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

Abstract 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 brain circuits involved in decision-making. 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 receptors and transcription factors involved in social experience-dependent changes in behaviors. We focused on pheromone receptors Or47b and Or67d, as well as transcription factors FruM and DsxM. Our findings suggest that social experience affects multiple genes in the central brain. Disrupting Or47b, Or67d, FruM, and DsxM function moderated the transcriptional responses through antagonistic interactions. Specifically, Or47b showed a primary association with transcriptional responses to social isolation in conjunction with DsxM function, while Or67d and FruM were linked to the regulation of responses to group housing. Notably, fruM and dsxM mutants exhibited more extensive transcriptional changes in the brain than Or mutants, particularly in FruM/DsxM target genes. While social experience did not lead to detectable alterations in the overall chromatin profile across the whole brain, mutants of the four genes showed significant changes in the enrichment of H3K4me3 and RNA polymerase II (RNAPolII) compared to wild type. Furthermore, mutants in fruM and dsxM 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.