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Title: Brain programming effects of glucocorticoids : implications for behaviour
Author: Welberg, Leonie Anna Maria
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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We investigated the effect of bypassing (using dexamethasone, DEX) or inhibiting (using carbenoxolone, CBX) feto-placental 11b-HSD in rats, on subsequent offspring HPA axis regulation and stress-induced behaviour. Pregnant Wistar rats were injected with CBX, DEX or vehicle daily throughout pregnancy. A separate group received DEX injections in the last week of pregnancy only (DEX3), as this had previously been shown to contain the critical time window for programming of hypertension and hyperglycaemia. All treatments reduced birth weight (CBX 12%, DEX1-3 15%, DEX3 7%). This was reversed by 4 and 6 weeks of life in DEX3 and CBX offspring, respectively, while offspring of dams treated with DEX throughout pregnancy had reduced body weight throughout life (7% at 5 months of age). Prenatal exposure to glucocorticoids resulted in increased basal corticosterone (CORT) levels (CBX 0.70 mg/dl, DEX3 0.76 mg/dl, control 0.40 mg/dl) and a trend (p=0.07) towards increased corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) in adult offspring. In addition, CBX offspring had reduced PVN glucocorticoid receptor (GR) mRNA and a prolonged stress response. Hippocampal GR and mineralocorticoid receptor (MR) mRNA expression was reduced only in DEX3 offspring, which also showed increased CRH mRNA levels in PVN. CBX and DEX3 rats displayed impaired non-spatial learning. In addition, exploratory behaviour in an open field was affected by prenatal glucocorticoid exposure, especially in DEX3 offspring, which showed reduced locomotion and rearing. The behavioural alternations are associated with increased expression of MR, GR and CRH mRNAs in the amygdala, a structure implicated in the expression of fear and anxiety. These data suggest that disturbance of the feto-placental enzymatic barrier to maternal glucocorticoids, or in utero exposure to DEX, reduces birth weight and produces permanent subtle alterations of the HPA axis combined with behavioural inhibition or impaired coping in aversive situations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available