Understanding signalling by a novel hormone receptor in the brain

"Our laboratory is interested in how hormones, in particular oestrogen, signal and how this signal drives social behaviours in animals. Signaling by oestrogens in the brain is known to be critical for several social behaviours that differ between males and females. One such social behaviour is reproductive behaviour or sex behaviour that is critically dependent on estrogen acting in the hypothalamus. What are the molecular mechanisms that oestrogen uses to drive these behaviours? Apart from the traditional view that these hormones act via gene transcription in cells by binding nuclear receptors such as the oestrogen receptor  or  (ER or ER), they can also signal via non-classical rapid ways such as kinase activation and changes in calcium levels. Such non-classical signaling is initiated by a membrane oestrogen receptor (mER) whose identity is currently unknown. One candidate for the mER that is capable of rapidly signaling in neuronal cells and that can bind oestrogen is a fairly recently discovered G-protein coupled receptor called GPR30 or GPER1. We have shown that GPR30 in the female mouse is required for the optimal expression of a behaviour known to be critically dependent on oestrogen signaling i.e. reproductive behaviour. We also showed that it can decrease anxiety in female mice when administered over long periods of time. However, much about this receptor in the brain remains unknown and hence this is a field ripe for research.

How does estrogen via GPR30 drive sex behaviour in female rodents? We have also shown that GPR30 is capable of rapidly phosphorylating the ER in the male hippocampus, a region of the brain important for learning. We have also shown that activation of this receptor increases the density of dendritic spines in hypothalamic neurons derived from males and females. Both these molecular processes may play a role in social behaviours in the female and male.

This project will explore the hypothesis that GPR30-mediated growth of spines in the hypothalamus is a mechanism that is important for male and female social behaviour. Our approach will include investigation of GPER30 expression in the hypothalamus and it’s ability to regulate and crosstalk with the ER. We will also explore the signaling pathways initiated by GPR30 that are important for spinogenesis. Lastly, the behavioural phenotype of GPR30 knockout animals will also be explored. If successful, the results from this project will show a novel role for GPR30 in the central nervous system and link a molecular mechanism i.e non-genomic signaling to a social behaviour. Techniques include primary cell cultures, protein chemistry, golgi impregnation and microscopy to detect spine density and behavioural analysis with genetically modified animal models. The student will be part of a vibrant endocrine group at the University of Reading, with an opportunity to get training in teaching pedagogy. In addition, the student will also have an opportunity to network with the investigator’s overseas collaborators. "