Dopaminergic mechanism underlying reward-encoding of punishment omission during reversal learning in Drosophila

Nat Commun. 2021 Feb 18;12(1):1115. doi: 10.1038/s41467-021-21388-w.


Animals form and update learned associations between otherwise neutral sensory cues and aversive outcomes (i.e., punishment) to predict and avoid danger in changing environments. When a cue later occurs without punishment, this unexpected omission of aversive outcome is encoded as reward via activation of reward-encoding dopaminergic neurons. How such activation occurs remains unknown. Using real-time in vivo functional imaging, optogenetics, behavioral analysis and synaptic reconstruction from electron microscopy data, we identify the neural circuit mechanism through which Drosophila reward-encoding dopaminergic neurons are activated when an olfactory cue is unexpectedly no longer paired with electric shock punishment. Reduced activation of punishment-encoding dopaminergic neurons relieves depression of olfactory synaptic inputs to cholinergic neurons. Synaptic excitation by these cholinergic neurons of reward-encoding dopaminergic neurons increases their odor response, thus decreasing aversiveness of the odor. These studies reveal how an excitatory cholinergic relay from punishment- to reward-encoding dopaminergic neurons encodes the absence of punishment as reward, revealing a general circuit motif for updating aversive memories that could be present in mammals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Avoidance Learning / physiology
  • Conditioning, Classical
  • Dopamine / metabolism*
  • Dopaminergic Neurons / physiology
  • Drosophila melanogaster / physiology*
  • Memory / physiology
  • Punishment*
  • Reversal Learning
  • Reward*
  • Smell / physiology
  • Synapses / physiology


  • Dopamine