Summary: A signaling receptor once thought to be active mainly during brain development is now shown to play a crucial role in adult learning and behavioral flexibility. New research demonstrates that the receptor Smoothened acts like a “tuning knob” in the adult striatum, coordinating the timing between dopamine and acetylcholine to shape how behaviors are learned and adapted.
The study reveals that Smoothened regulates the precise duration of acetylcholine pauses that permit dopamine to modify neural circuits. This timing determines how strongly a behavior is reinforced and how readily animals switch strategies when conditions change, offering fresh insight into mechanisms relevant to addiction and Parkinson’s disease.
Key Facts
- The Timing Regulator: Smoothened controls how long cholinergic interneurons pause their acetylcholine release. These pauses create the narrow windows when dopamine can induce plasticity.
- Flexibility vs. Persistence: Removing Smoothened prolongs those windows, so animals form habits faster and persist longer, but become less flexible when reward or effort contingencies change.
- Repurposed Pathways: The findings show the adult brain reuses embryonic signaling pathways—here, Smoothened—to manage fast, moment-to-moment learning and behavioral balance.
- Clinical Implications: Disrupted coordination between dopamine and acetylcholine could be an early sign of Parkinson’s disease or contribute to the excessive reinforcement cycles characteristic of addiction.
Source: CUNY
A signaling pathway well known for shaping the developing brain also helps govern how adults learn, adapt, and persist, according to research co-led by Andreas H. Kottmann, Associate Medical Professor of Neuroscience and Cognitive Neuroscience at the City University of New York Graduate Center.
Published online ahead of print in iScience, the study identifies Smoothened—a G-protein-coupled receptor traditionally linked to embryonic development—as a critical regulator of neurotransmitter timing in the adult striatum. By tuning the temporal relationship between dopamine and acetylcholine, Smoothened influences learning strength, habit formation, and the ability to change behavior when outcomes shift.
The striatum is a central hub for linking actions to outcomes and estimating the effort required to perform them. Successful learning in this region depends on tight coordination between dopamine, which reinforces actions, and acetylcholine, which controls neuronal readiness for change. Acetylcholine is released by a small population of cholinergic interneurons (CINs) that briefly pause their firing at key learning moments; those pauses create brief windows when dopamine can reshape synaptic connections.
Kottmann and co-author Santiago Uribe-Cano, formerly a doctoral candidate at the Graduate Center, found that Smoothened regulates how long these acetylcholine pauses last. High Smoothened activity shortens and sharpens the pause, narrowing the timeframe for dopamine-driven plasticity. When Smoothened is removed specifically from cholinergic neurons, the pauses lengthen and broaden the opportunity for dopamine to reinforce behavior.
“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 nature repurposes signaling pathways critical for embryonic development to manage dynamic learning processes in adulthood.” Uribe-Cano is currently a postdoctoral researcher in the Department of Psychiatry at Columbia University’s Vagelos College of Physicians and Surgeons.
At the behavioral level, animals lacking Smoothened in cholinergic neurons acquired motor tasks more quickly and worked more persistently for rewards. But this stronger reinforcement came at the expense of adaptability: those animals were less responsive to changes in effort or reward timing and slower to revise their behavior when conditions changed. That balance—between rapid reinforcement and behavioral flexibility—appears to depend on Smoothened’s control of neurotransmitter timing.
The discovery positions Smoothened as a potential target for disorders where motivation, habit formation, and reinforcement go awry. In Parkinson’s disease, dopamine neuron loss is a hallmark, but altered acetylcholine signaling and impaired learning flexibility can precede overt motor symptoms. Disruption in the dopamine–acetylcholine timing regulated by Smoothened may therefore emerge early in disease progression. Similarly, in addiction, powerful cycles of reinforcement driven by dopamine might be tempered by Smoothened signaling in cholinergic interneurons, suggesting new avenues to restore balance in motivation and habit circuits.
Funding: This research was supported by NIH grants and the American Parkinson’s Disease Association.
Key Questions Answered:
A: Acetylcholine provides a background signal that keeps circuits stable. For dopamine to encode a new memory or reinforce a behavior, that background activity must stop briefly. Smoothened acts like a gatekeeper, setting how long that silence lasts and therefore how much opportunity dopamine has to drive change.
A: Not always. Faster learning can lead to stronger, more persistent habits that are harder to break. The study shows animals without Smoothened learned tasks quickly but were less sensitive to cost or timing changes, a pattern reminiscent of compulsive or addictive behavior.
A: Parkinson’s is often framed as progressive dopamine loss, but this work suggests the temporal coordination between dopamine and acetylcholine may degrade earlier. Restoring Smoothened signaling could help rebalance those interactions before major cell loss and overt motor symptoms appear.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was provided by editorial staff.
About this neuroscience research news
Author: Shawn Rhea
Source: CUNY
Contact: Shawn Rhea – CUNY
Image: Image 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 central site for associative learning where dynamic interactions between dopamine (DA) and acetylcholine (ACh) shape behavior. ACh is produced by cholinergic interneurons (CINs), which integrate diverse inputs that give context to DA signals and influence behavioral outcomes.
Prior work showed that Smoothened (Smo) on CINs can suppress L-DOPA-induced dyskinesias, a motor complication tied to elevated DA in Parkinsonian brains. This study examines whether Smo signaling also regulates ACh dynamics, its coordination with DA, and motor learning in a healthy brain.
The authors report that CIN-specific Smo activity bidirectionally modifies ACh inhibition following dopaminergic or cholinergic activity. These changes affect the temporal organization of ACh and its coupling to DA in the dorsolateral striatum. Behaviorally, removing Smo from cholinergic neurons enhances motor learning and alters how animals adjust effort or timing to obtain rewards.
Overall, these results identify Smo as a modulator of striatal DA–ACh coordination, striatal learning, and effort management.