A 3D Neurosterol Atlas of Mouse Brain

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Cardiovascular Science

Abstract

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Technical Summary

The brain is a remarkably complex organ. To understand brain function, it requires multidisciplinary technologies and multiple levels of data. There are a number of big initiatives worldwide to map the brain. Current activities are focused on mapping gene expression, cell type and connectivity across the entire brain. Despite these efforts, little is known about the landscape of the metabolome or lipidome across the brain. The sterol category of lipids, including cholesterol, its precursors, and oxysterols and steroids, represent one of the dominating lipid classes in brain and sterol homeostasis plays a critical role in neurophysiology. It is recognised that a lack of quantitative spatial information on steroids and sterols/oxysterols in brain subregions is a key gap in our understanding of the mechanisms underlying health and healthy aging. The aim of this proposal is to create a web-based 3D Neurosterol Atlas of Mouse Brains utilising our recently-developed on tissue derivatisation and mass spectrometry imaging (MSI) technology.
On-tissue derivatisation overcomes the limitations of previous MSI techniques for analysis of low abundance and difficult to ionise sterol molecules. We have successfully combined on-tissue derivatisation with MALDI-MSI to image neurosteroids and cholesterol, and combined it with liquid-extraction for surface analysis (LESA) and liquid chromatography - mass spectrometry (LC-MS), i.e. LESA-LC-MS, to image cholesterol precursors and oxysterols, allowing isomer differentiation and structure identification. Here we will scale up our effort and use the Allen Mouse Brain Atlas as a template to create a web-based interactive 3D Neurosterol Atlas of Mouse Brain including developmental, young adult and aged mice of both sexes. The resource will support neuroscience research in many areas, including myelination and repair, neurotransmitter receptors, stress response and neuroprotection and regeneration.

Planned Impact

Understanding brain development and how the brain is affected by ageing is a vital key to unlock strategies to sustain a healthy lifespan. Key players in central neural pathways are sterols and steroids. To find out the location and in situ concentration of sterols/steroids in the brain requires specialised mass spectrometry technology and expertise which are not widely available. A free to access web-based 3D Neurosterol Atlas of Mouse Brain, across three life stages and both sexes, will provide researchers with easy access to this information. Females have long been under-represented in many areas of animal research. Gender-related differences in sterol metabolism and the glucocorticoid stress response have been reported, hence having access to female brains in the Atlas is of crucial importance. It will have significant impact on basic neuroscience, public health life-style recommendations, medical research and drug discovery.
Corticosteroid receptors are expressed in the CNS and are important in regulating the stress response, memory and behaviour. Glucocorticoid levels are locally controlled by enzymes, such as 11beta-HSD1 which generates activate glucocorticoids. Early life events programme stress responses and overexposure to elevated glucocorticoids with ageing accelerates cognitive decline. As such, inhibitors of 11beta-HSD1 are in clinical trials to treat dementia. A knowledge of glucocorticoid concentrations in the different regions of male and female brains throughout life, as provided by our Atlas, will provide baseline data to understand how the environment during pregnancy programmes the brain, how the stress axis is influenced by ageing and which areas of the brain are at greater risk. This will enable further investigations into how the stress axis can be optimised to extend health and independence.
N-Methyl-D-aspartate receptors (NMDARs) and GABA-A-type receptors (GABA-ARs) are implicated in neurological disorders including schizophrenia, epilepsy, depression, Alzheimer's disease (AD) and traumatic brain injury. Neurosteroids are endogenous allosteric modulators of NMDARs and GABA-ARs. Currently there is considerable interests in exploring the use of neurosteroids to treat these conditions and a number of ongoing clinical trials are in progress. Knowing the distribution of endogenous neurosteroids in the male and female brain in health and how they correlate to the location of interacting receptors is important for the design and optimisation of synthetic analogues which will improve the efficiency of drug development.
For many years cholesterol metabolism has been linked to AD and other neurodegenerative and cognitive disorders. Recently, a gene-therapy approach to increase the local expression of CYP46A1, the enzyme primarily responsible for cholesterol metabolism in brain, has shown promising effects in slowing down disease progression in mouse models of AD. Our Neurosterol Atlas of the healthy brain will provide an essential baseline to understand how cholesterol homeostasis varies between distinct functional regions of brain and with age. With this information, researchers can apply more targeted approaches to design novel therapeutic treatments and monitor sterol changes in focussed lesions.
This is an exciting opportunity for PDRAs to be involved in building the first 3D Neurosterol Atlas of Mouse Brain. Mass spectrometry imaging is an emerging and cutting-edge technology, pioneered in the sterol/steroid field by the applicants. The PDRAs will work closely with analytical scientists, neuroscientists and bioinformaticians. The experience they gain and the networks they will build will enhance their career development.
The Neurosterol Atlas can also be used as a teaching resource for undergraduate students and to engage public attention in understanding of the how brain works.

