A genome-wide approach to the molecular bases of punishment vs. relief learning in the fruit fly
Final Report Abstract
A painful experience leaves two opposing kinds of memory: Those events that preceded pain are later on remembered as bad; whereas those that happened once the pain subsided are subsequently regarded as good. In order to study the orchestration of these opposing memories at the level of genetic effectors and molecular mechanisms, we used the fruit fly, Drosophila melanogaster with a fairly well-characterized, relatively non-redundant genome and a rich genetic/ transgenic toolbox. Flies innately avoid electric shock. In addition, odours that precede shock are learned as predictors for punishment, to be avoided in the future; whereas odours that follow shock are later on approached as predictors for relief. Such punishment versus relief memories are evolutionarily conserved up to human, where their loss or exaggeration may well be important for psychiatric conditions related to pain and trauma. In order to study the genetic effectors of these three behaviours in the fly, we exploited the interindividual variability. At first sight, flies may seem indistinguishable from each other; they are however “individual” from the level of their genome up to the level of their behaviour. Within the framework of the Drosophila Genetic Reference Panel, female flies collected from nature were used to generate ~ 40 strains by extensive inbreeding of their progeny. These inbred strains were then characterized in terms of their transcriptomes and genomes. Within each inbred strain, flies are genetically identical to each other, as monozygotic twins are; whereas across strains, substantial genetic variability exists. We in turn uncovered strong variation in innate shock avoidance, punishment learning and relief learning across these inbred strains. We then identified for each kind of behaviour candidate genes whose sequences and/ or expression levels co-varied with the behavioural scores. The success of our approach was evident in the follow-up with respect to innate shock avoidance: the very first candidate genes were confirmed using specific mutants; while a bioinformatic gene-network analysis suggested a role for mechanosensory body-surface organs in shock sensation, an attractive novel hypothesis to be tested in the future. Given this successful follow up with respect to innate shock avoidance, the candidate gene pools for punishment and relief learning will now be the raw material for a long-term research program for comprehensively studying molecular mechanisms that differentiate between these opposite kinds of learning. Given the evolutionary conservation of gene-roles in learning, it seems reasonable to hope for translational potential of this endeavor.
Publications
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(2013) Memory decay and susceptibility to amnesia dissociate punishment- from relief-learning. Biol Lett 9: 20121171
Diegelmann S, Preuschoff S, Appel M, Niewalda T, Gerber B, Yarali A
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(2013) “Genome-wide analysis of innate electric shock- and odour-avoidance, punishment- and relief-learning”. Dissertation. Ludwig-Maximilians-Universität München
Appel M.
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(2014) Pain-relief learning in flies, rats, and man: basic research and applied perspectives. Learn Mem 21: 232-252
Gerber B, Yarali A, Diegelmann S, Wotjak CT, Pauli P, Fendt M
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(2015) Genome-wide association analyses point to candidate genes for electric shock avoidance in Drosophila melanogaster. Plos ONE 10: e0126986
Appel M, Scholz C-J, Müller T, Dittrich M, König C, Bockstaller M, Oguz T, Khalili A, Antwi-Adjei E, Schauer T, Margulies C, Tanimoto H, Yarali A
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(2015) Reversing Stimulus Timing in Visual Conditioning Leads to Memories with Opposite Valence in Drosophila. Plos ONE 10: e0139797
Vogt K, Yarali A, Tanimoto H
