Summary: A signaling receptor primarily known for sculpting the brain in the womb has been discovered to play a critical role in how adults learn and adapt. Research reveals that the receptor Smoothened acts as a “tuning knob” in the adult striatum.
The study shows that Smoothened regulates the precise timing between dopamine and acetylcholine. This molecular coordination determines how strongly a behavior is reinforced and how easily a person can switch strategies when conditions change, offering new insights into addiction and Parkinson’s disease.
Key Facts
- The Timing Regulator: Smoothened controls the duration of “pauses” in acetylcholine release. These pauses create the specific windows of time where dopamine can reshape neural connections.
- Flexibility vs. Persistence: When Smoothened is removed, these windows stay open longer, causing animals to learn faster and persist longer. However, they become “stubborn,” losing the flexibility to adjust when rewards change.
- Repurposed Biology: The study proves that the brain repurposes embryonic signaling pathways, traditionally used for growth, to manage moment-to-moment learning and behavioral balance in adulthood.
- Clinical Implications: Disruptions in this dopamine-acetylcholine coordination may be an early warning sign of Parkinson’s disease or a driving factor in the compulsive reinforcement cycles seen in addiction.
Source: CUNY
A signaling pathway best known for shaping the brain before birth also helps govern how adults learn, adapt, and persist in their behavior, according to new research co-led by Andreas H. Kottmann, associate medical professor of Neuroscience and Cognitive Neuroscience at the City University of New York Graduate Center.
The findings could open new directions for research on neurological disorders including Parkinson’s disease and addiction.
The study, recently released online ahead of print in iScience, found that Smoothened, a receptor long associated with embryonic development, also serves as a key regulator in the adult brain. By influencing the timing between dopamine and acetylcholine, two neurotransmitters central to learning, movement, and motivation, Smoothened helps determine how strongly behaviors are learned and how flexibly they can be adjusted over time.
The research focuses on the striatum, a deep brain region involved in linking actions to outcomes and evaluating the effort required to carry them out. Learning in the striatum depends on tightly coordinated signals between dopamine, which helps reinforce behavior, and acetylcholine, which helps determine when neurons are ready to change.
Acetylcholine is released by cholinergic interneurons, which briefly pause their activity at key moments during learning. Those pauses create narrow windows during which dopamine can reshape neural connections and strengthen useful behaviors. Kottmann and Santiago Uribe-Cano, then a doctoral candidate at the Graduate Center, found that Smoothened helps control how long those pauses last. When Smoothened activity is high, the pauses are shorter and more tightly regulated. When Smoothened is removed, the pauses last longer, increasing the window in which dopamine can drive learning-related changes.
“By adjusting how long acetylcholine steps aside, Smoothened effectively determines how strongly dopamine can reinforce recent actions in the adult brain,” Kottmann said.
“Our work reveals how effectively nature repurposes signaling pathways. It uses the same signals critical for embryonic development to control changes in the adult brain that underpin moment to moment learning.” Uribe-Cano is now a postdoctoral researcher in the Department of Psychiatry at Columbia University’s Vagelos College of Physicians and Surgeons.
The researchers also found that these molecular changes had clear behavioral effects. Animals lacking Smoothened in cholinergic neurons learned motor tasks more quickly and showed greater persistence in working for rewards. But that apparent advantage came with a cost: They were less sensitive to changes in effort or reward timing and slower to update their behavior when conditions changed.
“Smoothened appears to act as a tuning knob that prevents reinforcement signals from becoming too strong or too persistent,” Kottmann said. “Learning has to be finely controlled and balanced with behavioral flexibility. If this balance becomes disturbed, the consequences for brain health can be severe.”
By identifying Smoothened as a regulator of dopamine-acetylcholine timing, the study points to possible new targets for disorders marked by altered motivation, habit formation, and reinforcement.
In Parkinson’s disease, the loss of dopamine-producing neurons is a defining feature, but research has also shown that disruptions in acetylcholine signaling and learning-related flexibility can appear early in the disease. The new findings suggest that problems in the coordination of dopamine and acetylcholine may begin before widespread cell loss and movement symptoms emerge.
The findings may also have implications for addiction. Because drugs of abuse can drive powerful cycles of reinforcement, the researchers suggest that Smoothened signaling in cholinergic interneurons may help limit those effects by restoring balance between dopamine and acetylcholine. That could eventually inform efforts to develop treatments that support healthier patterns of motivation and behavior.
Funding: Funding support for this research included NIH grants and support from the American Parkinson’s Disease Association.
Key Questions Answered:
A: Think of acetylcholine as the background noise that keeps neurons stable. For dopamine to “write” a new memory or reinforce a behavior, that noise needs to stop momentarily. Smoothened acts as the gatekeeper that decides exactly how long that silence lasts.
A: Not necessarily. The study found that while lacking Smoothened made animals learn motor tasks more quickly, they became less sensitive to effort. They would keep working for a reward even if it wasn’t worth the trouble, which is a hallmark of addictive behavior or obsessive habits.
A: We usually think of Parkinson’s as a total loss of dopamine. This research suggests that before the cells die off, the timing between dopamine and acetylcholine might already be broken. Fixing the Smoothened pathway could potentially restore that balance before the major movement symptoms start.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience research news
Author: Shawn Rhea
Source: CUNY
Contact: Shawn Rhea – CUNY
Image: The image is credited to Neuroscience News
Original Research: Open access.
“The GPCR Smoothened on cholinergic interneurons modulates dopamine-associated acetylcholine dynamics, learning, and effort management” by Santiago Uribe-Cano and Andreas H. Kottmann. iScience
DOI:10.1016/j.isci.2026.115324
Abstract
The GPCR Smoothened on cholinergic interneurons modulates dopamine-associated acetylcholine dynamics, learning, and effort management
The striatum is a hub for associative learning where fluctuations in dopamine (DA) and acetylcholine (ACh) regulate behavior. ACh is released by cholinergic interneurons (CIN), which integrate diverse inputs that contextualize DA signals and shape behavior.
We previously observed that the GPCR Smoothened (Smo) on CINs suppresses L-DOPA-induced dyskinesias, a motor side effect resulting from medication elevated DA in the Parkinsonian brain.
Here, we examine whether Smo signaling modulates ACh dynamics, its coordination with DA, and motor learning in the healthy brain. We find that cholinergic neuron-specific Smo activity bidirectionally modulates ACh inhibition following dopaminergic or cholinergic neuron activity.
These effects alter the temporal organization of ACh and its coupling to DA in the dorsolateral striatum. Behaviorally, Smo ablation from cholinergic neurons promotes motor learning and alters adjustments in the effort or time to obtain reward.
These findings identify Smo as a modulator of striatal DA-ACh coordination, striatal learning, and effort-management.
