Behavioral insights from mouse models of forebrain--and amygdala-specific glucocorticoid receptor genetic disruption

Abstract

Genetic modulation of glucocorticoid receptor (GR) function in the brain using transgenic and gene knockout mice has yielded important insights into many aspects of GR effects on behavior and neuroendocrine responses, but significant limitations regarding interpretation of region-specific and temporal requirements remain. Here, we summarize the behavioral phenotype associated with two knockout mouse models to define the role of GRs specifically within the forebrain and amygdala. We report that forebrain-specific GR knockout mice exhibit impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased despair- and anxiety-like behaviors. In addition, mice with a disruption of GR specifically within the central nucleus of the amygdala (CeA) are deficient in conditioned fear behavior. Overall, these models serve as beneficial tools to better understand the biology of GR signaling in the normal stress response and in mood disorders.

Figure 1. a & b. [GR expression in control and FBRKO mice]

GR immuno-reactivity (white nuclei) is detected throughout neuronal populations in control mice (a.), but is markedly reduced or absent in the cortex, basolateral nucleus of amygdala (BLA) and basomedial amygdala (BMA) in FBGRKO mice. Note that GR expression is intact in the CeA and thalamus of the FBGRKO mice. c. [Cre-recombinase and GR staining in CeAGRKO mice]. Immunohistochemistry showing Cre immunoreactivity 2 weeks after LV-Cre infection