Understanding neural circuit dysfunction in polycystic ovary syndrome (PCOS)
Supervisor:Prof. Allan Herbison
Second Supervisors DepartmentWellcome Trust Sanger Institute
Web Page: https://www.pdn.cam.ac.uk/
Approximately one in five women in the UK suffer from polycystic ovary syndrome (PCOS) a condition typified by problems with fertility, high androgen levels, and altered metabolism. Accruing clinical and biomedical evidence indicate that over-activity of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator has a major role in generating the sub-fertility of women with PCOS. The GnRH pulse generator is responsible for driving the pulsatile release of reproductive hormones in the general circulation that control ovarian function (Herbison, Nature Endo Revs 2016). Recent studies involving the real-time imaging of neural activity in genetic mouse models have revealed that a population of kisspeptin neurons located in the arcuate nucleus (ARN) of the hypothalamus is the long-sought “GnRH pulse generator” (Clarkson et al., PNAS, 114, 2017).
This project aims to characterise the properties and activity of the ARN kisspeptin neurons in a well-established mouse model of PCOS. Female embryos exposed to high levels of androgen in utero develop a PCOS phenotype with abnormally fast GnRH pulses and disordered fertility. The candidate will start by using Cre-dependent adeno-associated viruses in Kiss1-Cre transgenic mouse lines to express the calcium indicator GCaMP selectively in ARN kisspeptin neurons (Han et al., Endocrinology 159, 2018). The on-going activity of this population of cells will then be measured using GCaMP fibre photometry in conscious freely-behaving mice to assess the characteristics of the pulse generator in PCOS mice. Subsequent studies will use the same mouse model to undertake single-cell RNAseq analyses of differential gene expression in ARN kisspeptin neurons from normal and PCOS mice. Finally, the candidate will examine the effects on GnRH pulse generation and fertility of modulating one or two selected genes specifically in ARN kisspeptin neurons using in vivo CRISPR gene editing. The PhD student in this project will join a dynamic team of multi-disciplinary neuroscientists and receive training in cutting-edge circuit neuroscience approaches at systems, cellular and molecular levels.
Primarily due to the unknown aetiology of the disorder, rather limited strategies are available for treating PCOS and, worldwide, these are administered with little consensus. Fertility medications are typically not effective and some women in the UK are still treated with “ovarian drilling” a laproscopic procedure of no empirical biomedical basis in which parts of the ovary are randomly destroyed. Most couples resort to in vitro fertilisation (IVF) when wishing to have a family. The infertility itself creates a huge psychosocial stress on the couple and associated family, while the need for treatment and IVF creates a substantial economic burden on the health system. It is estimated that there are 3.5 million women in the UK with PCOS.
This project represents a fundamental biomedical discovery project aimed at investigating the biological basis of the disordered pulse generator underlying infertility in PCOS. A well characterised mouse model of PCOS exists with elevated pulsatile luteinizing hormone secretion (an index of the GnRH pulse generator). Using the latest neuroscience approaches, the student will characterise the molecular and physiological properties of the pulse generator in this mouse model and attempt to restore hormonal pulsatility to normal. This will provide insight into the molecular aetiology of disordered pulsatile hormone secretion in PCOS and, potentially, lay the foundations for opening up new therapeutic opportunities in the clinic.