Can maternal neurosteroid treatment prevent the adverse effects of prenatal stress on the offspring’s brain and behaviour?

Stress exposure during pregnancy negatively impacts upon fetal brain development and increases the susceptibility of the offspring to psychiatric disorders in later life. Our lab has developed a rat model of prenatal stress in which the adult offspring exhibit enhanced stress responses, heightened anxiety and cognitive deficits [1]. Neurosteroids, such as allopregnanolone are neuroprotective, positively influence mood and cognition and suppress stress axis (hypothalamo-pituitary-adrenal, HPA axis) responses [2]. We have shown reduced expression of 5α-reductase (the rate-limiting enzyme responsible for allopregnanolone synthesis) in the brains of adult prenatally stressed rats, indicating deficits in neurosteroid production [3]. In accordance, treating adult prenatally stressed rats with allopregnanolone or androstandiol (5α-reduced metabolite of testosterone) normalises HPA axis responses to stress and reverses the anxious phenotype [3]. These data indicate prenatal stress effects can be reversed in adulthood with neurosteroids; however it is not known whether maternal neurosteroid treatment can prevent the adverse effects of prenatal stress on the offspring’s brain and behaviour. This project will combine pharmacological, molecular and behavioural approaches to address this question. Specifically, we will investigate whether maternal administration of allopregnanolone or ganaxolone (a synthetic non-metabolisable analogue of endogenous allopregnanolone) during pregnancy prevents prenatal stress-induced changes in HPA axis function and/or anxiety-like behaviour in the offspring. Since the placenta plays a key role in maintaining elevated neurosteroid levels during pregnancy and glucocorticoid and stress exposure evidently disrupt neurosteroidogenesis we will also investigate the impact of maternal allopregnanolone or ganaxolone with and without stress exposure on the neurosteroidogenic capacity of the placenta and the fetal brain. In each case any sex-specific effects will also be examined.

Training/techniques: The project will involve in vivo rat experiments (including recovery surgery, blood sampling and behavioural assessments) as well as radioimmunoassay, in situ hybridisation, western blotting, PCR and HPLC/mass spectrometry, bioimaging and statistical analyses.

Funding: This project is eligible for a University of Edinburgh 3year PhD studentship or Principal’s Career Development Studentship. ( http://www.ed.ac.uk/schools-departments/student-funding/postgraduate/uk-eu/university-scholarships/development)

International students should also apply for an Edinburgh Global Research Studentship (http://www.ed.ac.uk/schools-departments/student-funding/postgraduate/international/global/research).

Applications including a statement of interest and full CV with names and addresses (including email addresses) of two academic referees, should be sent to: Liz Archibald, The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, EH25 9RG or emailed to [Email Address Removed].

When applying for the studentship please state clearly the title of the studentship and the supervisor/s in your covering letter.

All applicants should also apply through the University’s on-line application system for September 2017 entry via http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=832

Applicants for the Principal’s career development studentship must also complete the specific on-line application form at http://www.ed.ac.uk/schools-departments/student-funding/postgraduate/uk-eu/university-scholarships/development