Defining brain region-specific glucocorticoid action during stress by conditional gene disruption in mice

The ability of an organism to adapt during stress has a significant impact on long-term survival and health. Maladaptive responses to stress have been associated with susceptibility to the development of mood disorders, including major depressive disorder (MDD) and generalized anxiety disorder. Importantly, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, the endocrine stress response, has been linked to these diseases. Here, we review recent data on the region-specific role of glucocorticoid receptor (GR) signaling in the behavioral, molecular and endocrine response to stress. Using a conditional deletion approach, we have shown that disruption of GR function in the forebrain of mice induces alterations in despair-like behavior and HPA axis function, reminiscent of MDD. Furthermore, in an effort to explore the sub-regional specificity of GR activity, we have developed a model to disrupt GR in the central nucleus of the amygdala. In our initial efforts to characterize these mice, we have demonstrated a critical role for GR in the formation of fear memory.