Date of Award
Doctor of Philosophy (PhD)
Psychology & Neuroscience
Robert L. Spencer
Hypothalamic-pituitary-adrenal (HPA) axis activation leads a tightly coordinated cascade release of secretagogue pro-hormones that ultimately result in the production and secretion of glucocorticoids. Glucocorticoids in turn provide important regulatory control over the HPA axis. Stress-stimulated HPA axis hormone secretion requires alteration in paraventricular nucleus (PVN) signaling activity and recruitment of signaling proteins to mediate the excitatory coupling mechanism that lead to hormone release. These responses are mediated by the extracellular signal-regulated kinase (ERK). We examined if glucocorticoid regulation of HPA hormone output corresponded with alteration in the phosphorylated (active) form of ERK (pERK) within the PVN. Dephosphorylation of pERK within in peripheral cell types has been shown to be dependent on glucocorticoid up-regulation of the mitogen-activated protein kinase phosphatase-1 (mkp-1) gene. Thus, we also explored whether glucocorticoid regulation of the HPA axis was associated with PVN or anterior pituitary mkp-1 gene upregulation. The last series of experiments in chapter 4 challenge the widely accepted model of glucocorticoid negative feedback. These experiments demonstrate a number of interesting novel characteristics about the interplay between stress, the HPA axis and glucocorticoids. First, stress-induced HPA axis activity has a differential hormone response which is determined by the timing of glucocorticoid exposure relative to the onset of stress. Second, stress can transiently evoke HPA axis resistance to the suppressive effects produced by glucocorticoid exposure during stress. The cumulative results of these studies demonstrate that negative feedback control of the HPA axis is functionally dependent on distinct temporal, spatial and physiological glucocorticoid actions.
Osterlund, Chad D., "Negative feedback control over the hypothalamic-pituitary-adrenal axis response to stress is a function of temporal, spatial and physiological actions of corticosterone" (2013). Psychology and Neuroscience Graduate Theses & Dissertations. 54.