Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors

Abstract

The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.

Treatment-resistant depression: are animal models of depression fit for purpose?

“…Additional models include loss of GR in dorsal raphe neurons (DRNGRKO), associated with increased stress coping behaviour (Vincent and Jacobson 2014), or loss of GR in DA neurons, which induces some resilience when GR have been inactivated in DA-innervated postsynaptic neurons, but not when they have been inactivated on presynaptic DA neurons (Barik et al 2013). To our knowledge, out of all of the mutants so far mentioned, the effects of antidepressant treatments have only been investigated in the FBGRKO mice, revealing normal responses to acute or chronic antidepressants (Boyle et al 2005;Vincent et al 2013). Additionally, viral-induced knockdown of GR in the prefrontal cortex had no effect on corticosterone or behaviour in the FST but increased sensitivity to chronic imipramine (Hussain and Jacobson 2015).…”

Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress

“…The CA1 field of the ventral hippocampus was analyzed because GR are prominently expressed in CA1 of floxed GR but not FBGRKO-T29-1 mice (7, 8, 59), and because the ventral hippocampus has limbic connections that are both distinct from the connections of the dorsal hippocampus and relevant to emotion-related behavior (16, 17, 34). Induction of c-fos gene expression in CA1 ventral hippocampus did not differ significantly among groups of floxed GR mice, although c-fos tended to be lower ( P =0.054) in defeated vs. control floxed GR mice treated with imipramine (Figure 3, vHPC).…”

“…The original model of forebrain GR deletion, derived on a mixed-strain background from the T50 founder line of the CamKIIα-Cre transgene, was reported to have a depression-like phenotype, consisting of increased depression-like behavior and elevated HPA activity relative to that in floxed GR mice (7). However, this depression-like phenotype was not found in mice with forebrain GR deletion derived on a pure C57BL/6 background from the T29-1 founder line of the CamKIIα-Cre transgene, even though forebrain GR deletion was at least as extensive (59). The latter mouse model, hereafter referred to as FBGRKO-T29-1 (59), offers a convenient model to test the role of forebrain GR in the behavioral effects of chronic stress, without potential confounds from baseline differences in HPA activity or depression-like behavior.…”

“…However, this depression-like phenotype was not found in mice with forebrain GR deletion derived on a pure C57BL/6 background from the T29-1 founder line of the CamKIIα-Cre transgene, even though forebrain GR deletion was at least as extensive (59). The latter mouse model, hereafter referred to as FBGRKO-T29-1 (59), offers a convenient model to test the role of forebrain GR in the behavioral effects of chronic stress, without potential confounds from baseline differences in HPA activity or depression-like behavior. The current experiments compared the effects of repeated social defeat stress or control cage exposures, with and without antidepressant treatment, on depression-related behavior in FBGRKO-T29-1 mice and their genetic controls, floxed GR mice.…”

Behavioral effects of glucocorticoids during the first exposures to the forced swim stress

“…In addition, stress and glucocorticoids are capable of inducing changes in GR expression in the brain (Paskitti et al 2000;Reul et al 1989;Sapolsky and McEwen 1985;Wang et al 2012), which in turn could lead to alterations in the behavioral effects of the hormone. At the same time, the role of the GRs in the mechanisms of depressive-like behavior remains a matter of debate even after the precise conditional knockout of these receptors in the forebrain regions including hippocampus and prefrontal cortex crucially involved in mood regulation (Solomon et al 2012;Vincent et al 2013). A potentially confounding feature in knockout experiments is that GR signaling is impaired not only in the behavioral responses to stress but also in a broad range of all functions regulated by this pathway.…”