Augmented hypothalamic corticotrophin-releasing hormone mRNA and corticosterone responses to stress in adult rats exposed to perinatal hypoxia

Abstract

Stressful events before or just after parturition alter the subsequent phenotypical response to stress in a general process termed programming. Hypoxia during the period before and during parturition, and in the postnatal period, is one of the most common causes of perinatal distress, morbidity, and mortality. We have found that perinatal hypoxia (prenatal day 19 to postnatal day 14) augmented the corticosterone response to stress and increased basal corticotrophin-releasing hormone (CRH) mRNA levels in the parvocellular portion of the paraventricular nucleus (PVN) in 6-month-old rats. There was no effect on the levels of hypothalamic parvocellular PVN vasopressin mRNA, anterior pituitary pro-opiomelanocortin or CRH receptor-1 mRNA, or hippocampus glucocorticoid receptor mRNA. We conclude that hypoxia spanning the period just before and for several weeks after parturition programmes the hypothalamic-pituitary-adrenal axis to hyper-respond to acute stress in adulthood, probably as a result of drive from the parvocellular CRH neurones.

Figure 1

Body weight at post-natal day (PD) 14–33, and at 5 and 6 months of age in rats exposed to perinatal normoxia vs. hypoxia from E19 (in utero) to PD14. N=7–8 per treatment group from 4 litters per treatment group. SEMs are smaller than the symbol size. Perinatal hypoxia body weights were significantly less than normoxic controls at each time point (P<0.001).

Figure 2

Left: Corticosterone response to restraint applied from 0–60 min in rats at 5–6 months of age. Rats were exposed to perinatal hypoxia (E19-PD14; N=18 from 7 litters) or normoxia (controls; N=15 from 6 litters). *different from 0 min; +different from normoxic control. Right: Integrated (area under curve minus baseline corticosterone) corticosterone response to restraint. *different from normoxia. (P<0.001)

Figure 3

Parvocellular CRH in the paraventricular nucleus of adult rats exposed to normoxia or perinatal hypoxia (E19-PD14) by in situ hybridization histochemistry (top). The image above is an example of a CRH mRNA histochemistry image from digitized images from x-ray films. N=5–6 brains per mean/ from 4 litters per mean. *different from normoxia (P<0.001).