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. 2015 Aug;156(8):2843-53.
doi: 10.1210/en.2015-1276. Epub 2015 Jun 5.

Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice

Matia B Solomon  1 , Matthew Loftspring  1 , Annette D de Kloet  1 , Sriparna Ghosal  1 , Ryan Jankord  1 , Jonathan N Flak  1 , Aynara C Wulsin  1 , Eric G Krause  1 , Rong Zhang  1 , Taylor Rice  1 , Jessica McKlveen  1 , Brent Myers  1 , Jeffrey G Tasker  1 , James P Herman  1
Affiliations

Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice

Matia B Solomon et al. Endocrinology. 2015 Aug.

Abstract

Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism.

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Figures

Figure 1.
Figure 1.
Photomicrographs of coronal forebrain sections illustrating expression of GR immunoreactivity in the PVN of GRflox/floxSim1cre− control (n = 8) (A) and GRflox/floxSim1cre+ PVN GR KD representative male mice (n = 8) (B). C, Male GRflox/floxSim1cre+ PVN GR KD mice have significantly less GR immunoreactivity in the PVN compared with GRflox/floxSim1cre− control mice; P < .05. Photomicrographs of NeuN immunoreactivity in the PVN of GRflox/floxSim1cre− control (D) and PVN GR KD male mice (E). F, GRflox/floxSim1cre+ PVN GR KD mice have similar NeuN immunoreactivity in the PVN compared with GRflox/floxSim1cre− control mice; P > .05. Scale bar, 50 μm. Data are represented as mean ± SEM.
Figure 2.
Figure 2.
Photomicrographs of coronal forebrain sections illustrating expression of GR in the medial prefrontal cortex (A and B), hippocampus (C and D), and amygdala (E and F) in GRflox/floxSim1cre− control (n = 8) and GRflox/floxSim1cre+ PVN GR KD male mice (n = 9), respectively. GRflox/floxSim1cre+ PVN GR KD and GRflox/floxSim1cre− control mice have similar GR immunoreactivity within these forebrain regions. Scale bar, 50 μm. fmi, forceps minor.
Figure 3.
Figure 3.
A, Male GRflox/floxSim1cre+ PVN GR KD mice (n = 9) have similar pituitary GR mRNA expression relative to GRflox/floxSim1cre− control mice (n = 7); P > .05. B, Female GRflox/floxSim1cre+ PVN GR KD mice (n = 8) have similar pituitary GR mRNA expression relative to GRflox/floxSim1cre− control mice (n = 8); P > .05. Data were normalized to the housekeeping gene L32 and expressed as percentage of control mice (GR flox). Data are represented as mean ± SEM.
Figure 4.
Figure 4.
Nadir and peak corticosterone concentration in (A) male GRflox/floxSim1cre− control (n = 8) and GRflox/floxSim1cre+ PVN GR KD male mice (n = 9) and (B) female GRflox/floxSim1cre− control (n = 14) and GRflox/floxSim1cre+ PVN GR KD female mice (n = 15). There is no difference in circadian rhythmicity of corticosterone between male GRflox/floxSim1cre+ PVN GR KD and GRflox/floxSim1cre− male control mice; P > .05. However, female GRflox/floxSim1cre+ PVN GR KD have significantly higher morning corticosterone concentrations relative to control female mice; P < .05. Data are represented as mean ± SEM.
Figure 5.
Figure 5.
Plasma ACTH responses to an acute restraint challenge at 15 minutes after restraint onset in (A) male GRflox/floxSim1cre− control mice (n = 9) and male GRflox/floxSim1cre+ PVN GR KD mice (n = 10) and (B) female GRflox/floxSim1cre− control (n = 10) and female GRflox/floxSim1cre+ PVN GR KD mice (n = 10). Male GRflox/floxSim1cre− PVN GR KD mice secreted significantly more ACTH in response to restraint stress compared with GRflox/floxSim1cre− control mice; P < .05., Female GRflox/floxSim1cre− PVN GR KD mice secrete significantly less ACTH in response to restraint stress compared with female GRflox/floxSim1cre− control mice; P < .05. Data are represented as mean ± SEM.
Figure 6.
Figure 6.
Time-course (A) and integrated (B) corticosterone response to a 30-minute restraint challenge in male GRflox/floxSim1cre− control (n = 17) and male GRflox/floxSim1cre+ PVN GR KD male mice (n = 14). Time-course (C) and integrated area under the curve (AUC) (D) corticosterone response in female GRflox/floxSim1cre− control (n = 15) and female GRflox/floxSim1cre+ PVN GR KD mice (n = 16). Male GRflox/floxSim1cre+ PVN GR KD mice secrete significantly more corticosterone at the 60-minute time point relative to male GRflox/floxSim1cre− control mice; P < .05. Male GRflox/floxSim1cre+ PVN GR KD mice also have a higher integrated stress response to restraint stress relative to control GRflox/floxSim1cre− mice; P < .05. Female GRflox/floxSim1cre+ PVN GR KD mice have significantly higher basal corticosterone (0 min) relative to female GRflox/floxSim1cre− control mice; P < .05. Integrated corticosterone response to an acute restraint challenge is similar in control and PVN GR KD female mice. Data are represented as mean ± SEM.
Figure 7.
Figure 7.
Time-course (A) and integrated area under the curve (AUC) (B) corticosterone response to a novel stressor (forced swim test) after a history of chronic stress exposure in male GRflox/floxSim1cre−control (n = 13) and male GRflox/floxSim1cre+ PVN GR KD mice (n = 15). Time-course (C) and integrated (D) stress response to forced swim test after a history of chronic stress in female GRflox/floxSim1cre−control (n = 12) and female GRflox/floxSim1cre+ PVN GR KD (n = 12) mice. Data are represented as mean ± SEM.
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