Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress

• Glucocorticoids primarily mobilize energy in response to homeostatic challenge.
• The forebrain receives glucocorticoid feedback and mediates stress responsiveness.
• Glucocorticoid actions on synapses, circuits, and behavior promote adaptation.
• Adaptive capacity and adaptive cost interact to determine risk for pathology.

Environmental stimuli that signal real or potential threats to homeostasis lead to glucocorticoid secretion by the hypothalamic–pituitary–adrenocortical (HPA) axis. Glucocorticoids promote energy redistribution and are critical for survival and adaptation. This adaptation requires the integration of multiple systems and engages key limbic-neuroendocrine circuits. Consequently, glucocorticoids have profound effects on synaptic physiology, circuit regulation of stress responsiveness, and, ultimately, behavior. While glucocorticoids initiate adaptive processes that generate energy for coping, prolonged or inappropriate glucocorticoid secretion becomes deleterious. Inappropriate processing of stressful information may lead to energetic drive that does not match environmental demand, resulting in risk factors for pathology. Thus, dysregulation of the HPA axis may promote stress-related illnesses (e.g. depression, PTSD). This review summarizes the latest developments in central glucocorticoid actions on synaptic, neuroendocrine, and behavioral regulation. Additionally, these findings will be discussed in terms of the energetic integration of stress and the importance of context-specific regulation of glucocorticoids.