LAUSR

Social challenges like territorial intrusions evoke behavioral responses in widely diverging species. Recent work has showed that evolutionary “toolkits”—genes and modules with lineage‐specific variations but deep conservation of function—participate in the behavioral response to social challenge. Here, we develop a multispecies computational‐experimental approach to characterize such a toolkit at a systems level. Brain transcriptomic responses to social challenge was probed via RNA‐seq profiling in three diverged species—honey bees, mice and three‐spined stickleback fish—following a common methodology, allowing fair comparisons across species. Data were collected from multiple brain regions and multiple time points after social challenge exposure, achieving anatomical and temporal resolution substantially greater than previous work. We developed statistically rigorous analyses equipped to find homologous functional groups among these species at the levels of individual genes, functional and coexpressed gene modules, and transcription factor subnetworks. We identified six orthogroups involved in response to social challenge, including groups represented by mouse genes Npas4 and Nr4a1, as well as common modulation of systems such as transcriptional regulators, ion channels, G‐protein‐coupled receptors and synaptic proteins. We also identified conserved coexpression modules enriched for mitochondrial fatty acid metabolism and heat shock that constitute the shared neurogenomic response. Our analysis suggests a toolkit wherein nuclear receptors, interacting with chaperones, induce transcriptional changes in mitochondrial activity, neural cytoarchitecture and synaptic transmission after social challenge. It shows systems‐level mechanisms that have been repeatedly co‐opted during evolution of analogous behaviors, thus advancing the genetic toolkit concept beyond individual genes.