People and animals generally prefer to avoid effort, when given a choice¹. Yet they often place greater value on rewards that require more effort to obtain^2,3. Although this effect is widespread across species, its neural basis has not been well understood. A new study led by 2020 SFARI Fellows-to-Faculty awardee Neir Eshel of Stanford University now reveals how acetylcholine signaling in the brain’s reward center amplifies dopamine release when rewards are hard won.

Touponse and colleagues focused on the nucleus accumbens (NAc), where the neurotransmitter dopamine reinforces reward-seeking behavior^4,5. Previous work had shown that dopamine signals increase not only with reward size, but also with the effort required to obtain the reward⁶. What drives this relationship, however, was unclear. To find out, the researchers designed a behavioral task in which mice had to perform increasing numbers of nose pokes to receive the same sucrose reward. At the same time, genetically encoded sensors in the NAc produced fluorescent signals when dopamine or acetylcholine was released, allowing the researchers to track these neurotransmitters in real time.

When rewards followed greater effort, a specialized class of neurons within the NAc released increasing amounts of acetylcholine. This release arrived just ahead of the dopamine surge at reward delivery, suggesting that acetylcholine primed the system for an amplified response. Acting through nicotinic receptors on nearby dopamine neurons, acetylcholine boosted dopamine release selectively in high-effort trials, while dopamine responses to low-effort rewards remained unchanged.

To pinpoint where this amplification originates, the team used optogenetics, a technique in which pulses of light are used to activate or silence specific neurons with millisecond precision. Dopamine neurons in the midbrain send long projections to the NAc, and one possibility was that effort drives stronger firing of the projection neurons. By directly stimulating dopamine neurons in the NAc, or silencing those in the midbrain, the researchers showed that this is true and that the enhancement originates locally, identifying a new point of control over dopamine signaling in the brain’s reward circuitry.

Disrupting cholinergic signaling in the NAc also made animals less willing to work as tasks grew more demanding. Their willingness to collect easily obtained sucrose rewards, however, was unchanged. These findings suggest that acetylcholine and dopamine work together specifically to support motivation when the cost of reward is high.

The work also helps to resolve a long-standing inconsistency in the field. Laboratory studies using brain tissue had shown that acetylcholine can drive dopamine release through nicotinic receptors^7,8. Yet studies in living animals failed to find the same effect, leaving it unclear whether this interaction had any behavioral relevance^9,10. These conflicting findings appear to come down to reward context: only by varying effort requirements were the researchers able to unmask it.

These results may have broader implications. The nicotinic receptors central to this mechanism are the same ones through which nicotine in cigarettes exerts its reinforcing effects¹¹. The authors suggest that understanding how this acetylcholine–dopamine pathway shapes reward seeking may offer new insights into addictive behavior. Such a mechanism may also have evolutionary value, helping animals persist in seeking rewards when resources are scarce and costs are high.

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