The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) are powerful regulators of associative learning 1–9 . Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations 10–13 . However, these hypotheses have yet to be tested directly because it has not been possible to precisely interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a double transgenic mouse model enabling simultaneous genetic access to the brain’s DA and 5HT systems. Anterograde axon tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recordings of DA and 5HT input activity in the NAc posterior medial shell revealed that DA axons are excited by rewards while 5HT axons are inhibited. Optogenetically blunting DA and 5HT reward responses simultaneously blocked learning about a reward-predictive cue. Optogenetically reproducing both DA and 5HT responses to reward, but not either one alone, was sufficient to drive the acquisition of new associations. Altogether, these results demonstrate that striatal integration of inverse DA and 5HT signals is a crucial mechanism gating associative learning.

Striatal integration of inverse dopamine and serotonin signals gates learning