Behavior-specific changes in transcriptional modules lead to distinct and predictable neurogenomic states

Abstract

Using brain transcriptomic profiles from 853 individual honey bees exhibiting 48 distinct behavioral phenotypes in naturalistic contexts, we report that behavior-specific neurogenomic states can be inferred from the coordinated action of transcription factors (TFs) and their predicted target genes. Unsupervised hierarchical clustering of these transcriptomic profiles showed three clusters that correspond to three ecologically important behavioral categories: aggression, maturation, and foraging. To explore the genetic influences potentially regulating these behavior-specific neurogenomic states, we reconstructed a brain transcriptional regulatory network (TRN) model. This brain TRN quantitatively predicts with high accuracy gene expression changes of more than 2,000 genes involved in behavior, even for behavioral phenotypes on which it was not trained, suggesting that there is a core set of TFs that regulates behavior-specific gene expression in the bee brain, and other TFs more specific to particular categories. TFs playing key roles in the TRN include well-known regulators of neural and behavioral plasticity, e.g., Creb, as well as TFs better known in other biological contexts, e.g., NF-κB (immunity). Our results reveal three insights concerning the relationship between genes and behavior. First, distinct behaviors are subserved by distinct neurogenomic states in the brain. Second, the neurogenomic states underlying different behaviors rely upon both shared and distinct transcriptional modules. Third, despite the complexity of the brain, simple linear relationships between TFs and their putative target genes are a surprisingly prominent feature of the networks underlying behavior.Apis mellifera | gene regulation | social behavior | systems biology B ehavior is influenced by both heritable and environmental factors, sometimes via massive changes in brain transcriptomes (1). An emerging insight is that these changes induce shifts in "neurogenomic states" rather than activation of particular genes only in local neural circuits (2). This has led to the idea that distinct neurogenomic states underlie distinct behaviors (1), but it is not known how these states are defined or maintained. Further, the regulatory architecture of behaviorally relevant neurogenomic states has not been studied, and it is not known whether behavior is subserved by the kinds of transcriptional regulatory networks (TRNs) known for other phenotypes (3-6).We applied tools and perspectives from molecular systems biology-used to study transcriptional regulation in the brain and elsewhere (3-6)-to transcript profiles from the BeeSpace Project, which used microarray analysis to study hereditary and environmental influences on brain gene expression and social behavior (Methods). This provided a unique aggregate dataset from a single laboratory (G.E.R.), using the same analytical platform, protocols, and analysis procedures (7). Because the natural behavioral repertoire of the honey bee (Apis mellifera) is perhaps the best studied of any nonhuman a...

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