Regulation of the hypothalamic-pitutary-adrenal axis by the glucocorticoid receptor and corticotropin-releasing hormone

Abstract

Stress often precipitates or exacerbates mental illness. The hypothalamic-pituitary-adrenal (HPA) axis is the canonical pathway that mediates an organism’s response to stress. Acute stress increases HPA axis activity, leading to short-term increases in plasma glucocorticoid (GC) levels. While short term increases in GC are beneficial because it prepares an organism to adequately respond to the stressor, long-term increases in GC results in damaging effects in the brain and periphery leading to disease. Effective negative feedback by GC acting on glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) and anterior pituitary is essential to prevent the deleterious effects of excess GC. In the first part of this dissertation, we investigate the effects of disrupted negative feedback at the level of the PVN on behavior and neuroendocrine activity. Using mice that express Cre-recombinase primarily in the PVN (Sim1Cre) in combination with floxed-GR mice, we delete GR specifically in the PVN. PVN GR deletion (Sim1Cre-GRe3Ä) disrupted negative feedback of GC secretion, and resulted in elevated morning and evening levels of GC in adult mice. There was also augmented stress-induced GC increases as a result of PVN GR loss in adult mice that did not occur during adolescent. In adolescence, we observed gender-specific differences in basal and stress-induced HPA axis regulation. Despite HPA axis hyperactivation and impaired negative feedback in adult Sim1Cre-GRe3Ä mice, basal anxiety and despair behavior were unaltered in adulthood, but we identified potential a gene x environment interactions that cause increased anxiety in Sim1Cre-GRe3Ä mice in an anxiogenic settings. HPA axis hyperactivity is associated with altered activity in limbic regions, such as increased mRNA levels of corticotropin-releasing hormone (CRH) in the central nucleus of the amygdala (CeA). In part 2 of this dissertation, we use lentivirus-induced overexpression of CRH in the CeA of adolescent mice in an effort to isolate the contributions of CeA CRH in the development of stress-related pathology. These studies provide evidence for the role of GR and CRH signaling in HPA axis and behavior regulation.