Nicotinic control of dopamine release shapes striatal output and engages adaptive action selection.

Abstract

Acetylcholine and dopamine significantly modulate striatal circuits and are essential for reward learning and action selection. Cholinergic interneurons can locally trigger dopamine release through beta2-containing nicotinic acetylcholine receptors expressed on dopamine axons1-3. However, the causal contribution of this local cholinergic control of dopamine to behaviour and striatal output remains unresolved, with recent studies reaching contrasting conclusions about the extent and behavioural relevance of local acetylcholine-dopamine coupling4-6. Here, to directly test the causal contribution of this pathway, we conditionally deleted beta2-containing nicotinic acetylcholine receptors from midbrain neurons in adult mice. This manipulation selectively abolished cholinergic interneuron-evoked dopamine release in the striatum. In a reward-based instrumental task, mice lacking this pathway showed decrements in effort that depended on the reinforcement context, and failed to adjust actions in a choice task when effort and reward costs varied. Substantia nigra beta2-containing nicotinic acetylcholine receptor deletion also markedly weakened cholinergic interneuron-mediated disynaptic inhibition of striatal projection neurons, showing that disruption of beta2-dependent cholinergic control of dopamine alters how cholinergic activity is transmitted to striatal output. Together, these findings establish the importance of local acetylcholine-dopamine coupling for regulating striatal output and influencing whether actions are sustained and adjusted as effort, reward, and outcomes change.