Dysregulated motivation to consume psychoactive substances leads to addictive behaviors that often result in serious health consequences. Understanding the neuronal mechanisms that drive drug consumption is crucial for developing new therapeutic strategies. The fruit fly Drosophila melanogaster offers a unique opportunity to approach this problem with a battery of sophisticated neurogenetic tools available, but how they consume these drugs remains largely unknown. Here, we examined drug self-administration behavior of Drosophila and the underlying neuronal mechanisms. We measured the preference of flies for five different psychoactive substances using a two-choice feeding assay and monitored its long-term changes. We found that flies show acute preference for ethanol and methamphetamine, but not for cocaine, caffeine or morphine. Repeated intake of ethanol, but not methamphetamine, increased over time. Preference for methamphetamine and the long-term escalation of ethanol preference required the dopamine receptor Dop1R1 in the mushroom body. The protein level of Dop1R1 increased after repeated intake of ethanol, but not methamphetamine, which correlates with the acquired preference. Genetic overexpression of Dop1R1 enhanced ethanol preference. These results reveal a striking diversity of response to individual drugs in the fly and the role of dopamine signaling and its plastic changes in controlling voluntary intake of drugs.
Multicellular organisms are composed of specialized cells with distinct proteomes. While recent advances in single-cell transcriptome analyses have revealed differential expression of mRNAs, cellular diversity in translational profiles remains to be understood. By performing RNA-seq and Ribo-seq from genetically labelled cell types in Drosophila, we profiled the transcriptome and translatome of neuronal and glial cells in the brain. This comparative profiling revealed substantial posttranscriptional regulation of protein expression. We further found that translational efficiency of proteins fundamental to neuronal functions, such as ion channels and neurotransmitter receptors, was maintained low especially in glia, leading to preferential translation in neurons. Notably, the distribution of ribosome footprints on these mRNAs exhibited a remarkable bias towards the 5′ untranslated regions (UTR) in glial cells. Using a transgenic reporter system, we provide evidence that the UTR confer translational suppression selectively in glia. Overall, these findings underscore the profound impact of translational regulation in shaping cell identity and provide new insights into the molecular mechanisms driving cell-type diversity.
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