Deletion of forebrain glucocorticoid receptors impairs neuroendocrine stress responses and induces depression-like behavior in males but not females

Abstract

Dysfunction in central glucocorticoid signaling is implicated in hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation and major depression. In comparison with men, women are twice as likely to suffer from depression and have heightened HPA axis responses to stress. We hypothesized that this striking increase in stress vulnerability in females may be because of sex differences in central glucocorticoid signaling. The current study tests the role of the forebrain type II glucocorticoid receptor (GR) on HPA axis function in female mice and depression-like behavior in both female and male mice. This was accomplished by using mice with selective deletion of GR in forebrain cortico-limbic sites including the prefrontal cortex, hippocampus, and basolateral amygdala (forebrain glucocorticoid receptor knockout mouse (FBGRKO)). In order to examine HPA axis function in female FBGRKO, we measured nadir, peak circadian and restraint-induced corticosterone concentrations in female FBGRKO. The data indicate that unlike male FBGRKO, basal and stress-induced corticosterone concentrations are not increased in female FBGRKO. Given the pronounced effect of central glucocorticoid signaling on mood, we also examined the necessity of corticolimbic GR on depression-like behavior with the sucrose preference and forced swim tests (FST) in male and female FBGRKO mice. Consistent with previous studies, male FBGRKO displayed increased depression-like behavior as indicated by greater immobility in the FST and decreased sucrose preference compared with littermate controls, effects that were not observed in females. Overall the findings indicate a marked sex difference in the function of forebrain GR on HPA axis regulation and depression-like behaviors, and may have implications for therapeutic approaches using GR-modulating drugs.

Figure 1

Expression of GR in female mice. GR immunoreactivity in the CeA (A and B), PVN (C and D), medial prefrontal cortex (E and F) hippocampus (G and H), and basolateral amygdala of female littermate control (A, C, E, G and I) and FBGRKO (B, D, F, H and J) mice.

Figure 1

Expression of GR in female mice. GR immunoreactivity in the CeA (A and B), PVN (C and D), medial prefrontal cortex (E and F) hippocampus (G and H), and basolateral amygdala of female littermate control (A, C, E, G and I) and FBGRKO (B, D, F, H and J) mice.

Figure 2

(A) Nadir and peak corticosterone concentrations in male FBGRKO and littermate controls previously published in (Furay et al., 2008). Male FBGRKO have significantly elevated nadir corticosterone concentrations (p <0.05) relative to male littermate controls. There are no differences in peak corticosterone concentrations between male FBGRKO and littermate controls (p >0.05). (B) There is no difference in nadir or peak corticosterone concentrations between female FBGRKO and littermate controls (ps > 0.05) (n=11–12). **Although the basal neuroendocrine data from the males was previously published, the female and males were from the same study. As such, the data for the males is included for a side by side comparison.

Figure 3

(A) Plasma corticosterone concentrations in response to a 30-min restraint in male FBGRKO and littermate controls previously published (Furay et al., 2008). Male FBGRKO have significantly lower corticosterone at 30 min and significantly higher corticosterone concentrations at 120 min time points relative to male littermate controls (ps<0.05) and (B) female control and FBGRKO mice. Unlike male FBGRKO, there is no difference in restraint-induced corticosterone concentrations at the 30 or 120 min time points between FBGRKO female mice (p >0.05). All analyses were conducted such that the relative effect of the loss of forebrain GR was only examined within the same sex (n=11–12). **Although the stress-induced neuroendocrine data from the males was previously published, the female and males were from the same study. As such, the data for the males are included for a side by side comparison.

Figure 4

FST Behavioral Analyses. (A) Male FBGRKO mice are significantly more immobile compared to male controls (*p <0.05). (B) In contrast, female FBGRKO and control female mice do not differ in their display of immobility (p >0.05). (C) There was no significant difference in swimming between male FBGRKO and their respective controls (p >0.05). (D) However, there was a trend for female FBGRKO mice to swim more compared with their respective controls (p=0.07). (E) Male FBGRKO displayed less climbing than male controls (*p<0.05). (F) There was a trend for female FBGRKO to display less climbing compared with their respective controls (p =0.07). All analyses were conducted such that the relative effect of the loss of forebrain GR was only examined within the same sex (n=7–8).

Figure 5

Sucrose Consumption and Preference. (A) Male FBGRKO had decreased sucrose preference compared with male controls (p <0.05). (B) Female FBGRKO do not differ from their respective controls in with regards to sucrose preference (p >0.05). All analyses were conducted such that the relative effect of the loss of forebrain GR was only examined within the same sex (n=7–8).