Journal Article

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

Gyles, Trevonn M, Carona-Acosta, Astrid, Godino, Arthur, Fisher-Foye, Rachel L, Sial, Omar, Durand-de Cuttoli, Romain, Kipp, Brian T, Browne, Caleb J, Markovic, Tamara, Nwakama, Chinonso A, Ramakrishnan, Aarthi, Li, Long, Yim, Yun Young, Shen, Li, Holt, Leanne M, Parise, Eric M, Rivera, Matthew, Minier-Toribio, Angelica M, Nestler, Eric J, Bolaños-Guzmán, Carlos A, Parise, Lyonna F, Russo, Scott J, Daly, Teagan, Estill, Molly, Zhang, Bin

2026

Overview

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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory Preprints
• Subject: Mental depression / Neurological diseases / Nucleus accumbens / Phenotypes / Sex / Social interactions / Stress / Transcription