Linking Cholinergic Interneurons, Synaptic Plasticity, and Behavior during the Extinction of a Cocaine-Context Association

Highlights

• Cholinergic interneurons in the nucleus accumbens regulate cocaine-context extinction

• They modulate presynaptic glutamatergic plasticity onto medium spiny neurons

• These behavioral and synaptic effects occur during cocaine, but not food, extinction

• Cholinergic interneurons do not drive reinforcement or plasticity on their own

Summary

Despite the fact that cholinergic interneurons are a key cell type within the nucleus accumbens, a relationship between synaptic plasticity and the in vivo activity of cholinergic interneurons remains to be established. Here, we identify a three-way link between the activity of cholinergic interneurons, synaptic plasticity, and learning in mice undergoing the extinction of a cocaine-context association. We found that activity of cholinergic interneurons regulates extinction learning for a cocaine-context association and generates a sustained reduction in glutamatergic presynaptic strength onto medium spiny neurons. Interestingly, activation of cholinergic interneurons does not support reinforcement learning or plasticity by itself, suggesting that these neurons have a modulatory rather than a reinforcing function.