Striatal acetylcholine enables behavioral flexibility

Acetylcholine is one of the major neurotransmitters in the brain. The highest density of cholinergic markers is found in the striatum, a basal ganglia region that has been associated with behavioral flexibility. In our recent study, we showed a causal role of the cholinergic interneurons of the striatum in set-shifting in the rat. The set-shifting task required an attentional shift from one stimulus dimension to another, in order to respond appropriately after a change of governing rules. In the experiment the cholinergic interneurons were ablated by a specific immunotoxin injected into either the dorsomedial or ventral striatum, and the effects of the lesions on set-shift performance were measured. Neither lesion had an effect on initial discrimination in which rats had to learn a strategy based on lever location. However, when rats encountered a rule change after the set-shift, lesioned animals were more likely to persist in using an old strategy, and less likely to explore new strategies. Dorsomedial cholinergic ablation impaired a shift of set that required attention to the previously irrelevant stimulus. On the other hand, ventral cholinergic lesions had an effect on shifting a strategy when a novel stimulus was introduced as a new important cue. These observations suggested a specific role of striatal acetylcholine in set-shifting: suppression of a previously correct but now invalid strategy and exploration for a new rule. Both dorsomedial and ventral striatal cholinergic systems appear to play this role, but in different contexts.