Social stress during pregnancy programs the central neurosteroid system and hypothalamo-pituitary-adrenal (HPA) axis stress responses of the offspring

Exposure to stress during pregnancy can programme adult hypothalamo-pituitary-adrenal (HPA) axis responses to stress. In rats, prenatal social stress (PNS; 10 min/day on gestational days 16-20) results in exaggerated HPA responses to an acute stressor in the adult offspring.
Neurosteroids can reduce HPA responses and we previously found that peripheral administration of the 5alpha-reduced metabolites of testosterone (androstandiol) or progesterone (allopregnanolone) reverse the hyper-responsive HPA phenotype in male and female PNS offspring, respectively. Here we tested whether PNS rats have deficits in central neurosteroid production. We quantified mRNA expression for 5α-reductase (5alphaR) in the central nervous system of control and PNS, male and female rats by in situ hybridisation and measured allopregnanolone concentrations in brain homogenates of hypothalamus and midbrain by radioimmunoassay.
5alphaR mRNA levels were significantly lower in the nucleus tractus solitarii (NTS) of both male and female PNS rats compared with controls. 5alphaR mRNA was also reduced in the paraventricular nucleus (PVN) of the PNS males, however there was no change in PNS females. Allopregnanolone concentrations were significantly lower in the hypothalamus and midbrain of PNS males. In females there was no difference in allopregnanolone levels in the midbrain, however there was a significant increase in the hypothalamus of PNS females compared with controls.
Next, we injected adenoviral vectors (AdV-5alphaR) to up-regulate 5alphaR (and 3alpha-hydroxysteroid dehydrogenase, 3alphaHSD) mRNA expression, or control AdV (AdV-eGFP) into the NTS. Nine days later control and PNS female rats were blood sampled pre- and post interleukin-1β (IL-1B, 500ng/kg iv). IL-1B increased plasma ACTH levels in control offspring, but responses were greater in PNS/sham (AdV-eGFP) offspring. AdV-5alphaR treatment increased 5alphaR and 3alphaHSD mRNA in the NTS and normalised HPA axis hyper-responses in the PNS rats. Hence, down-regulation of neurosteroid production in the brainstem may explain HPA axis hyper-responsiveness in prenatally programmed offspring.
Support: BBSRC/CAPES