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(BBSRC DTP) Epigenetic mechanisms of behavioural, placental and cognitive impairment in a neurodevelopmental model for schizophrenia

Project Description

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 the offspring developing cognitive disorders across the lifespan (Knuessel et al. 2014). It is most likely that this induces a vulnerability which leads to social stressors experienced during adolescence exacerbating an existing phenotype and neuropathology. Whether this relates to changes directly affecting brain development in utero, altered maternal behaviour, adolescent brain development or a combination of these, is unclear. Further, the mechanisms underlying such effects remain poorly defined.

Maternal stressors result in epigenetic modifications (DNA methylation and histone 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 (Akbarian 2014).

The placenta plays a crucial role in maternal-fetal interactions, the modulation of fetal adaptive responses 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. Recent genome-wide association studies have identified risk factor genes for schizophrenia which adversely affect placentation (Ursini et al. 2018) and a link between reduced placenta weight and increased risk for schizophrenia has been identified (Wahlbeck et al. 2001). We propose that epigenetic mechanisms mediate the effects of maternal stressors on placental function leading to altered brain development and later impaired cognitive development.

The proposed project capitalizes on our recently established rat model of maternal immune activation (Murray et al. 2019) and seeks to investigate epigenome-by-environment interactions that link to schizophrenia development. We will use a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological and functional development with fetal brain development and adolescent environmental conditions to offspring behavioural traits. Evaluation of placental morphological development and function, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in our rodent neurodevelopmental model of schizophrenia will be conducted. The project therefore offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses. This multidisciplinary project will suit candidates with relevant backgrounds who wish to apply their skills to a significant research question using cutting-edge technologies.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.


Akbarian, S. (2014). Epigenetic mechanisms in schizophrenia. Dialogues in Clinical Neuroscience 16(3): 405-417.

Estes, M. L. and A. K. McAllister (2016). Maternal immune activation: Implications for neuropsychiatric disorders. Science 353(6301): 772-777.

Knuessel, I. et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology 10:643-646.

Murray KN, Edye ME, Manca M, Vernon AC, Oladipo JC, Fasolino V, Harte MK, Mason V, Grayson B, McHugh PC, Knuessel I, Prinssen EP, Hager R, Neill JC. 2019. Evolution of a maternal immune (mIA) model in rats: early developmental effects. Brain, Behaviour, and Immunity 75:48-59.

Ursini, G., G. Punzi, et al. (2018). Placental gene expression mediates the interaction between obstetrical history and genetic risk for schizophrenia Convergence of placenta biology and genetic risk for schizophrenia. Nature Medicine 24:792-801.

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