show Abstracthide AbstractAnimals exhibit dramatic immediate behavioral plasticity in response to social interactions, and brief social interactions can shape the future social landscape. However, the molecular mechanisms contributing to behavioral plasticity are unclear. Here, we show that the genome dynamically responds to social interactions with multiple waves of transcription associated with distinct molecular functions in the brain of male threespined sticklebacks, a species famous for its behavioral repertoire and evolution. Some biological functions (e.g., hormone activity) peaked soon after a brief territorial challenge and then declined, while others (e.g., immune response) peaked hours afterwards. We identify transcription factors that are predicted to coordinate waves of transcription associated with different components of behavioral plasticity. Next, using H3K27Ac as a marker of chromatin accessibility, we show that a brief territorial intrusion was sufficient to cause rapid and dramatic changes in the epigenome. Finally, we integrate the time course brain gene expression data with a transcriptional regulatory network, and link gene expression to changes in chromatin accessibility. This study reveals rapid and dramatic epigenomic plasticity in response to a brief, highly consequential social interaction. Overall design: Adult males were collected from Putah Creek, a freshwater population, in spring 2013 and maintained in the lab on a 16:8 (L:D) photoperiod and at 18° C in separate 9-liter tanks. Males were provided with nesting material including algae, sand and gravel and were visually isolated from neighbors. All males were in the ‘territorial’ phase of the nesting cycle, i.e. defending a territory. Males were randomly assigned to either the experimental or control group. Males in the experimental group were presented with a smaller, unrelated male intruder confined to a flask. Males in the control groups were presented with an empty flask. At the same time as a confined intruder was introduced to an experimental male’s tank, an empty flask was introduced into a paired control male’s tank. After 5 min the flask was removed, and after a predetermined period (see below) males were quickly netted and sacrificed by decapitation within seconds following an IACUC approved protocol (#15077) of the University of Illinois at Urbana-Champaign. For RNA Sequencing diencephalon and telencephalon tissue samples were collected 30, 60 or 120 minutes after the flask was introduced, with n=10 males per time point (5 experimental and 5 control).