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.

Keywords: Adrenocorticotropic hormone; Circadian regulation; Corticosterone; Corticotropin-releasing hormone; Glucocorticoid receptor; Hypothalamic–pituitary–adrenal axis; Metabolism; Paraventricular nucleus of the hypothalamus; Pituitary; Stress.

Figure 1. Glucocorticoid Receptor Expression in Genetic Mouse Models

Sagittal brain sections depicting areas of GR mRNA expression and deletion in mice with targeted GR deletion. Orange circles (●) represent GR and targeted regions are in yellow highlight and blue font. A. Adult control mice ubiquitously express GR mRNA in the entire brain and pituitary, with higher expression in limbic regions. B. Adult GR^NesCre mice have GR loss in the entire brain, neurons and glial cells. C. FBGRKO mice have GR loss in forebrain neurons during adulthood. D. At postnatal day 6 GR expression is low and limited to few brain region (blue font). GR^CaMKCre mice have GR loss in most of the neurons in brain and cells in the pituitary at P6. E. Adult Sim1Cre-GRe3Δ mice have GR loss primarily in PVN neurons. F. GR^POMCCre mice have GR loss in the anterior pituitary cells throughout life. Abbreviations: Anterior pituitary, A Pit; Basolateral nucleus of the amygdala, BLA; Bed nucleus of the stria terminalis, BnST; Central nucleus of the amygdala, CeA; Hippocampal areas, CA1, CA2, CA3; Cerebellum, Cereb; Cingulate cortex, Cing Ctx; Dentate gyrus, DG; Frontal cortex, Fr Ctx; Inferior colliculus, InfC; Locus coeruleus, LC; Medial nucleus of the amygdala, MeA; Occipital cortex, Occ Ctx; Periaqueductal gray, PAG; Parietal cortex, Par Ctx; Paraventricular hypothalamic nucleus, PVN; Raphe nucleus, RN; Septum, Sep; Supraoptic nucleus, SN; Superior colliculus, SupC; Thalamus, Thal;

Figure 2. Schematic of CORT levels in GR-targeted Mice

This figure depicts the relative increases in plasma CORT levels in GR^NesCre, GR^CaMKCre, GR^POMCCre, and Sim1Cre-GRe3Δ compared to controls at postnatal day 6 and in adulthood. Values on the y-axis represent estimates of plasma CORT values provided from respective articles. Controls are averaged values from individual studies.