Compromising tyrosine hydroxylase function extends and blunts the temporal profile of reinforcement by dopamine neurons in Drosophila

Abstract

For a proper representation of the causal structure of the world, it is adaptive to consider both evidence for and evidence against causality. To take punishment as an example, the causality of a stimulus is unlikely if there is a temporal gap before punishment is received, but causality is credible if the stimulus immediately precedes punishment. In contrast, causality can be ruled out if the punishment occurred first. At the behavioral level, this is reflected in the associative principle of timing-dependent valence reversal: aversive memories are formed when a stimulus occurs before the punishment, whereas memories of appetitive valence are formed when a stimulus is presented upon the relieving termination of punishment. We map the temporal profile of memories induced by optogenetic activation of the PPL1-01 neuron in the fly Drosophila melanogaster (of either sex), and find that compromising tyrosine hydroxylase function, either acutely by pharmacological methods or by cell-specific RNAi, extends and blunts this profile. Specifically, it i) enhances learning with a time gap between the stimulus and PPL1-01 punishment (better trace conditioning), ii) impairs learning when the stimulus immediately precedes PPL1-01 punishment (worse delay conditioning), and iii) prevents learning about a stimulus presented after PPL1-01 punishment has ceased (worse relief conditioning). Under conditions of low dopamine, we furthermore observe a role for serotonin that is pronounced in trace conditioning, weaker in delay conditioning, and absent in relief conditioning. We discuss the psychiatric implications if related alterations in the temporal profile of reinforcement were to occur in humans.Significance statement Acting in conformity with the causal structure of the world is important for survival in animals and humans alike. To do so, it is crucial to consider both evidence for and evidence against causality. For example, the causality of a stimulus is a reasonable assumption if it precedes punishment, whereas causality can be ruled out if the punishment occurred first. This is reflected in the opposite memories that are established through the 'bad' occurrence versus the 'good' termination of punishment. We find in the fruit fly Drosophila melanogaster that compromising dopamine synthesis establishes a distortion of these processes and discuss the psychiatric implications if such distortions were to occur in humans.