The hypothalamic-pituitary-adrenal axis is a critical neurohormonal network regulating homeostasis and coordinating stress responses. Here we demonstrate that an oscillating pattern of plasma cortisol is important for maintenance of healthy brain responses as measured by functional neuroimaging and behavioral testing. Our data highlight the crucial role of glucocorticoid rhythmicity in (i) modulating sleep behavior and working memory performance, and (ii) regulating the human brain’s responses under emotional stimulation. Current optimal cortisol replacement therapies for patients with primary or secondary adrenal insufficiently are associated with poor psychological status, and these results suggest that closer attention to aspects of chronotherapy will benefit these patients and may also have major implications for improved glucocorticoid dynamics in stress and psychiatric disease.Abstract
Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.