Dysfunction of the hypothalamic-pituitary-adrenal axis in male rat offspring with prenatal food restriction: Fetal programming of hypothalamic hyperexcitability and poor hippocampal feedback

Abstract

Prenatal food restriction (PFR) induces dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis in the adult offspring. The aim of the present study was to identify the underlying mechanism of this process. Pregnant rats were placed on a restricted diet between gestational day 11 and 21. The offspring were fed with a high-fat diet and were subjected to unpredictable chronic stress (UC S) from postnatal week 17 to 20. A higher serum corticosterone (COR T) level was observed in the PFR fetuses. Although lower arginine vasopressin (AVP), hippocampal vesicular glutamate transporter 2 (vGLU T2) and glutamic acid decarboxylase 65 (GAD 65) mRNA expression levels were detected in the hippocampi of PFR fetuses, the ratio of the mRNA expression levels of vGLU T2 and GAD 65 was higher compared with that of the controls, which was accompanied by histopathological and ultrastructural abnormalities of both the hypothalamus and hippocampus. However, there were no marked changes in the hippocampal expression levels of glucocorticoids receptor (GR) and mineralocorticoids receptor (MR) or the ratio of MR/GR ratio. After the fetuses had matured, lower serum COR T and adrenocorticotropic hormone (AC TH) levels were observed in PFR rats without UC S when compared with the control. A higher rise rate of serum AC TH was also observed after UC S when compared with that in rats without UC S. Furthermore, the hypothalamic mRNA expression level of corticotrophin-releasing hormone (CR H) was lower in PFR rats without UC S, while expression levels of CR H, AVP, GAD 65 and vGLU T2 were enhanced after UC S when compared with the control, accompanied by an increased vGLU T2/GAD 65 expression ratio. MR mRNA expression was lower, and GR mRNA expression was higher in the hippocampus of the PFR rats without UC S when compared with the control. However, the mRNA expression levels of both MR and GR in the PFR rats were higher compared with those of the control after UC S, which was accompanied histopathological changes in the dentate gyrus, cornu ammonis (CA 1) and CA 3 areas. In summary, it was suggested that PFR induced fetal alterations of the HPA axis manifesting as hypothalamic hyperexcitability and poor hippocampal feedback, which persisted to adulthood and affected the behavior of the rat offspring.