Existing evidence highlights sleep’s critical role in regulating cortisol stress recovery; the underlying neural pathways remain unclear. To address this gap, the current study aims to elucidate the neurobiological pathway linking objective sleep efficiency to cortisol stress recovery using functional magnetic resonance imaging (fMRI), with a focus on the functional connectivity (FC) between prefrontal cortex (PFC) and hippocampus.

Seventy-seven participants completed an acute stress task during a task-dependent and resting-state fMRI scanning. Salivary samples were collected and analyzed as an indicator of cortisol stress recovery. Objective sleep efficiency was measured the night before the fMRI scanning. Using Seed-based gPPI and resting-state FC analysis, we examined the mediating role of PFC-hippocampus FC in the association between objective sleep efficiency and cortisol stress recovery, both during the stress task and in the post-stress resting-state.

Objective sleep efficiency was significantly related to cortisol stress recovery but not with cortisol reactivity. Neurologically, higher sleep efficiency was linked to enhanced prefrontal activity and increased the left dlPFC-hippocampus FC during the acute stress task. Importantly, objective sleep efficiency promoted cortisol stress recovery by the weakened resting-state left dlPFC-hippocampus FC.

This study highlights the pivotal role of left dlPFC-hippocampus regulation underlying sleep’s effect on HPA axis recovery to acute stress. These results suggest a model whereby high objective sleep efficiency promotes adaptive stress recovery through dynamic reallocation of neural resources across acute stress process, characterized by task-dependent coupling and post-stress decoupling of frontal-hippocampal circuitry.

Altered stress responses are closely linked to mental disorders, but the role of brain structure in acute cortisol responses to psychosocial stress remains underexplored, particularly in healthy individuals. Previous studies, with predominantly small samples, primarily focused on selected limbic regions and functional measures. Thus, this study investigates associations between brain structure and cortisol responses to psychosocial stress, exploring if hypothalamic–pituitary–adrenal axis reactivity can be predicted from brain morphology.

Our study included 291 subjects (157 females, 18–62 years) and consisted of two parts. First, a confirmatory analysis examined associations between specific cortical surface area, thickness, and subcortical volume with stress-induced cortisol increases using Permutation Analysis of Linear Models (PALM). Second, we conducted an exploratory whole-brain vertex-wise analysis, followed by out-of-sample prediction of cortisol increases from structural measures.

We found consistent negative associations between cingulate cortex (CC) sub-structures and acute cortisol increases. In PALM- and whole-brain analysis, a smaller surface area of the left rostral and caudal anterior cingulate cortex (cACC), posterior cingulate cortex, and right cACC were associated with higher cortisol stress responses, particularly in males. The left cACC surface area emerged as the most promising predictor in machine learning analyses. Additionally, other fronto-limbic structures were also associated with or predictive of acute cortisol reactivity.

Our findings demonstrate that cortical and subcortical structural measures, particularly smaller surface areas of the CC, predict acute hormonal stress responses. Notably, the left cACC emerged as the most consistent predictor, emphasizing its important role in stress reactivity.