The neuroendocrinology of stress: Glucocorticoid signaling mechanisms.

Glucocorticoid signaling plays major roles in energy homeostasis and adaptation to adversity, and dysregulation of this process is linked to systemic and psychological pathology. Over the last several decades, new work has challenged many of the long-standing assumptions regarding regulation of glucocorticoid secretion and glucocorticoid signaling mechanisms, revealing an exquisite complexity that accompanies the important and perhaps global role of these hormones in physiological and psychological regulation. New findings have included discovery of membrane signaling, direct neural control of the adrenal, a role for pulsatile glucocorticoid release in glucocorticoid receptor signaling, marked sex differences in brain glucocorticoid biology, and salutary as well as deleterious roles for glucocorticoids in long- and short-term adaptations to stress. This review covers some of the major lessons learned in the area of mechanisms of glucocorticoid signaling, and discusses how these may inform the field moving forward.