Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ∼2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several associative learning tasks and in sleep regulation, revealing the extent to which information flow is segregated into distinct channels and suggesting possible roles for the multi-layered MBON network. We also show that optogenetic activation of MBONs can, depending on cell type, induce repulsion or attraction in flies. The behavioral effects of MBON perturbation are combinatorial, suggesting that the MBON ensemble collectively represents valence. We propose that local, stimulus-specific dopaminergic modulation selectively alters the balance within the MBON network for those stimuli. Our results suggest that valence encoded by the MBON ensemble biases memory-based action selection.

This study presents a new assay for investigating alcohol reward in Drosophila. Flies learned to associate cues with ethanol intoxication and developed a long-lasting attraction for the ethanol-paired cue. Dopamine neurons were necessary for expression of this conditioned preference. Mutations in a regulator of Notch signaling disrupted the formation of this memory. The rewarding properties of drugs contribute to the development of abuse and addiction. We developed a new assay for investigating the motivational properties of ethanol in the genetically tractable model Drosophila melanogaster. Flies learned to associate cues with ethanol intoxication and, although transiently aversive, the experience led to a long-lasting attraction for the ethanol-paired cue, implying that intoxication is rewarding. Temporally blocking transmission in dopaminergic neurons revealed that flies require activation of these neurons to express, but not develop, conditioned preference for ethanol-associated cues. Moreover, flies acquired, consolidated and retrieved these rewarding memories using distinct sets of neurons in the mushroom body. Finally, mutations in scabrous, encoding a fibrinogen-related peptide that regulates Notch signaling, disrupted the formation of memories for ethanol reward. Our results thus establish that Drosophila can be useful for understanding the molecular, genetic and neural mechanisms underling the rewarding properties of ethanol.

Toward Addiction: Addiction can result when substances, such as drugs or alcohol, co-opt the brain's natural reward system. Shohat-Ophir et al. (p. 1351 ; see the Perspective by Zars ) explored this potential in Drosophila by examining the relationship between the natural reward stimulated by mating and the unnatural reward offered by ethanol consumption. Males deprived of mating increased consumption of ethanol, and, when permitted to mate following deprivation, their ethanol consumption decreased. At a mechanistic level, mating increased the neurotransmitter neuropeptide F (NPF), while mate deprivation decreased NPF levels.

Animal studies have been instrumental in providing knowledge about the molecular and neural mechanisms underlying drug addiction. Recently, the fruit fly Drosophila melanogaster has become a valuable system to model not only the acute stimulating and sedating effects of drugs but also their more complex rewarding properties. In this review, we describe the advantages of using the fly to study drug-related behavior, provide a brief overview of the behavioral assays used, and review the molecular mechanisms and neural circuits underlying drug-induced behavior in flies. Many of these mechanisms have been validated in mammals, suggesting that the fly is a useful model to understand the mechanisms underlying addiction.

The neural circuits that mediate behavioral choice evaluate and integrate information from the environment with internal demands and then initiate a behavioral response. Even circuits that support simple decisions remain poorly understood. In Drosophila melanogaster, oviposition on a substrate containing ethanol enhances fitness; however, little is known about the neural mechanisms mediating this important choice behavior. Here, we characterize the neural modulation of this simple choice and show that distinct subsets of dopaminergic neurons compete to either enhance or inhibit egg-laying preference for ethanol-containing food. Moreover, activity in α′β′ neurons of the mushroom body and a subset of ellipsoid body ring neurons (R2) is required for this choice. We propose a model where competing dopaminergic systems modulate oviposition preference to adjust to changes in natural oviposition substrates. Significance Flies use fermenting fruit as a food source and a site for oviposition. One of the main metabolites of fermentation is ethanol. When provided with different choices in the laboratory, female flies prefer to lay their eggs on food supplemented with ecologically relevant concentrations of ethanol. We show that different subsets of dopaminergic neurons have opposing effects on oviposition preference. We propose that in the wild, this may be a mechanism by which flies choose oviposition sites that are optimal for offspring fitness and survival and that this choice is highly dependent on context.