Cross-species systems analyses reveal a conserved brain transcriptional response to social challenge

Behavioral responses to social challenges like territorial intrusion occur in widely diverging species. Recent work has suggested that evolutionary - genes and pathways with lineage-specific variations but deep conservation of function - participate in the behavioral response to social challenge. Here, we studied this toolkit at scale by probing brain transcriptomic responses to social challenge in three distantly related species: honey bees, mice, and three-spined stickleback fish. We aggregated multi-species RNA-seq expression data from specific brain regions and time points after social challenge, achieving spatio-temporal resolution substantially greater than previous work. We conducted sequencing in parallel across species, allowing fair comparison of responses. Because of our complex study design, we developed new comparative analytical methods - including a new cross-species network analysis algorithm. We identified six orthogroups of genes involved in a conserved response to social challenge, including groups represented by Npas4 and Nr4a1 , as well as conserved modulation of gene systems such as transcriptional regulators, ion channels, G-protein coupled receptors, and synaptic proteins. We identified two deeply conserved gene modules enriched in mitochondrial fatty acid metabolism and heat shock proteins. Our analysis of this multi-species spatio-temporal expression dataset spanning phyla describes a system wherein nuclear receptors, interacting with chaperones, induce transcriptional changes in mitochondrial activity, neural cytoarchitecture, and synaptic transmission. These data provide support for the hypothesis that core genes and gene sets conserved across animal species have been repeatedly co-opted during evolution of analogous behaviors and may therefore be considered essential toolkits of response to social challenge.