Social experience alters behaviors by reprogramming the Fruitless pathway and circadian state in Drosophila

From flies to humans, social experience affects various cognitive and behavioral processes. Previous studies have shown that group housing suppresses many behaviors like courtship, aggression, and feeding in Drosophila melanogaster, in addition to resetting the circadian state. Here, we focus on group housing-induced courtship suppression. To determine the mechanisms by which social experience modulates courtship behaviors, we performed bulk tissue RNAseq and single-cell RNAseq from cells expressing FruitlessM (FruM) and DoublesexM (DsxM), two transcription factors that label interconnected neural circuits for socially driven behaviors, from grouped or isolated male brains. These revealed that social isolation alters fru and dsx levels throughout the brain. Knocking down fruM in different fruM-positive neuron subpopulations in the brains has diverse effects on social experience-dependent changes in courtship. Furthermore, group housing increases the expression of stripe (sr) and Hormone receptor-like in 38 (Hr38) genes encoding neural activity-induced transcription factors in most neurons within social circuits. We found that knocking down sr in fruM-positive neurons effectively eliminates the impact of social experience by increasing courtship in group-housed males. Importantly, social experience also alters the expression of FruM/DsxM putative target genes regulating circadian states throughout the brain. Disrupting the function of multiple circadian genes diminishes the effect of group housing on courtship. Our findings suggest that group housing/social enrichment suppresses courtship by reprogramming the circadian arousal state, whereas courtship-elevating effects of social experience rely on unique influences of FruM expression and function in different neurons within social and clock circuits. These results are significant as they point to modulation of circadian arousal state as a possible central strategy for mediating the pleiotropic effects of social experience on organismal responses.