Understanding how social experiences are represented in the brain and shape future responses is a major challenge in the study of behavior. We addressed this problem by studying behavioral, transcriptomic and epigenetic responses to intrusion in honey bees. Previous research showed that initial exposure to an intruder provokes an immediate attack; we now show that this also leads to longer-term changes in behavior in the response to a second intruder, with increases in the probability of responding aggressively and the intensity of aggression lasting 2 and 1 h, respectively. Previous research also documented the whole-brain transcriptomic response; we now show that in the mushroom bodies (MBs) there are 2 waves of gene expression, the first highlighted by genes related to cytoskeleton remodeling, and the second highlighted by genes related to hormones, stress response and transcription factors (TFs). Overall, 16 of 37 (43%) of the TFs whose cis-motifs were enriched in the promoters of the differentially expressed genes (DEGs) were also predicted from transcriptional regulatory network analysis to regulate the MB transcriptional response, highlighting the strong role played by a relatively small subset of TFs in the MB's transcriptomic response to social challenge. Whole brain histone profiling showed few changes in chromatin accessibility in response to social challenge; most DEGs were 'ready' to be activated. These results show how biological embedding of a social challenge involves temporally dynamic changes in the neurogenomic state of a prominent region of the insect brain that are likely to influence future behavior.

Contemporary mouse genetic reference populations are a powerful platform to discover complex disease mechanisms. Advanced high-diversity mouse populations include the Collaborative Cross (CC) strains, Diversity Outbred (DO) stock, and their isogenic founder strains. When used in systems genetics and integrative genomics analyses, these populations efficiently harnesses known genetic variation for precise and contextualized identification of complex disease mechanisms. Extensive genetic, genomic, and phenotypic data are already available for these high-diversity mouse populations and a growing suite of data analysis tools have been developed to support research on diverse mice. This integrated resource can be used to discover and evaluate disease mechanisms relevant across species. The Challenge of Complex Disease Complex diseases present compelling biomedical challenges that can be studied using human and nonhuman animal genetics. Although advances in human genetics have identified loci for many heritable complex diseases [1-8], there are several well-known limitations of genomewide association studies (GWASs). (i) For many human disease loci, the biological mechanism of action is unknown. (ii) When little is known about a locus, the path from genetic association to clinically actionable targets is unclear. (iii) Disease process or developmental trajectory is not always obvious from a causal genetic variant. (iv) GWAS results may not generalize across human subpopulations. (v) Medical records and participant phenotyping is often incomplete, imprecise, and retrospective, whereas model organism phenotyping can include in-depth, prospective, and standardized measures. (vi) Sample size requirements are formidable in human GWASs. (vii) Power is insufficient to study interacting genetic loci. (viii) Studies of genetic interaction with development, environment, and sex are largely intractable. Further, heterogeneous diseases like psychiatric disorders manifest with overlapping symptoms, intertwined disease trajectories [9], and complex genetic regulation [9,10]. In summary, the SNP-to-disease association model underlying GWASs cannot readily capture complex disease biology without further biological context. These challenges are often tractable with discovery genetics in model organisms.

Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution.

Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants.

Animals 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.