Pheromone circuits and transcriptional cascades modulating transcriptional and chromatin states in the Drosophila central brain with social experience

Social experience significantly influences the behavioral and physiological responses of animals, including humans. In many animals, social isolation increases aggression, courtship, locomotion, and feeding while disrupting sleep. This occurs when peripheral neurons detect social signals, such as pheromones, which activate decision-making circuits in the brain. However, the molecular and circuit mechanisms of how chronic social isolation or enrichment alter gene expression and affect neuronal function and behavior remain unclear. In this study, we examined how transcription patterns and chromatin marks in male Drosophila brains change in response to social experience, and the effect of pheromone circuits and transcription factors involved in social circuit function. We focused on pheromone receptors Or47b and Or67d, as well as transcription factors Fru ^M and Dsx ^M . Our findings suggest that social experience affects multiple genes in the central brain. Disrupting Or47b, Or67d, Fru ^M , and Dsx ^M function moderated the transcriptional responses through antagonistic interactions. Specifically, Or47b circuits predominantly mediated transcriptional responses to social isolation through Dsx ^M function, while Or67d and Fru ^M regulated responses to group housing. Notably, mutants of fru ^M and dsx ^M exhibited more extensive transcriptional changes in the brain than Or mutants, especially for Fru ^M /Dsx ^M target genes. While social experience did not lead to detectable alterations in the overall chromatin profile in the whole brain, mutants of the four genes resulted in significant changes in the enrichment of H3K4me3 and RNA polymerase II (RNAPolII) compared to wild type. Furthermore, mutants in fru ^M and dsx ^M generally eliminated social experience-dependent changes in sleep and locomotion behaviors, whereas Or mutants exhibited more modest disruptions. Overall, our results uncover the pheromone circuits and transcriptional cascades in regulating molecular and behavioral responses to social experience.