Factors determining the time-course of the response of the hypothalamus-pituitary-adrenal axis to stress: Much more than negative glucocorticoid feedback.

The consequences of hypothalamic-pituitary-adrenal (HPA) axis activation depend on the area under the curve of the response, including the post-stress period. However, scarce attention has been paid to factors other than negative glucocorticoid feedback (nGF) that can affect its time course. Here, I analyze the influence of stressor characteristics, aging, and prior early life and adult stress experiences. Although nGF contributes to shape the initial response, the decline during prolonged emotional stress may largely stem from a safety signal triggered when stress exposure lacks real damage, alongside an inability to sustain a high response to severe stressors. This safety signal appears to be the primary factor reducing the response after repeated experience with the same stressor, particularly during post-stress recovery. The brain origin and processes determining this safety signal remain to be characterized.