A silent eligibility trace enables dopamine‐dependent synaptic plasticity for reinforcement learning in the mouse striatum

Abstract Dopamine‐dependent synaptic plasticity is a candidate mechanism for reinforcement learning. A silent eligibility trace – initiated by synaptic activity and transformed into synaptic strengthening by later action of dopamine – has been hypothesized to explain the retroactive effect of dopamine in reinforcing past behaviour. We tested this hypothesis by measuring time‐dependent modulation of synaptic plasticity by dopamine in adult mouse striatum, using whole‐cell recordings. Presynaptic activity followed by postsynaptic action potentials (pre–post) caused spike‐timing‐dependent long‐term depression in D1‐expressing neurons, but not in D2 neurons, and not if postsynaptic activity followed presynaptic activity. Subsequent experiments focused on D1 neurons. Applying a dopamine D1 receptor agonist during induction of pre–post plasticity caused long‐term potentiation. This long‐term potentiation was hidden by long‐term depression occurring concurrently and was unmasked when long‐term depression blocked an L‐type calcium channel antagonist. Long‐term potentiation was blocked by a Ca 2+ ‐permeable AMPA receptor antagonist but not by an NMDA antagonist or an L‐type calcium channel antagonist. Pre–post stimulation caused transient elevation of rectification – a marker for expression of Ca 2+ ‐permeable AMPA receptors – for 2–4‐s after stimulation. To test for an eligibility trace, dopamine was uncaged at specific time points before and after pre‐ and postsynaptic conjunction of activity. Dopamine caused potentiation selectively at synapses that were active 2‐s before dopamine release, but not at earlier or later times. Our results provide direct evidence for a silent eligibility trace in the synapses of striatal neurons. This dopamine‐timing‐dependent plasticity may play a central role in reinforcement learning.