Brain-wide circuit dynamics underlying stress susceptibility and resilience in male mice
Abstract
Understanding the neurobiological mechanisms of stress susceptibility is key to advancing our insight into stress-related psychopathology like post-traumatic stress disorder (PTSD). Because traumatic events are unpredictable, capturing brain activity during or right after trauma is extremely difficult in humans, creating a critical gap in understanding how neural responses lead to long-term behavioral consequences. This study leverages a controlled animal model to overcome this limitation, enabling time-locked, whole-brain mapping of neural activity as a function of the individual’s susceptibility to stress. We used a mouse model for severe stress, segregating male mice into stress-susceptible and resilient groups. We analyzed and contrasted their whole-brain neuronal activity pre-, peri- and post-stress exposure and compared functional connectivity of the salience (SN), default mode (DMN) and executive control network (lateral cortical network (LCN) in rodents). We found that stress-susceptible mice exhibited pre-existing hyperactivity in the lateral orbital area, a potential risk factor for stress vulnerability, and heightened retrosplenial cortex activity peri- and post-stress, potentially contributing to a maladaptive memory for the stressful event. Upon stress exposure, susceptible mice showed strong recruitment of visual and memory-related areas, whereas resilient mice displayed marked reductions in retrosplenial activity and increased activation in the agranular insula and ventral striatum. Observations of enhanced intra-SN and SN-DMN connectivity in susceptible mice mirrored those observed in individuals with PTSD. Moreover, susceptible mice displayed aberrant DMN-LCN connectivity pre- and peri-stress. These findings reveal circuit-level signatures of stress susceptibility that mirror human PTSD and point to novel potential biomarkers and targets for mechanistic intervention.
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BibTeX
@article{dirven2026brainwide,
title = {{Brain-wide circuit dynamics underlying stress susceptibility and resilience in male mice}},
author = {Bart C. J. Dirven and Moritz Negwer and Andriana Botan and Riv Maas and Lennart van Melis and Sanne Merjenburgh and Rebecca van Rijn and Joanes Grandjean and Judith R. Homberg and Tamas Kozicz and Marloes J. A. G. Henckens},
journal = {Translational Psychiatry},
year = {2026},
month = oct,
doi = {10.1038/s41398-026-04477-6},
url = {https://www.nature.com/articles/s41398-026-04477-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Brain-wide circuit dynamics underlying stress susceptibility and resilience in male mice
AU - Bart C. J. Dirven
AU - Moritz Negwer
AU - Andriana Botan
AU - Riv Maas
AU - Lennart van Melis
AU - Sanne Merjenburgh
AU - Rebecca van Rijn
AU - Joanes Grandjean
AU - Judith R. Homberg
AU - Tamas Kozicz
AU - Marloes J. A. G. Henckens
PY - 2026
DA - 2026/10/06
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04477-6
UR - https://www.nature.com/articles/s41398-026-04477-6
AB - Understanding the neurobiological mechanisms of stress susceptibility is key to advancing our insight into stress-related psychopathology like post-traumatic stress disorder (PTSD). Because traumatic events are unpredictable, capturing brain activity during or right after trauma is extremely difficult in humans, creating a critical gap in understanding how neural responses lead to long-term behavioral consequences. This study leverages a controlled animal model to overcome this limitation, enabling time-locked, whole-brain mapping of neural activity as a function of the individual’s susceptibility to stress. We used a mouse model for severe stress, segregating male mice into stress-susceptible and resilient groups. We analyzed and contrasted their whole-brain neuronal activity pre-, peri- and post-stress exposure and compared functional connectivity of the salience (SN), default mode (DMN) and executive control network (lateral cortical network (LCN) in rodents). We found that stress-susceptible mice exhibited pre-existing hyperactivity in the lateral orbital area, a potential risk factor for stress vulnerability, and heightened retrosplenial cortex activity peri- and post-stress, potentially contributing to a maladaptive memory for the stressful event. Upon stress exposure, susceptible mice showed strong recruitment of visual and memory-related areas, whereas resilient mice displayed marked reductions in retrosplenial activity and increased activation in the agranular insula and ventral striatum. Observations of enhanced intra-SN and SN-DMN connectivity in susceptible mice mirrored those observed in individuals with PTSD. Moreover, susceptible mice displayed aberrant DMN-LCN connectivity pre- and peri-stress. These findings reveal circuit-level signatures of stress susceptibility that mirror human PTSD and point to novel potential biomarkers and targets for mechanistic intervention.
SN - 2158-3188
ER -