Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice
Open accessAbstract
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.
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Previous work has demonstrated that mice show large changes in neural gene expression 70 minutes following social challenges.
“Previous work has demonstrated that mice do indeed show large changes in neural gene expression 70 minutes following social challenges [12,30], but it should be noted that many changes in gene expression associated with social status change may take longer to manifest and will not be observable at this time point.”
From Rapid changes in plasma corticosterone and medial amygdala transcriptome profiles during social status change reveal molecular pathways associated with a major life history transition in mouse dominance hierarchies (2025) · cites this paper as [30]
The Results report substantial changes in brain gene expression after social challenge, including differential expression at the 60-minute sampling point. But the paper sampled at 30, 60, and 120 minutes after intruder removal, not 70 minutes after challenge; its Methods describe a five-minute encounter. The specific 70-minute timing is therefore not supported by this source. (LLM, conf=0.86)
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- Adnani L, Langevin LM, Gautier E, Dixit R, Parsons K, Li S, Kaushik G, Wilkinson G, Wilson R, Childs S, 2015 Zac1 regulates the differentiation and migration of neocortical neurons via Pac1. J Neurosci 35: 13430– 13447. 26424889 PMC6605482
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- Authors
- Saul, M. C., Seward, C. H., Troy, J. M., Zhang, H., Sloofman, L. G., Lu, X., Weisner, P. A., Caetano-Anolles, D., Sun, H., Zhao, S. D., Chandrasekaran, S., Sinha, S., & Stubbs, L.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Broad Institute (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-03-29
- Volume
- 27
- Issue
- 6
- Pages
- 959-972
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC5453329
- OpenAlex
- W2602664771
- Cited by
- 46
- References
- 106
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 7 · 2017: 3 · 2016: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Simons Foundation (SFLife 291812)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- social challenges, agonistic encounters, chromatin accessibility, estrogen-related receptor alpha, nuclear receptors, energy metabolism, hypothalamus, frontal cortex, amygdala, oligodendrocytes, neurons, cell type deconvolution, transcriptional regulatory networks, mice
- MeSH terms
- ERRalpha Estrogen-Related Receptor, Agonistic Behavior, Amygdala, Animals, Chromatin, Energy Metabolism, Frontal Lobe, Hypothalamus, Male, Neurons, Oligodendroglia, Protein Binding, Receptors, Estrogen, Stress, Psychological, Transcription Factors, Transcription, Genetic, Signal Transduction, Gene Expression Regulation, Developmental, Gene Expression Profiling, Mice, Gene Regulatory Networks
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