Hypercortisolemia, hippocampal glucocorticoid receptors, and fast feedback

Glucocorticoids are critical for survival. The absence of glucocorticoids leads to the inability of the organism to cope with stress and subsequent death. However, diseases of glucocorticoid excess, such as Cushing's disease, make it clear that 'too much circulating glucocorticoids is also bad.' The need to control the circulating levels of glucocorticoids to prevent oversecretion leads to an elaborate set of checks and balances, in particular, the levels of glucocorticoid 'feedback' to the controlling elements to turn off glucocorticoid secretion and consequently maintain the homeostatic range of glucocorticoids. In order to accomplish these goals, multiple types of feedback exist which appear to use different intracellular mechanisms. In addition to multiple types of feedback, there are multiple sites of feedback including numerous limbic areas that influence the inhibition of the stress response. In this article, we will discuss the role of hippocampal limbic circuits in modulation of the stress response and the evidence which support the theory that changes in these circuits are associated with feedback abnormalities. We will review studies in humans which suggest that damage to the hippocampus can lead to changes in glucocorticoid feedback, and finally we will review the evidence that glucocorticoids themselves can lead to changes in hippocampal neurons resulting in feedback abnormalities.