Edinburgh Research Explorer

SEX-DEPENDENT OVERWRITING OF PRENATALLY PROGRAMMED STRESS RESPONSES IN RATS WITH NEUROACTIVE STEROIDS

Research output: Contribution to conferencePoster

Related Edinburgh Organisations

Original languageEnglish
Publication statusUnpublished - 2013
Event5th Parental Brain Conference - Regensburg, Germany
Duration: 11 Jul 201314 Jul 2013

Conference

Conference5th Parental Brain Conference
CountryGermany
CityRegensburg
Period11/07/1314/07/13

Abstract

Maternal social stress exposure during pregnancy results in enhanced hypothalamo-pituitary-adrenal (HPA) axis responses to stress in the male and female adult offspring.
Here we tested whether the 5α-reduced (5αR) metabolites of progesterone (allopregnanolone) and testosterone (androstandiol) can normalise HPA responses in prenatally stressed (PNS) rats. Allopregnanolone normalised ACTH responses to interleukin-1β (IL-1; a potent activator of the HPA axis) in PNS females, but not PNS males. However, androstandiol reversed the hyperactive HPA response in PNS males. Next we measured central allopregnanolone levels as an indicator of central 5αR activity. Allopregnanolone levels were significantly lower in hypothalamic, midbrain and whole brain homogenates from male PNS rats compared with controls; however this effect was not observed in PNS females. To further examine a role for reduced capacity for central neurosteroid production in PNS rats we quantified 5αR mRNA expression by in situ hybridisation. In males, PNS was associated with reduced expression of 5αR mRNA in brain regions that provide excitatory drive to the HPA axis (PVN and nucleus tractus solitarii; NTS). Conversely, 5αR mRNA was significantly increased in PNS males in limbic areas that exert an inhibitory influence over HPA axis activity (medial prefrontal cortex and the dorsal part of the lateral septum). In PNS females, 5αR mRNA expression was significantly reduced compared with controls only in the NTS.
Next, we hypothesised that up-regulation of 5αR expression in the NTS would reverse the hyperactive HPA axis responses to IL-1β in PNS rats. Adenovirus (AdV)-mediated gene transfer to up-regulate expression of 5αR and 3αHSD in the NTS normalised HPA axis responses in female PNS rats. Hence, 5-reduced steroids can over-write programming of hyperactive HPA axis responses to immune challenge, in PNS rats. Evidently, down-regulation of neurosteroid production in the brain underlies, at least in part, HPA axis hyper-responsiveness in PNS offspring. [Funding: BBSRC/CAPES]

Event

5th Parental Brain Conference

11/07/1314/07/13

Regensburg, Germany

Event: Conference

ID: 8543791