This study by Xiong et al. evaluated the cortisol awakening response (CAR) that occurs 30-45 minutes after awakening, which depicts brain readiness rather than a byproduct of stress. Psycho-NeuroEndocrine-Developmental (PNED) Preparedness model integrated findings from neuroimaging and behavioral studies to demonstrate the role of CAR in the optimization of cognitive/emotional functioning. CAR uses mineralocorticoid and glucorticoid receptors (MR/GR) signaling, mobilizing energy resources and modulating neuronal excitability across networks, such as the hippocampus and amygdala. Evidence showed that individuals with a more robust CAR exhibited greater neural efficiency, as seen by the reduced prefrontal and hippocampal activation and more adaptive functional connectivity. In contrast, blunted CAR led to the over-recruitment of the limbic structures and impaired emotional discrimination, showing a reduced cognitive-affective efficiency. Early environmental adversity and socioeconomic disadvantage were associated with a reduced CAR and atypical amygdala-prefrontal coupling in children, indicating that gene-environment interactions shape the neuroendocrine architecture of CAR. The PNED model shows CAR as a circadian-behavioral tool to anticipate daily demands by coordinating neurobiological preparedness over endocrine aspects.