Dopamine facilitates associative memory encoding in the entorhinal cortex

Mounting evidence shows that dopamine in the striatum is critically involved in reward-based reinforcement learning 1 , 2 . However, it remains unclear how dopamine reward signals influence the entorhinal–hippocampal circuit, another brain network that is crucial for learning and memory 3 – 5 . Here, using cell-type-specific electrophysiological recording 6 , we show that dopamine signals from the ventral tegmental area and substantia nigra control the encoding of cue–reward association rules in layer 2a fan cells of the lateral entorhinal cortex (LEC). When mice learned novel olfactory cue–reward associations using a pre-learned association rule, spike representations of LEC fan cells grouped newly learned rewarded cues with a pre-learned rewarded cue, but separated them from a pre-learned unrewarded cue. Optogenetic inhibition of fan cells impaired the learning of new associations while sparing the retrieval of pre-learned memory. Using fibre photometry, we found that dopamine sends novelty-induced reward expectation signals to the LEC. Inhibition of LEC dopamine signals disrupted the associative encoding of fan cells and impaired learning performance. These results suggest that LEC fan cells represent a cognitive map of abstract task rules, and that LEC dopamine facilitates the incorporation of new memories into this map. Cell-type-specific electrophysiological recording, fibre photometry and optogenetic manipulations in mice show that dopamine signals from the ventral tegmental area to the lateral entorhinal cortex have a key role in cue–reward associative learning.