Unravelling a novel role for the mineralocorticoid receptor in dentate gyrus neurogenesis.

Lead Research Organisation: University of Bristol
Department Name: Bristol Medical School


Why do stressful events have a long-term impact on the brain? With the tremendous rise in the number of people suffering from stress-related mental disorders finding an answer to this question is more important than ever. Stressful events can have a long-lasting impact which includes the formation of memories of such events. Usually, these memories help the individual to cope with the experience and be better prepared in case of a similar event. However, a mental health problem (e.g. post-traumatic stress disorder (PTSD), major depression, anxiety) can develop if a situation is extremely traumatic or exposure to stress becomes chronic. It is still not clear how the brain processes stressful challenges. It has been well established though that stress-induced glucocorticoid hormones play a key role through their actions on a part of the brain (the hippocampus) that is crucial for responding to stress including the formation of memories of the stressful event itself. Interestingly, the hippocampus is one of the main brain systems where new neurons are incorporated throughout life. Adult neurogenesis, plays a principal role in memory formation of events and places and is sensitive to stress. We recently found that glucocorticoid hormones, through binding to their receptors (the mineralocorticoid and glucocorticoid receptors (Mifsud & Reul, Proc. Natl. Acad. Sci. USA 2016)), influence the expression of more than 60 neurogenesis associated genes in the hippocampus. This is a significant step forward in the investigation of the effects of stress on the hippocampus in terms of stress coping and memory formation. The aim of this project is to elucidate the role of glucocorticoids in the effects of stressful challenges on hippocampal progenitor pools and neuronal differentiation and maturation. This multidisciplinary research will be conducted both in stress/behavioural models (stress coping, memory formation in adolescence, adulthood, ageing) in vivo and in primary cell culture/progenitor cell lines in vitro. The successful PhD student will apply various state-of the-art technologies including epigenetic (chromatin immuno-precipitation (ChIP), bisulfite pyrosequencing (for DNA methylation analysis)), molecular (RNA, genome analysis, gene silencing), neuroanatomical (RNAscope, double/triple immuno-fluorescence), cell culture (primary/progenitor cell lines), experimental animal (behavioural models), and bioinformatics (R, Bioconductor, Ingenuity Pathway Analysis) technologies and methods. This project will be supervised by Professor Johannes Reul, Dr Oscar Cordero Llana and Dr Karen Mifsud at the University of Bristol and Professor Jonathan Mill at the University of Exeter.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M009122/1 01/10/2015 31/03/2024
2282980 Studentship BB/M009122/1 01/10/2019 30/09/2023 Samantha Haque
Description 1. This work has defined a novel role of the mineralocorticoid receptor (MR) in neuronal differentiation and ciliogenesis is human foetal neural progenitor cells.
2. This work has so far characterised the involvement of the MR in the adult neurogenesis process in the rat dentate gyrus.
3. This award has conducted ChIP-seq analysis for two transcription factors in the rat hippocampus, and is presently doing the bioinformatic analysis and validation work on this.
Exploitation Route Results of this award, including the ChIP-seq data, will be used by the research group and other research groups in future research focusing on embryonic and adult neurogenesis.
Sectors Pharmaceuticals and Medical Biotechnology,Other

URL https://www.nature.com/articles/s41467-021-24967-z
Title Voluntary dosing methods to rats 
Description The research group including SH have developed a method in which rats are given an MR-antagonist drug, spironolactone, through a voluntary dosing method. The drug is dissolved in condensed milk and a syringe containing the drug and vehicle are placed through cage bars for rats to approach and drink at their own pace. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? Yes  
Impact Rats do not need unnecessary handling when administering this drug so there are no adverse stress effects from drug dosing procedures. 
URL https://www.nature.com/articles/s41467-021-24967-z
Description Poster Presentation at the 3rd Munich Winter Conference on Stress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact SH attended the 3rd Munich Winter Conference on Stress on March 2022. SH presented a poster titled 'Critical role of the mineralocorticoid receptor in differentiation of human foetal neural progenitor cells'. The conference had approximately 300 attendees, all who conduct research within the stress field and vary from PhD students to Prinicipal Investigators.
Year(s) Of Engagement Activity 2022
Description Short video for Nature Science in Shorts 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Research group including SH made a short video titled 'When is a stress hormone more than a stress hormone'. This explained novel discoveries in the field of neuroscience based on their recent publication and was published as part of Nature's Science in Shorts collection.
Year(s) Of Engagement Activity 2022
URL https://www.youtube.com/watch?v=vcIKt_zsxUs&feature=youtu.be