Abstract

Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated preparation function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design using Dexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.