Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice. [RNA-Seq data set]

Agonistic encounters with conspecifics are powerful effectors of future behavior that evoke strong and durable neurobiological responses. We recently identified a deeply conserved “toolkit” of transcription factors (TFs) that respond to social challenge across diverse species in coordination with distinct conserved signatures of energy metabolism and developmental signaling. To further characterize this response and its transcriptional drivers in mice, we examined gene expression and chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged and control animals over time. The data revealed a complex spatiotemporal pattern of metabolic, neural, and developmental transcriptomic signatures coordinated with significant shifts in the accessibility of distally located regulatory elements. Transcriptional regulatory network and motif analyses revealed an interacting network of TFs correlated with differential gene expression across the tissues and time points we assayed, including the early-acting and conserved regulator of energy metabolism and development, ESRRA. Cell-type deconvolution analysis attributed the early metabolic activity implicated by our transcriptomic analysis primarily to oligodendrocytes and the developmental signal to neurons, and we confirmed the presence of ESRRA in both oligodendrocytes and neurons throughout the brain. To assess the role of this nuclear receptor as an early trigger of this coordinated response, we used chromatin immunoprecipitation to map ESRRA binding sites to a set of genes involved in metabolic regulation and enriched in challenge-associated differentially expressed genes. Together, these data support a rich model linking metabolic and neural responses to social challenge, and identify regulatory drivers with unprecedented tissue and temporal resolution. Overall design: Territory-holding resident mice were males from the C57BL/6J strain co-housed with females to establish a territory. Intruder mice were males from the BALB/C strain. Animals were housed in a 12L:12D animal room until the resident-intruder paradigm was undertaken. Before behavior work, male C57BL/6J animals were cohoused with members of the same sex for two weeks, housed alone for a week, and then housed with a single C57BL/6J female for a week to establish a territory. Thus, before behavior work, the animals were allowed to habituate to our animal facility for four weeks. Three hours before testing, females were removed from the resident males’ cages. Immediately before the trial, residents’ cages were inserted into a blank-walled chamber. For experimental mice, we introduced unfamiliar intruder BALB/cJ male mice. Intruders were contained within a stainless steel wire ~1cm mesh cage to prevent animals from making contact and injuring one another. Control animals were exposed to the same cage, but containing a paper cup instead of an intruder mouse. The cages were removed in both intruder and control conditions after five minutes. After exposure to the intruder or control stimulus, resident animals were allowed to sit in a dark and quiet place for either 30 minutes, 60 minutes, or 120 minutes. Residents were then immediately euthanized by cervical dislocation. As soon as animals were euthanized, we extracted three brain regions of interest from our animals: frontal cortex, hypothalamus, and amygdala. This yielded tissue samples from which RNA was extracted. The RNA samples were pooled to generate libraries for sequencing. For control mice there were 5 replicates for all combinations of time after stimulus (30, 60, 120 minutes) and brain region (frontal cortex, hypothalamus, amygdala) except for hypothalamus from control mice after 30 minutes (3 replicates) and for frontal cortex from control mice after 120 minutes (6 replicates). For experimental mice there were 5 replicates for all combinations of time after stimulus (30, 60, 120 minutes) and brain region (frontal cortex, hypothalamus, amygdala) except for frontal cortex from experimental mice after 120 minutes (6 replicates).

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Saul MC, Seward CH, Troy JM, Zhang H, Sloofman LG, Lu X, Weisner PA, Caetano-Anolles D, Sun H, Zhao SD, Chandrasekaran S, Sinha S, Stubbs L