A shared transcriptional network in the nucleus accumbens supports resilience to chronic stress across sex
Year: 2026
Type: preprint
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.
Authors: Trevonn M. Gyles, Leanne M. Holt, Lyonna F. Parise, Rachel L. Fisher-Foye, Arthur Godino, Caleb J. Browne, Brian T. Kipp, Angelica M. Minier-Toribio, Tamara Markovic, Teagan Daly, Romain Durand-de Cuttoli, Long Li, Aarthi Ramakrishnan, Molly Estill, Matthew Rivera, Yun Young Yim, Astrid Carona-Acosta, Omar Sial, Chinonso A. Nwakama, Carlos A. Bolaños-Guzmán, Li Shen, Bin Zhang, Scott J. Russo, Eric M. Parise, Eric J. Nestler
Institutions: Icahn School of Medicine at Mount Sinai, Texas A&M University
Language: English
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Multidisciplinary Training in Cardiovascular Biology, G66900451, Neural Circuit Mechanisms of Stress-Impaired Social Reward, Epigenetic Mechanisms of Chronic Stress Action, Sex Differences in Neural Circuit Mechanisms of Aggression, Training Program in Substance Use Disorders, Gene Expression Profiling of Stress Resilient Mice within the Nucleus Accumbens
OpenAlex ID: W7130349577