Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria‐like behavior and impairs hypothalamic‐pituitary‐adrenocortical axis feedback inhibition

Abstract

Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Since we previously showed that antidepressants used to treat depression and anxiety decrease DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic- and antidepressant-like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic pituitary adrenal (HPA) axis. Adeno-associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP (DRN-GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 10d of social defeat or control handling and tested for anxiety-like behavior (open field test, elevated plus maze), depression-like behavior (sucrose preference, forced swim test (FST), tail suspension (TST)), social interaction, and circadian and stress-induced HPA activity. DRN GR deletion decreased anxiety-like behavior in control but not in defeated mice. DRN GR deletion decreased FST and tended to decrease TST despair-like behavior in both control and defeated mice, but did not affect sucrose preference. Exploration of social (a novel mouse) as well as neutral targets (an empty box) was increased in DRNGRKO mice, suggesting that DRN GR deletion also promotes active coping. DRN GR deletion increased stress-regulated HPA activity without strongly altering circadian HPA activity. We have shown a novel role for DRN GR to mediate anxiety- and despair-like behavior and to regulate HPA negative feedback during acute stress.

Enhancement of Stress Resilience Through Histone Deacetylase 6–Mediated Regulation of Glucocorticoid Receptor Chaperone Dynamics

“…Our observation that the HDAC6 inhibitor ACY-738 restores social approach behaviors without changing peripheral hormone responses in the DEX/CRF test suggests that circuits mediating ACY-738 GR-dependent action are dissociable from those involved in GR-mediated regulation of peripheral glucocorticoids. This view is in line with recent observations indicating that ablation of GR in dopaminergic and serotonergic systems enhances socioaffective responses without major effects on regulation of stress-induced hormone responses (64; 65). …”

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

“…Further, the GR NesCre and Sim1Cre-GRe3D mice show increased corticosterone levels after stress (Laryea et al 2015). 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).…”

Dissection of glucocorticoid receptor-mediated inhibition of the hypothalamic–pituitary–adrenal axis by gene targeting in mice

“…But recent findings show that GR in DR serotonergic neurons also is critical for modulating the effects of stress. Vincent and Jacobson have shown that deletion of GR in DR neurons (DRNGRKO) does not affect basal HPA axis activity, but decreases anxiety and behavior and caused increased stress coping behavior (Vincent and Jacobson, 2014). Upon application of an acute stressor, plasma CORT is increased in DRNGRKO mice, demonstrating stress reactivity.…”