Publications

10 25 50
 
Description Developing an MS-based spatial proteomics approach: application to cardiovascular research
Amount £25,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2022 
End 04/2023
 
Description Early Career Grant
Amount £10,000 (GBP)
Organisation Society for Endocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2021 
End 08/2022
 
Description Finding a Cure for Aortic Stenosis
Amount £194,310,352 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2023 
End 03/2028
 
Description Friedman Award for Scholars in Health
Amount $49,261 (CAD)
Organisation University of British Columbia 
Sector Academic/University
Country Canada
Start 01/2023 
End 07/2023
 
Description Mass spectrometry imaging of glucocorticoids in the mouse thymus
Amount $6,000 (CAD)
Organisation United Kingdom Research and Innovation 
Sector Public
Country United Kingdom
Start 01/2023 
End 07/2023
 
Description Moray Endowment Fund
Amount £2,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 01/2023 
End 08/2023
 
Description STARSS: Establishment of Specialized Team for Advanced Research on Separation Science
Amount 10,000 Kč (CZK)
Organisation European Union 
Sector Public
Country European Union (EU)
Start 07/2022 
End 12/2022
 
Description Spatial profiling of lipoprotein (a) and plaque vulnerability
Amount £250,000 (GBP)
Organisation Heart Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2023 
End 10/2026
 
Description Visiting PhD Scholar for University of British Columbia 
Organisation University of British Columbia
Country Canada 
Sector Academic/University 
PI Contribution The student has just arrived to carry out steroi imaging studies in our group. They do not have access to the instrumental resources in Canada and wish to learn from our expertise. My team will train them. The University has included them in an agreeed exchange programme
Collaborator Contribution The parnter has enabled the grants between our groups and provided the biological materials. They have submitted an abstract the the US Endocrine Society meeting June 2024. They sueprvisro has applied to visit Edinburghfor sabbatical late 2024.
Impact The student has given a Centre wide talk in March and has submitted an abstract to attend the European Society for Endocrinology in Istanbul while in the UK. They have submitted an abstract to the Amrican Endocrine Society meeting June 2024.
Start Year 2022
 
Description Visiting PhD Scholar from Charles University Prague 
Organisation Charles University
Country Czech Republic 
Sector Academic/University 
PI Contribution I hosted a PhD scholar on a EU funded exchange scheme (STARSS) for 4 months to enable advanced skills training
Collaborator Contribution The partners suppoeted the student financially and invited me to visit and speak at their University Oct 2022. The student returned to theUK to present a poster at a meeting in Nov 2023. (BES 2023)
Impact The student presented their work at the Scottish Metabolomics Network, The British Endocrine Societies Conference (x2) and in their home Unviersity. The pilot data collected helped fund a pilot grant. The data analysis challenges allowed us to initiate collaboration with two industrial companies and we are now beta testing new software as an academic partner.
Start Year 2022
 
Title Beta testing software for Ion mobility Imaging 
Description The company Molecular Discovery are developing enw osftware. We work with their existing software under academic license. We are helping them with an academic dataset under MTA to intergate Waters data into a vendor neutral platform. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2023 
Impact Still under development 
 
Description Talk at Symposium celebrating the career of Cedric Shackleton 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A Sympoisum was organised to highlight steroid research related to MS innovations
Year(s) Of Engagement Activity 2022
URL https://steroidmassspec2022.wordpress.com/
 
Description Talk for Lipidmap Webinar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 75 researchers attending the Lipidmaps webinars which happen monthly. I have joined the Lipidmaps consortium adn was introducing my field of interest
Year(s) Of Engagement Activity 2024
URL https://www.youtube.com/watch?v=7uAdsTaIa70
 
Description Talk to Royal Microscopy Society, Edinburgh Facility Groups 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Introducing MS imaging to microscopy professionals to show overlap in fields.
Year(s) Of Engagement Activity 2024
 
Description Video for "Love your liver " week British Liver Trust 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A team of researchers involved in liver research made a series of short video excerpts to adveritsie the types of studies conducted in Edinburgh Mecial School. I covered chemistry and how it can impact of liver research. The videos were put out on Instragram and Twitter and the Unviersity media channels.
Year(s) Of Engagement Activity 2022
URL https://youtu.be/e94eZHvgnng
 
Description Webinar for BMSS Lipid SIG 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I gave a webinar as part of the series of the Lipid special interest group for BMSS
Year(s) Of Engagement Activity 2022
URL https://www.bmss.org.uk/special-interest-groups/lipidomics/