A unifying psycho-neuroendocrine-developmental model for the cortisol awakening response primes human cognition and...

Awakening is the daily switch from sleep to wakefulness, re-engaging sensing, movement, and prediction for survival. This transition accompanies with the cortisol awakening response (CAR), a hallmark of the hypothalamic-pituitary-adrenal (HPA) axis activity, which serves as a sensitive neuroendocrine marker that influences human brain, emotion, cognition and health. Alterations in CAR are considered as a transdiagnostic risk factor for various psychiatric disorders. Here we synthesize multidisciplinary findings to propose a unifying Psycho-NeuroEndocrine-Developmental (PNED) Preparedness model that elucidates CAR's proactive role in optimizing neural efficiency and dynamic resource allocation for anticipated cognitive and emotional demands across developmental contexts. We begin by reviewing the physiological bases of CAR and its associations with cognitive-emotional functioning. Subsequently, we integrate recent evidence demonstrating how CAR strategically primes hippocampal-prefrontal interactions to support memory and executive control, amygdala-prefrontal circuitry for emotion processing shaped by early life experiences, and large-scale neural network dynamics underlying executive and emotional functions. Mechanistically, CAR functions as a temporal orchestrator by setting up a tonic state of neuroendocrine activity that mobilizes metabolism and energy supply through mineralocorticoid and glucocorticoid receptor-dependent modulations of neuronal excitability. This process facilitates reactivation of routine memory engrams and prospective memory representations, enabling individuals to anticipate daily demands and challenges. The PNED model conceptualizes CAR as a proactive rather than reactive mechanism that works with stress-sensitive mediators, stimulus/task-driven phasic catecholaminergic actions to enable flexible allocation of neural resources. This perspective highlights CAR-induced brain preparedness that may underlie individual differences in vulnerability and resilience to stress across development, and positions CAR-mediated brain network interactions as promising targets for intervention. Finally, we discuss translational opportunities and future directions, including CAR-optimized chronotherapies and neuromodulation strategies. Collectively, our proposed model offers a unified framework for understanding CAR's involvement in psychological, neuroendocrine, and developmental processes in ever-changing environmental contexts, with potential implications for personalized approaches to mental health disorders.