Summary: Researchers have discovered that Smoothened, a signaling receptor best known for guiding brain development before birth, also plays a crucial role in adult learning and behavioral flexibility. In the adult striatum, Smoothened acts like a tuning knob that adjusts the timing between dopamine and acetylcholine signals, shaping how strongly behaviors are reinforced and how readily they can be changed.
The study shows Smoothened controls the precise duration of acetylcholine pauses that create brief windows when dopamine can modify synaptic connections. That timing determines whether a behavior becomes persistent or remains flexible, with implications for conditions such as addiction and Parkinson’s disease.
Key Facts
- The Timing Regulator: Smoothened controls how long cholinergic interneurons pause acetylcholine release, defining narrow periods when dopamine can drive synaptic change and behavioral reinforcement.
- Flexibility vs. Persistence: Removing Smoothened lengthens those pause windows. Animals learn certain motor tasks faster and persist longer in seeking rewards, but they lose flexibility and struggle to adapt when reward conditions change.
- Repurposed Biology: The findings show that signaling pathways once thought exclusive to embryonic brain development are reused in adulthood to control rapid learning and behavioral balance.
- Clinical Implications: Disrupted coordination between dopamine and acetylcholine may be an early indicator of Parkinson’s disease and could also contribute to compulsive reinforcement cycles 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.
These results point to new avenues for studying neurological disorders, including Parkinson’s disease and addiction, by highlighting molecular mechanisms that coordinate motivation, habit formation, and effort-based decisions.
Published online ahead of print in iScience, the study identifies Smoothened (Smo), a G-protein coupled receptor (GPCR) associated with embryonic development, as a key regulator in the adult striatum. By modulating the timing between dopamine (DA) and acetylcholine (ACh) signals, Smoothened helps determine both how strongly behaviors are reinforced and how flexibly animals update actions as conditions change.
The focus of the research is the dorsolateral striatum, a deep brain region that links actions to outcomes and evaluates the effort required to obtain rewards. Learning in this region depends on tightly coordinated interactions between DA, which reinforces behavior, and ACh, which gates when neurons are permissive to change.
Acetylcholine is released by cholinergic interneurons (CINs) that briefly pause their firing at critical moments during learning. Those pauses create narrow windows where dopamine can alter synapses and strengthen useful behaviors. Kottmann and Santiago Uribe-Cano, then a doctoral candidate at the Graduate Center, found that Smoothened controls the duration of those pauses: higher Smoothened activity shortens pauses and tightens timing, while removing Smoothened prolongs pauses and expands the window for dopamine-driven plasticity.
“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 shows how biological systems reuse developmental signaling to manage fast, experience-dependent changes in adult neural circuits,” added Uribe-Cano, who is now a postdoctoral researcher in the Department of Psychiatry at Columbia University’s Vagelos College of Physicians and Surgeons.
Behavioral experiments mirrored the molecular findings. Animals lacking Smoothened in cholinergic neurons learned motor tasks more rapidly and showed greater persistence when working for rewards, yet they were less responsive to changes in effort or reward timing and slower to shift strategies when outcomes changed. In other words, increased learning speed came at the cost of reduced behavioral flexibility.
“Smoothened appears to act as a tuning knob that prevents reinforcement signals from becoming excessively strong or persistent,” Kottmann said. “Effective learning requires a balance between forming stable habits and retaining the flexibility to adapt. When that balance is altered, the consequences for brain health can be significant.”
Identifying Smoothened as a regulator of DA–ACh timing suggests potential new therapeutic targets for disorders involving motivation, habit formation, and maladaptive reinforcement. In Parkinson’s disease, for example, dopamine neuron loss is a central feature, but altered acetylcholine signaling and disrupted learning-related flexibility may occur early. The study raises the possibility that coordination problems between DA and ACh could arise before widespread cell loss and motor symptoms, and that modulating Smoothened signaling might help restore balance.
Similarly, in addiction, drugs of abuse can produce excessive reinforcement cycles. The researchers propose that Smoothened signaling in cholinergic interneurons may serve to curb those cycles by rebalancing DA and ACh interactions, offering a conceptual path toward interventions that promote healthier motivation and decision-making.
Funding: This research was supported by NIH grants and funding from the American Parkinson’s Disease Association.
Key Questions Answered:
A: Acetylcholine acts like background stabilizing activity. For dopamine to mark an event for learning—essentially “writing” a change—the acetylcholine signal must pause briefly. Smoothened helps set the exact length of that pause so dopamine can effectively reshape synapses.
A: Not always. Faster acquisition can lead to stronger persistence even when circumstances change. In the study, animals without Smoothened learned some tasks more quickly but continued pursuing rewards despite increased effort or diminished payoff—a pattern linked to compulsive behavior.
A: Parkinson’s is commonly viewed through the lens of dopamine neuron loss, but these findings suggest the temporal coordination between dopamine and acetylcholine can break down earlier. Targeting pathways like Smoothened might help restore DA–ACh balance before the full spectrum of movement symptoms appears.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff to clarify implications for Parkinson’s disease and addiction.
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 central hub for associative learning where coordinated fluctuations in dopamine (DA) and acetylcholine (ACh) shape behavior. ACh is released by cholinergic interneurons (CINs), which integrate diverse contextual inputs that regulate how DA signals influence learning and action selection.
Earlier work showed that Smoothened (Smo) on CINs can suppress L-DOPA-induced dyskinesias. This study examined whether Smo signaling also modulates ACh dynamics, its temporal coupling with DA, and motor learning in the healthy brain.
The researchers found that CIN-specific Smo activity bidirectionally regulates ACh inhibition following dopaminergic or cholinergic neuron activation. These effects change the timing of ACh and its coupling to DA in the dorsolateral striatum. Behaviorally, removing Smo from cholinergic neurons enhanced motor learning and altered how animals adjust effort or timing to obtain reward.
Together, these findings identify Smoothened as a modulator of striatal DA–ACh coordination, striatal learning mechanisms, and effort management.