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

Gyles, T. M.; Holt, L. M.; Parise, L. F.; Fisher, R.; Godino, A.; Browne, C. J.; Kipp, B.; Minier-Toribio, A.; Markovic, T.; Daly, T.; Durand, R.; Li, L.; Ramakrishnan, A.; Estill, M.; Rivera, M.; Yim, Y. Y.; Carona-Acosta, A.; Sial, O.; Nwakama, C.; Bolanos-Guzman, C.; Shen, L.; Zhang, B.; Russo, S.; Parise, E.; Nestler, E. J.

doi:10.64898/2026.02.17.706464

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bioRxiv · 10.64898/2026.02.17.706464

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

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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.

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Gyles, T. M., Holt, L. M., Parise, L. F., Fisher, R., Godino, A., Browne, C. J., Kipp, B., Minier-Toribio, A., Markovic, T., Daly, T., Durand, R., Li, L., Ramakrishnan, A., Estill, M., Rivera, M., Yim, Y. Y., Carona-Acosta, A., Sial, O., Nwakama, C., Bolanos-Guzman, C., Shen, L., Zhang, B., Russo, S., Parise, E., Nestler, E. J.. 2026-02-18. A shared transcriptional network in the nucleus accumbens supports resilience to chronic stress across sex.. https://doi.org/10.64898/2026.02.17.706464

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