ABSTRACT The goal of this proposal is to determine how epigenetic pathways regulate plasticity in social behaviors using the model ant Harpegnathos saltator. Specifically, we will test the hypothesis that external social cues are conveyed to chromatin by neuropeptides that regulate downstream transcription factors and associated epigenetic pathways to enable stable changes in social behavior. Epigenetic pathways are often disrupted in neurodevelopmental and behavioral disorders. Harpegnathos ants are an ideal model system to study brain epigenetics because workers and queens have the same genes but display distinct social behaviors. Furthermore, adult Harpegnathos workers can become queens via a remarkable phenotypic transition that involves plastic changes in reproduction, metabolism, and behavior. We have discovered that the ant homolog of the human gonadotropin-releasing hormone, the neuropeptide corazonin, is downregulated as Harpegnathos workers become queens and showed that it is necessary and sufficient to stimulate hunting in workers. Our preliminary data show that vasopressin, a neuropeptide with conserved social roles in mammals, is also preferentially expressed in worker brains, especially in those who do not express high levels of corazonin. In Aim 1, we will determine whether these two neuropeptides act on distinct or overlapping neuronal, molecular, and epigenetic pathways and whether they drive distinct social behaviors. Our previous work also revealed that Kr-h1, a transcription factor induced by corazonin, prevents unscheduled activation of “socially inappropriate” genes in the brain, thereby maintaining proper social behavior in both workers and gamergates. Preliminary studies identified another transcription factor, Fd3F, which is repressed by corazonin and might promote social plasticity in opposition to Kr-h1. Fd3F shares homology with pioneer transcription factors in other species, suggesting that an ability to reprogram chromatin states might underpin its function in behavioral reprogramming. In Aim 2, we will identify the changes on transcription and chromatin by which these transcription factors regulate brain and behavioral plasticity during adult caste transitions in Harpegnathos. The proposed experiments will leverage our previous experience with in vivo manipulation of gene expression in ant brains followed by behavioral and functional genomics analyses. Given that the neuropeptides, transcription factors, and epigenetic regulators investigated in this proposal are deeply conserved, our results should have broad impact on our understanding of how these molecular processes regulate social behavior.