5-reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats

Maternalsocialstressduringlatepregnancyprogramshypothalamo-pituitary-adrenal(HPA)axishyper-responsivenesstostressors,suchthatadultprenatallystressed(PNS)offspringdisplayexaggeratedHPAaxisresponsestoaphysicalstressor(systemicinterleukin-1 (cid:3) ; IL-1 (cid:3) ) in adulthood, compared with controls. IL-1 (cid:3) acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3 (cid:3) -androstanediol(3 (cid:3) -diol;5 (cid:2) -reducedmetabolitesofprogesteroneandtestosterone,respectively)weregivensubacutely(over24h)toPNSrats to seek reversal of the “programmed” hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1 (cid:3) (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3 (cid:3) -diol normalized HPA axis responses to IL-1 (cid:3) in PNS males. Impairedtestosteroneand progesteronemetabolismorincreasedsecretioninPNSratswasindicatedbygreaterplasmatestosteroneandprogesteroneconcentrationsinmaleandfemalePNSrats,respectively.Deficitsincentralneurosteroidproductionwereindicatedbyreduced5 (cid:2) -reductasemRNAlevelsinbothmaleandfemale PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5 (cid:2) reductaseand3 (cid:2) -hydroxysteroiddehydrogenasemRNAsintheNTS,andthisnormalizedhyperactiveHPAaxisresponsestoIL-1 (cid:3) .Thus,downregu-lationofneurosteroidproductioninthebrainmayunderlieHPAaxishyper-responsivenessinprenatallyprogrammedoffspring,andadministrationof5 (cid:2) -reducedsteroidsacutelytoPNSratsoverridesprogrammingofhyperactiveHPAaxisresponsestoimmunechallengeinasex-dependentmanner.

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