A shared transcriptional network in the nucleus accumbens supports resilience to chronic stress across sex

Although chronic stress increases the risk for depression, only a subset of exposed individuals develop psychiatric illness. The biological mechanisms that protect against depression remain incompletely understood, particularly at the molecular level. Here, we identify a transcriptional network in the nucleus accumbens (NAc), a central brain reward region, that supports stress resilience in both sexes and demonstrate the causal contribution of key hub genes. Using chronic social defeat stress, RNA-seq, and co-expression network analysis, we find sex-specific but overlapping gene modules linked to resilience, anchored by shared hub genes embedded within a common network architecture. Overexpression of these hub genes in stress-naive mice confers stress protection and induces a transcriptional state that is discrete from both susceptible and resilient profiles. These findings position resilience as a structured and targetable molecular phenotype and provide a basis for investigating sex-informed mechanisms of stress adaptation.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-02-18
DOI
https://doi.org/10.64898/2026.02.17.706464
Primary Topic
Stress Responses and Cortisol
Type
article
Field-Weighted Citation Impact
0.00
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article

A shared transcriptional network in the nucleus accumbens supports resilience to chronic stress across sex

Eric M. Parise, Omar K. Sial, Yun Young Yim, Estill Mr et al.
bioRxiv (Cold Spring Harbor Laboratory)
Stress Responses and Cortisol
article

A shared transcriptional network in the nucleus accumbens supports resilience to chronic stress across sex

Eric M. Parise, Omar K. Sial, Yun Young Yim, Estill Mr, Arthur Godino, Chinonso A. Nwakama, Tamara Markovic, Matthew J. Rivera, Leanne M. Holt, Aarthi Ramakrishnan, Rebecca E. Fisher, Li Shen, Brian T. Kipp, Long Li, Scott J Russo, Romain Durand, Lyonna F Parise, Astrid Carona-Acosta, Carlos Bolanos-Guzman, Eric J. Nestler, Angelica Minier-Toribio, Teagan Daly, Bin Zhang
article en

Abstract

Although chronic stress increases the risk for depression, only a subset of exposed individuals develop psychiatric illness. The biological mechanisms that protect against depression remain incompletely understood, particularly at the molecular level. Here, we identify a transcriptional network in the nucleus accumbens (NAc), a central brain reward region, that supports stress resilience in both sexes and demonstrate the causal contribution of key hub genes. Using chronic social defeat stress, RNA-seq, and co-expression network analysis, we find sex-specific but overlapping gene modules linked to resilience, anchored by shared hub genes embedded within a common network architecture. Overexpression of these hub genes in stress-naive mice confers stress protection and induces a transcriptional state that is discrete from both susceptible and resilient profiles. These findings position resilience as a structured and targetable molecular phenotype and provide a basis for investigating sex-informed mechanisms of stress adaptation.

bioRxiv (Cold Spring Harbor Laboratory)
Allen Institute for Brain Science (US), Texas A&M University (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 48%
Stress Responses and Cortisol
DOIOpen Access PDFOpenAlex
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