Hypoactivity of the hypothalamo-pituitary-adrenocortical axis during recovery from chronic variable stress

Abstract

Chronic stress induces both functional and structural adaptations within the hypothalamo-pituitary-adrenocortical (HPA) axis, suggestive of long-term alterations in neuroendocrine reactivity to subsequent stressors. We hypothesized that prior chronic stress would produce persistent enhancement of HPA axis reactivity to novel stressors. Adult male rats were exposed to chronic variable stress (CVS) for 1 wk and allowed to recover. Plasma ACTH and corticosterone levels were measured in control or CVS rats exposed to novel psychogenic (novel environment or restraint) or systemic (hypoxia) stressors at 16 h, 4 d, 7 d, or 30 d after CVS cessation. Plasma ACTH and corticosterone responses to psychogenic stressors were attenuated at 4 d (novel environment and restraint) and 7 d (novel environment only) recovery from CVS, whereas hormonal responses to the systemic stressor were largely unaffected by CVS. CRH mRNA expression was up-regulated in the paraventricular nucleus of the hypothalamus (PVN) at 16 h after cessation of CVS, but no other alterations in PVN CRH or arginine vasopressin mRNA expression were observed. Thus, in contrast to our hypothesis, reductions of HPA axis sensitivity to psychogenic stressors manifested at delayed recovery time points after CVS. The capacity of the HPA axis to respond to a systemic stressor appeared largely intact during recovery from CVS. These data suggest that chronic stress selectively targets brain circuits responsible for integration of psychogenic stimuli, resulting in decreased HPA axis responsiveness, possibly mediated in part by transitory alterations in PVN CRH expression.

Fig. 1

Timeline of experimental procedure. Rats arrived and acclimated to the animal colony for 1 wk before the onset of the CVS protocol. Rats were exposed to CVS for 1 wk or remained undisturbed in their home cages as unhandled controls. Independent groups of control or chronically stressed rats were given an acute stress challenge (novel environment, restraint, or hypoxia exposure) after 16 h, 4 d, 7 d, or 30 d recovery from chronic stress.

Fig. 2

Chronically stressed rats tested at 16 h recovery exhibit transient augmentation of plasma ACTH, whereas chronically stress rats challenged at 7 d recovery exhibit an attenuated plasma ACTH response to novel environment exposure. Plasma ACTH levels at 20, 40, and 60 min after the end of a 5-min exposure to a novel environment at 16 h (A), 4 d (B), 7 d (C), or 30 d (D) recovery from CVS. Values represent mean ± sem; n = 6 per group. *, P < 0.05 vs. control group.

Fig. 3

Chronically stressed rats tested at 4 d and 7 d recovery exhibit an attenuated plasma corticosterone response to novel environment exposure. Plasma corticosterone levels at 20, 40, and 60 min after the end of a 5 min exposure to a novel environment at 16 h (A), 4 d (B), 7 d (C), or 30 d (D) recovery from CVS. Values represent mean ± sem; n = 6 per group. *, P < 0.05 vs. control group.

Fig. 4

Chronically stressed rats tested at 16 h recovery exhibit slightly lower plasma ACTH levels than controls 20 min after placement into a hypoxia chamber, whereas chronically stressed rats tested at 7 d recovery exhibit higher plasma ACTH levels. Plasma ACTH levels at 20, 40, and 60 min after placement into the hypoxia chamber at 16 h (A), 4 d (B), 7 d (C), or 30 d (D) recovery from CVS. Values represent mean ± sem; n = 6 per group. *, P < 0.05 vs. control group.

Fig. 5

Plasma corticosterone levels in chronically stressed rats do not differ from controls after placement into a hypoxia chamber. Plasma corticosterone levels at 20, 40, and 60 min after placement into the hypoxia chamber at 16 h (A), 4 d (B), 7 d (C), or 30 d (D) recovery from CVS. Values represent mean ± sem; n = 6 per group.

Fig. 6

CRH mRNA expression in the PVN is up-regulated 16 h after CVS cessation, but no alterations are observed at any other recovery time point. AVP mRNA expression in the parvocellular PVN is not altered by prior CVS exposure. Semiquantitative analysis of CRH (A) and AVP (B) mRNA expression. Values represent mean ± sem; n = 6–12 per group. *, P < 0.05 vs. control group.

Fig. 7

Chronically stressed rats tested at 4 d recovery exhibit an attenuated plasma ACTH response 30 min after novel restraint stress challenge. Plasma ACTH levels could not be determined at 16 h or 30 d recovery due to technical difficulties with the ACTH assay. Plasma ACTH levels at 0, 30, 60, and 120 min after placement into plastic restrainers for 30 min at 4 d (A) or 7 d (B) recovery from CVS. Values represent mean ± sem; n = 8 per group. *, P < 0.05 vs. control group.

Fig. 8

Chronically stressed rats tested at 4 d recovery exhibit an attenuated plasma corticosterone response 30 and 60 min after novel restraint stress challenge. Plasma corticosterone levels at 0, 30, 60, and 120 min after placement into plastic restrainers for 30 min at 16 h (A), 4 d (B), 7 d (C), or 30 d (D) recovery from CVS. Values represent mean ± sem; n = 8 per group. *, P < 0.05 vs. control group.