Limbic functional connectivity during stress induction and post-stress rest regulates cortisol stress reactivity and recovery differently

The hypothalamic-pituitary-adrenal (HPA) axis and its end-product cortisol play an important role in adaptation to stressful situations. Previous studies have suggested brain regions in the limbic area (e.g., basolateral amygdala-BLA, centromedial amygdala-CMA, hippocampus) regulate cortisol stress response (i.e., initial cortisol stress reactivity and a late recovery). However, whether these limbic areas regulate cortisol stress reactivity and recovery differently remains elusive. Using the Seed-to-Voxel gPPI analysis, we explored the functional connectivity (FC) between the limbic area and other brain regions during stress induction and their association with cortisol stress reactivity. Similarly, we explored their FC during post-stress rest and their association with cortisol stress recovery. We found that both BLA and CMA connectivity related to cortisol stress reactivity during stress induction, with similarity in FC with precuneus and differences in FC with angular gyrus, precentral gyrus, and PFC; the BLA rather than CMA connectivity with PFC linked to cortisol stress recovery during post-stress rest. Furthermore, the hippocampal-PFC connectivity only affected cortisol stress recovery during post-stress rest, and in a different direction from the effect of BLA-PFC connectivity. Our findings provide important insight into the neurobiological etiology underlying how limbic FC regulates HPA axis stress reactivity and recovery. This highlights the importance of targeting acute stress reactivity and recovery separately in interventions for stress-related disorders.