Neural mechanisms of extinction learning
Final Report Abstract
Animals need to constantly re-assess learned information. This malleability of memory offers a promising strategy to alleviate maladaptive memories in human patients. However, the neural circuit mechanisms underlying memory re-evaluation remain largely unknown. We took advantage of the tractability of the brain of Drosophila melanogaster to depict the circuit motifs underlying two memory re-evaluation processes, memory extinction and reconsolidation. Reexposing flies to a learned cue but without the expected consequences reduces the conditioned response, a phenomenon known as memory extinction. Using thermogenetic and optogenetic approaches, we demonstrated that the reduction of the learned response arises from the acquisition of a new but opposing memory driven by the antagonistic dopaminergic system: learning about the omission of anticipated reward depends on punishment coding dopamine neurons, whereas the absence of expected punishment is coded by the dopaminergic reward system. This antagonism in the dopamine system required during initial learning and extinction learning seems to be a general principle since it has been recently shown that in mice and rats extinction of aversive memory is mediated by reward associated dopamine neurons from the ventral tegmental area. In our work, functional multi-photon calcium imaging allowed us to demonstrate that the aversive memory trace survives memory extinction and that an additional reward-like memory trace is formed at a different location. Electron- and light microscopy in combination with live imaging revealed the logic and the ultrastructure of how these two parallel, but opposing memories are integrated to steer learned behavior. Further, we showed that presenting an indirect reminder, the unpaired odor, triggers a cycle of destabilization and restabilization, a process known as reconsolidation. Reconsolidation is discussed to be an update mechanism to adjust existing memories and is currently the most promising strategy to render traumatic memories. We showed that in the fly, once the memory is in a vulnerable state, it requires the sequential activity of two distinct sets of dopamine neurons to be reconsolidated to persist over time. The involvement of the two different sets of dopamine neurons, one required during memory stabilization after initial learning and the other exclusively during memory reconsolidation, suggesting that re-stabilization partially resembles the original memory formation but also contains reconsolidation specific processes. In summary, our work shows that the omission of expected reward or punishment is coded by the opposing valence coding system. Further, the data provides a mechanistic understanding of how memory extinction leads to parallel memories and how these memories are integrated to drive behavior. In addition, we provide the first insights into the neural circuitry involved in memory reconsolidation in flies.
Publications
- Activity of defined mushroom body output neurons underlies learned olfactory behavior in Drosophila. Neuron. 2015 Apr 22;86(2):417-27
Owald D, Felsenberg J, Talbot CB, Das G, Perisse E, Huetteroth W, Waddell S
(See online at https://doi.org/10.1016/j.neuron.2015.03.025) - Memory-Relevant Mushroom Body Output Synapses Are Cholinergic. Neuron. 2016 Mar 16;89(6):1237-1247
Barnstedt O, Owald D, Felsenberg J, Brain R, Moszynski JP, Talbot CB, Perrat PN, Waddell S.
(See online at https://doi.org/10.1016/j.neuron.2016.02.015) - 4.26 - Neural Networks for a Reward System in Drosophila, Editor(s): John H. Byrne, Learning and Memory: A Comprehensive Reference (Second Edition), Academic Press, 2017, Pages 505-522
Felsenberg J, Waddell S
(See online at https://doi.org/10.1016/B978-0-12-809324-5.21127-9) - Re-evaluation of learned information in Drosophila. Nature. 2017 Apr 13;544(7649):240-244
Felsenberg J, Barnstedt O, Cognigni P, Lin S, Waddell S
(See online at https://doi.org/10.1038/nature21716) - Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila. Curr Opin Neurobiol. 2018 Apr; 49:51-58
Cognigni P, Felsenberg J, Waddell S
(See online at https://doi.org/10.1016/j.conb.2017.12.002) - Integration of Parallel Opposing Memories Underlies Memory Extinction. Cell. 2018 Oct 18;175(3):709-722.e15
Felsenberg J, Jacob PF, Walker T, Barnstedt O, Edmondson-Stait AJ, Pleijzier MW, Otto N, Schlegel P, Sharifi N, Perisse E, Smith CS, Lauritzen JS, Costa M, Jefferis GSXE, Bock DD, Waddell S
(See online at https://doi.org/10.1016/j.cell.2018.08.021)
