Glucocorticoid regulation of peptide genes in neuroendocrine CRH neurons: A complexity beyond negative feedback

This review will examine our current knowledge of a fundamental property of CRH neuroendocrine neurons: how the major endpoint of the HPA axis-adrenal glucocorticoids-interacts with the mechanisms controlling the expression of the genes that encode ACTH secretogogues. A great deal of work over the past 25 years has led to the notion that this question has an ostensibly simple answer: glucocorticoids inhibit peptide gene expression using “negative feedback” at the CRH neuron and elsewhere. However, closely examining how glucocorticoids act in different physiological circumstances reveals a much more complex set of answers, particularly if we consider how the processes that control peptide synthesis and release are coupled. Out of this examination emerges a more flexible and complex framework for examining the integrative mechanisms controlling the CRH neuron. Although we will mostly focus on the Crh gene, relevant aspects of the vasopressin (Avp) and pro-enkephalin (pEnk) gene regulatory mechanisms will also be discussed.