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.