BALANCING GOOD AND BAD: SEROTONIN SIGNALS BIAS MEMORY CONSOLIDATION TOWARDS POSITIVE OR NEGATIVE EXPERIENCES

The ability to remember positive and negative experiences and adapt behavior accordingly allows every living being to survive and thrive in challenging environments. In many species, dopamine transmits the valence of an experience, yet little is known about how gating mechanisms act to ensure that only relevant information is stored as a long-term memory (LTM). How internal states and previous experiences acutely or chronically tune these gating mechanisms to skew memory storage and behavior is even less understood. We recently identified a molecular and cellular correlate of an aversive memory gate in the fly brain, mediated by serotonergic suppression of dopaminergic signals. Here, combining a behavioral paradigm to generate appetitive or aversive olfactory LTM with high-resolution functional imaging data, we investigated how context-dependent plasticity in this circuitry affects the consolidation of positive and negative memories. Intriguingly, we found that blocking serotonin activity during consolidation suppresses aversive LTM and, at the same time, facilitates appetitive LTM. This antagonistic effect of serotonin signals is driven via conserved inhibitory serotonin receptors (5-HT-1ARs) in memory-gating dopaminergic neurons. Moreover, we identified starvation-induced post-synaptic adaptations involving changes in inhibitory 5-HT-1ARs receptors in these neurons. These state-dependent changes have the potential to reconfigure memory gating dynamics, biasing the consolidation of appetitive and aversive experiences based on internal state. Altogether, our findings shed light on how context-dependent plasticity, shaped by serotonergic modulation of dopaminergic circuits, could steer experience-dependent decision-making in both healthy and pathological brains.