Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress

C. Nasca, Caroline Menard, Georgia Hodes, Benedetta Bigio, Catherine Pena, Zachary Lorsch, Danielle Zelli, Anjali Ferris, Veronika Kana, Immanuel Purushothaman, Josh Dobbin, Marouane Nassim, P. DeAngelis, Miriam Merad, Natalie Rasgon, Michael Meaney, Eric J. Nestler, Bruce S. McEwen, Scott J. Russo

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: Previous studies identified several separate risk factors for stress-induced disorders. However, an integrative model of susceptibility versus resilience to stress including measures from brain-body domains is likely to yield a range of multiple phenotypic information to promote successful adaptation to stress. Methods: We used computational and molecular approaches to test whether 1) integrative brain-body behavioral, immunological, and structural domains characterized and predicted susceptibility or resilience to social defeat stress (SDS) in mice and 2) administration of acetyl-L-carnitine promoted resilience at the SDS paradigm. Results: Our findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The copresence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, we provide initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience at the SDS paradigm. Conclusions: The current findings of multidimensional brain-body predictors of susceptibility versus resilience to stress provide a starting point for in vivo models of mechanisms predisposing apparently healthy individuals to develop the neurobiological and behavioral deficits resulting from stress exposure. This framework can lead to novel therapeutic strategies to promote resilience in susceptible phenotypes.

Original languageEnglish (US)
Pages (from-to)483-491
Number of pages9
JournalBiological Psychiatry
Volume86
Issue number6
DOIs
StatePublished - Sep 15 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Keywords

  • Acetylcarnitine
  • Biomarkers
  • Epigenetic
  • Individual differences
  • Phenotype
  • Risk factors

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    Nasca, C., Menard, C., Hodes, G., Bigio, B., Pena, C., Lorsch, Z., Zelli, D., Ferris, A., Kana, V., Purushothaman, I., Dobbin, J., Nassim, M., DeAngelis, P., Merad, M., Rasgon, N., Meaney, M., Nestler, E. J., McEwen, B. S., & Russo, S. J. (2019). Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress. Biological Psychiatry, 86(6), 483-491. https://doi.org/10.1016/j.biopsych.2019.06.030