing symptoms but also on restoring or retraining the learning processes that teach actions to be inhibited or modified.
Targeted medicine
Because the new results identify specific interactions between defined neuron types within precise striatal territories, they offer a clearer anatomical and functional target for future interventions. “These findings give great targeting information for treatment,” Professor Balleine says. “They open the possibility of re-directing therapies toward the striatum and toward particular connections between neurons, rather than treating downstream motor pathways alone.”
Dr Matamales cautions that while the results in mice are promising, further research is needed to confirm how directly these mechanisms translate to the human brain. Still, she is optimistic that framing basal ganglia disorders in terms of learning and circuit-specific dysfunction will spur new experimental therapies that complement symptom management with approaches that restore adaptive learning.
“Our data strengthen the connection between striatal neurons and cognitive processes involved in learning and adaptation,” she says. “That perspective could guide future breakthroughs that explain how the brain learns and how it flexibly updates behavior in response to changing environments.”
Source:
University of New South Wales
Media Contacts:
Lachlan Gilbert – University of New South Wales
Image Source:
The image is adapted from the University of New South Wales news release.
Original Research: Closed access. Article title: “Local D2- to D1-neuron transmodulation updates goal-directed learning in the striatum” by Miriam Matamales et al., published in Science (DOI: 10.1126/science.aaz5751).
Abstract
Local D2- to D1-neuron transmodulation updates goal-directed learning in the striatum
Extinction learning enables animals to withhold voluntary actions that are no longer tied to reward and thus provides essential behavioral control. Although such learning has been linked to dopamine signals in the striatum, the circuit-level reorganization that supports updated goal-directed control was previously unclear. By mapping a dopamine-dependent transcriptional activation marker across large ensembles of D1- and D2-expressing spiny projection neurons in mice, the authors demonstrate an extensive, dynamic D2-to-D1 transmodulation across the striatum that is required to update prior goal-directed learning. These results indicate that D2-SPNs suppress outdated D1-SPN plasticity within functionally relevant striatal territories to reshape voluntary action.