Glucocorticoids are secreted in times of stress to provide a host of physiological responses necessary to cope with the stress. However, an excess of glucocorticoids are harmful to the organism. Thus, it is necessary to regulate secretion of glucocorticoids to prevent over-secretion. This is accomplished through negative feedback at a number of sites. The turning off of secretion during the rising phase of corticosteroid secretion following stress is known as fast feedback. In addition, there is a level sensitive feedback that is proportional to the amount of glucocorticoid secreted with the stressor. This proportional feedback occurs several hours following the stress and is easily demonstrated in vitro at the pituitary. Besides stress induced rises in glucocorticoid there is a strong circadian rhythm that drives glucocorticoids to stress induced levels at the zenith while clamping glucocorticoids to very low levels at the nadir. Negative feedback is clearly involved in regulating this rhythm. This circadian rhythm provides a naturalistic model for understanding these various feedback types. This project examines the interface of neuronal circuits with glucocorticoid feedback and its impact on circadian rhythm. Specifically, two hypotheses are tested: 1) that there is a critical low point of cortisol necessary to resensitize the receptor and trigger the circadian drive; or 2) that absolute levels are less critical than a variation between the high and low points of the rhythm, i.e., a flattened rhythm produces abnormalities of cortisol feedback. To test these hypotheses, three different corticosterone preparations of varying lengths of action administered in the zenith vs. the nadir of the time rhythm will be measured administered. Glucocorticoid feedback will be measured with two paradigms -- in vitro in short-term anterior pituitary suspensions and in vivo using a stress-fast feedback model. This fast feedback model tests the ability of neuronal circuits to terminate stress induced CRH release. The changes in these feedback measures will be correlated with direct measurement of glucocorticoid receptors in the hippocampus, hypothalamus and anterior pituitary. Such studies will help in sorting out if there are feedback changes that are not dependent upon changes in glucocorticoid receptors, and provide paradigms for studying the mechanisms underlying these forms of feedback. These studies will provide further leads for studying the connection between the brains's role in HPA axis changes in depression.
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