Dynamic resilience: stress phenotypes impact opioid-taking behavior, brain activity, and gene expression.
- 1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- 2Department of Chemical Engineering, Virginia Tech, Blacksburg, VA, 24061, USA.
- 3Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
Abstract
Stress is a common experience with individual differences in vulnerability. While some individuals succumb to lasting maladaptive behaviors, such as substance use disorders, others demonstrate resilience-a dynamic ability to return to baseline functioning over time. Assessing stress-related behaviors at a single time point may overlook key aspects of resilience. Chronic social defeat stress (CSDS) was used to investigate phenotypic stability in male mice. At 24 h post-final defeat, the anticipated distribution of susceptible and resilient phenotypes was observed; upon retesting three weeks later, most animals maintained their original stress phenotype. To evaluate potential differences in initial addiction liability we examined intravenous self-administration (IVSA) of remifentanil in susceptible and resilient mice. One-week post-CSDS, all stressed mice increased opioid intake, regardless of phenotype. At three weeks, susceptible mice maintained high opioid intake while resilient mice returned to baseline levels. This behavioral recovery was mirrored by neuronal activity. Susceptible mice exhibited persistently high neural activity (cFOS) in the basolateral amygdala (BLA), a key stress and fear center, and in the nucleus accumbens (NAc), a hub for motivation. In contrast, resilient mice showed normalized activity in the NAc at three weeks, which was accompanied by a systematic reprogramming of the NAc transcriptome. Our findings show that resilience is an active neuroadaptive process characterized by the recovery of specific brain circuits, not merely the absence of pathology. By moving beyond a single timepoint, we identify the BLA and NAc as critical nodes governing the transition, offering new targets for intervention in substance use disorders.
Related
- A hierarchical Bayesian model for dynamic phenotypes in multi-environment trials with genotype by environment interaction
- Dynamic endothelial ephrin-B2 and EphB4 expression characterizes hyaloid vessel regression
- Endogenous SMN Heterogeneity Defines Dynamic States of Motor Neuron Vulnerability and Resilience
- Targeting SUFU-mediated GLI activity alleviates ciliopathic phenotypes
- Beyond arousal: pupil fluctuations, neural activity, and behavior
BibTeX
@article{tyner2026dynamic,
title = {{Dynamic resilience: stress phenotypes impact opioid-taking behavior, brain activity, and gene expression.}},
author = {Emma Tyner and Kyle A Windisch and Xin Zhang and Shiv A Raman and Chang Lu and Julie A Blendy},
journal = {Translational psychiatry},
year = {2026},
month = aug,
doi = {10.1038/s41398-026-04339-1},
url = {https://europepmc.org/article/MED/43009495},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Dynamic resilience: stress phenotypes impact opioid-taking behavior, brain activity, and gene expression.
AU - Emma Tyner
AU - Kyle A Windisch
AU - Xin Zhang
AU - Shiv A Raman
AU - Chang Lu
AU - Julie A Blendy
PY - 2026
DA - 2026/08/14
JO - Translational psychiatry
DO - 10.1038/s41398-026-04339-1
UR - https://europepmc.org/article/MED/43009495
AB - Stress is a common experience with individual differences in vulnerability. While some individuals succumb to lasting maladaptive behaviors, such as substance use disorders, others demonstrate resilience-a dynamic ability to return to baseline functioning over time. Assessing stress-related behaviors at a single time point may overlook key aspects of resilience. Chronic social defeat stress (CSDS) was used to investigate phenotypic stability in male mice. At 24 h post-final defeat, the anticipated distribution of susceptible and resilient phenotypes was observed; upon retesting three weeks later, most animals maintained their original stress phenotype. To evaluate potential differences in initial addiction liability we examined intravenous self-administration (IVSA) of remifentanil in susceptible and resilient mice. One-week post-CSDS, all stressed mice increased opioid intake, regardless of phenotype. At three weeks, susceptible mice maintained high opioid intake while resilient mice returned to baseline levels. This behavioral recovery was mirrored by neuronal activity. Susceptible mice exhibited persistently high neural activity (cFOS) in the basolateral amygdala (BLA), a key stress and fear center, and in the nucleus accumbens (NAc), a hub for motivation. In contrast, resilient mice showed normalized activity in the NAc at three weeks, which was accompanied by a systematic reprogramming of the NAc transcriptome. Our findings show that resilience is an active neuroadaptive process characterized by the recovery of specific brain circuits, not merely the absence of pathology. By moving beyond a single timepoint, we identify the BLA and NAc as critical nodes governing the transition, offering new targets for intervention in substance use disorders.
SN - 2158-3188
ER -