A fundamental unknown in understanding mechanisms of disease, and therefore improving therapy, is how stressors experienced during critical developmental periods influence the genesis or ‘programming’ of adult disease (Estes & McAllister 2016). In particular, stressors experienced during pregnancy may increase the likelihood of offspring developing cognitive disorders across their lifespan (Knuesel et al. 2014). Whether this is due to changes directly affecting brain development in utero, altered maternal care behaviour, adolescent brain development or a combination of these, is unclear, and the mechanistic pathways underpinning affected traits remain poorly defined.
Maternal stressors result in epigenetic modifications in placental tissue and offspring brain and are likely to be key candidate mechanisms leading to altered gene expression and thus developmental changes in the brain resulting in cognitive and behavioural disturbances (Woods et al. 2021).
The placenta plays a crucial role in maternal-fetal interactions. Modulation of fetal adaptive responses, contributed to by changes in placental function (Ursini et al. 2018; Kowash et al. 2022), may lead to an increased susceptibility to development of neuropsychiatric disease later in life. Placental development is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. We have recently established a link between reduced placenta weight, dysfunctional amino acid transport and increased risk for neurodevelopmental disease (e.g. schizophrenia), associated with altered fetal brain growth (Kowash et al. 2022). We propose that epigenetic mechanisms mediate the effects of maternal stressors, such as infection during pregnancy, on placental function leading to altered brain development and later impaired cognitive development.
The proposed project capitalizes on our recently established neurodevelopmental rat model of maternal immune activation (Murray et al. 2019, Kowash et al. 2022), seeking to investigate prenatal effects of maternal immune activation on placental function and fetal neurodevelopment and the mechanisms that link to dysfunctional adult behavioural and cognitive phenotypes reminiscent of schizophrenia. We will use multidisciplinary approaches to map functional changes along a developmental timeline that links placental function with fetal brain development and adolescent environmental conditions to offspring behavioural traits. Evaluation of placental development and function, molecular array studies, epigenomic, histological and functional analyses in brain together with behavioural interactions, cognitive and behavioural analyses in our rodent neurodevelopmental model will be conducted. The project offers broad scientific training covering mammalian disease and neurobehavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses. This multidisciplinary project offers candidates multiple skills to investigate a significant research question using cutting-edge technologies.
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
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