Abnormal corticosterone regulation in an immature rat model of continuous chronic stress

Abstract

Neuroendocrine correlates of chronic stress in human infants have not been established. The goal of the present study was to create an animal model of continuous chronic stress using the immature rat to measure basal plasma corticosterone, and secretion of plasma corticosterone in response to an acute stress. This was achieved by modulation of the cage environment for rat pups and their mothers. During postnatal days 2-9, pups were maintained in three groups: (1) handled, (2) not handled and with ample bedding; and (3) not handled with limited bedding. On postnatal day 9, some pups from each group were subjected to acute cold-separation stress and were killed 90, 240, or 360 min later along with unstressed controls. The group not handled and with limited bedding manifested increased plasma corticosterone output even without cold exposure and a sustained increase of plasma corticosterone after cold-separation stress. Plasma corticosterone interanimal variability was increased and body weight was decreased in these pups, typical of a state of chronic stress. The first model of continuous stress in infant rats in which upregulation of hypothalamic-pituitary-adrenal axis is achieved without maternal separation is presented. This paradigm may more closely approximate the human situation of chronically stressed, neglected infants.

Figure 1

(a) Plasma corticosterone (CORT) of the Three experimental groups under basal (undisturbed, and without cold stress) conditions. NHNB, nonhandled with no access to bedding. Values are mean ± SEM. The handled group was not examined at 360 min. (b) Integrated area under the curve representative of total CORT output over time. *P < 0.05 for (1) nonhandled vs. NHNB at 240 min, (2) handled time 0 vs. handled at 240 min; and (3) NHNB time 0 vs. NHNB at 240 min. **P < 0.01 for handled vs. NHNB at 240 min.

Figure 2

(a, b. and c) Cold-separation stress-induced plasma corticosterone (CORT) values as compared with those in nonstressed “controls” in handled animals (a), nonhandled animals (b), and (c) chronically stressed (nonhandled with no access to bedding, NHNB) experimental groups. Controls: no exposure to cold. (Scale is increased in 2c.) The magnitude of the stress response between groups attained significance only for the NHNB group versus the nonhandled group at 360 min (P < 0.05). *P < 0.05. **P < 0.01.

Figure 3

Interanimal variability of plasma corticosterone (CORT) in the three experimental groups: Basal (no cold-separation stress) state (a), after cold-separation stress (b).

Figure 4

Group weights of handled, nonhandled, and chronically stressed pups. A single group of handled pups was weighed; therefore, no SEM is shown. *P < 0.05.