title: Dissection of glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis by gene targeting in mice.
abstract: Negative feedback regulation of glucocorticoid (GC) synthesis and secretion occurs through the function of glucocorticoid receptor (GR) at sites in the hypothalamic-pituitary-adrenal (HPA) axis, as well as in brain regions such as the hippocampus, prefrontal cortex, and sympathetic nervous system. This function of GRs in negative feedback coordinates basal glucocorticoid secretion and stress-induced increases in secretion that integrate GC production with the magnitude and duration of the stressor. This review describes the effects of GR loss along major sites of negative feedback including the entire brain, the paraventricular nucleus of the hypothalamus (PVN), and the pituitary. In genetic mouse models, we evaluate circadian regulation of the HPA axis, stress-stimulated neuroendocrine response and behavioral activity, as well as the integrated response of organism metabolism. Our analysis provides information on contributions of region-specific GR-mediated negative feedback to provide insight in understanding HPA axis dysregulation and the pathogenesis of psychiatric and metabolic disorders.
authors.affiliation: Neuroscience Graduate Program, School of Medicine, Vanderbilt University, Nashville, TN, United States; Center for Preterm Birth Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, ML 7009, Cincinnati, OH 45229, United States. Electronic address: Gloria.n.laryea@vanderbilt.edu.
authors.forename: Gloria
authors.initials: G
authors.lastname: Laryea
authors.affiliation: Center for Preterm Birth Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, ML 7009, Cincinnati, OH 45229, United States. Electronic address: lisa.muglia@cchmc.org.
authors.forename: Lisa
authors.initials: L
authors.lastname: Muglia
authors.affiliation: Center for Preterm Birth Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, ML 7009, Cincinnati, OH 45229, United States. Electronic address: melinda.arnett@cchmc.org.
authors.forename: Melinda
authors.initials: M
authors.lastname: Arnett
authors.affiliation: Center for Preterm Birth Research, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, ML 7009, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, ML 7009, Cincinnati, OH 45229, United States. Electronic address: Louis.muglia@cchmc.org.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
mesh_terms: D000818:Animals; D018390:Gene Targeting; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D011965:Receptors, Glucocorticoid
keywords: Adrenocorticotropic hormone; Circadian regulation; Corticosterone; Corticotropin-releasing hormone; Glucocorticoid receptor; Hypothalamic–pituitary–adrenal axis; Metabolism; Paraventricular nucleus of the hypothalamus; Pituitary; Stress