Hearing at speed: a fast high-resolution imaging platform at the UCL Ear Institute

Lead Research Organisation: University College London
Department Name: Ear Institute

Abstract

The UCL Ear Institute is an international centre of excellence for research in the auditory and vestibular field. Since its inception in 2005 the Institute's Imaging Facility has underpinned the research of the Institute's staff as well as of multiple collaborators from UCL and from other Institutions.

Research groups at the Ear Institute are studying the cell biology and physiology of cells in the inner ear and the auditory brain. The research undertaken is heavily dependent on the availability of high quality imaging from cells and tissues, with the ability to utilise the confocal principle being critical to resolve the small and complex structures of the audiovestibular system. Understanding the dynamic changes that occur during normal physiological function and during trauma is critical for the Institute to work towards its defining goal of "Understanding Hearing and Fighting Deafness".

This application aims to replace the (now unsupported) core confocal imaging system. In the process it is proposed to add the ability to carry out near super-resolution experiments in the current Facility provision. In addition to the essential role of underpinning the local research activities, the imaging systems and researchers at the Ear Institute have also been central to the development of imaging approaches and techniques through collaborations both within UCL and external to UCL. The new fast super resolution imaging system will be accessible to a variety of different researchers through the wider UCL community and its existing networks and also to UK research teams in the auditory and vestibular research fields through collaborative activity. The requested imaging platform will facilitate the continued excellence and provide enhanced capabilities for numerous ongoing research projects at the UCL Ear Institute and in the wider community.

The UCL Ear Institute is a stand-alone Division position on the Gray's Inn Road dislocated from the main UCL Bloomsbury Campus. Since its inception in 2005 it has housed an imaging facility that incorporates an inverted Zeiss 510 microscope, a PerkinElmer Ultraview (now Volocity) spinning disk confocal and a Upright Zeiss 510NLO multi-photon confocal system. The oldest of these systems (now 14 years old) is the Inverted LSM 510. This microscope is now two generations behind current technology. This grant will support the replacement of the inverted confocal system with a faster, more sensitive and more flexible system that will also provide new super-resolution capabilities to the Ear Institute.

Technical Summary

The principle objective of this application is to provide a new fast super-resolution facility at the UCL Ear Institute and also to replace the outdated but heavily-used core confocal microscope at this Internationally recognised off-campus research centre.

We are requesting funds to purchase a highly flexible laser scanning confocal system, a Zeiss 880 Fast Airyscan, equipped with spectral detection and unmixing, highly sensitive gallium arsenide (GaAsP) detectors and a 32-element Airyscan detector along with a range of excitation lasers from 405 through to 633nm.

This new core Institute facility instrument will provide us with:
(i) improved sensitivity and reduced photobleaching, with faster image capture for all users allowing acquisition of larger data sets;
(ii) near super-resolution imaging to 140nm;
(iii) improved high speed live-imaging capabilities with reduced phototoxicity and excellent optical sectioning.

The near super resolution capability will be a new addition to the Institute's imaging expertise. In addition, it will include the Fast Airyscan mode that allows for imaging of a 480x480 pixel array at up to 27 frames per second, using longer pixel integration (or dwell time) to provide enhanced capabilities for measuring dynamic responses such as intracellular Ca2+ dynamics. The enhanced sensitivity of the new detectors and the 880 Airyscan system will allow much improved and more comprehensive data acquisition from less tissue; thus the reduced tissue usage is in line with 3R principles. The new confocal system will enhance our current imaging capabilities whilst providing the consistency of the work environment for the research groups.

Planned Impact

This state-of-the-art fast, sensitive super-resolution confocal microscope will underpin a wide range of research activities within the UCL Ear Institute. Our Institute brings together some of the most influential academics and clinicians in the world with a passion to understand hearing and fight deafness. Recent bibliometric analysis of the most cited articles in England carried out by RAND, confirms that we are producing the most important research in the fields of "deafness and hearing problems" and "audiology & speech-language pathology".

In the UK, some 70% of people over 70 suffer from age-related hearing loss. A particular theme of the research at the Ear Institute is a study the audiovestibular system through the life-course, a highlighted BBSRC area, and a number of research groups will use the imaging platform to deliver and even enhance their research projects. In the short to medium term the primary beneficiaries of the research that will be underpinned by this essential platform technology will be the scientists that will use the outputs to design new and better experiments to develop therapeutic strategies to alleviate the effects of age-related hearing loss. In the longer term it will be the all of those who suffer from hearing loss and balance defects, since many aspects of the work in the Institute (funded by the BBSRC, MRC, Action on Hearing Loss and the Wellcome Trust among others), aims to prevent hearing loss or alleviate its effects.
 
Title Prize-Winning Images of the Brain: Editor's Choice from The Art Of Neuroscience (Liquid Gold) 
Description Confocal image selected on Scientific American website and in Scientific American Mind (Nov/Dec 2018), vol 29, pg31-41 
Type Of Art Image 
Year Produced 2018 
Impact Published in Scientific American Mind (Nov/Dec 2018), vol 29, pg31-41 
URL https://www.scientificamerican.com/article/prize-winning-images-of-the-brain1/
 
Description The key objectives for this equipment award were to 1) To provide a new fast super-resolution facility at the UCL Ear Institute and 2) To replace the outdated but heavily-used core current confocal microscope at this unique off-campus research centre. This has been fully achieved and the confocal system is now an essential part of the Institute's activity The new system has increased research capability and has also resulted in the training of ~15 researchers.
Exploitation Route The data generated by this system has been used for multiple publications and for further grant applications and funding.
Sectors Education,Other

 
Description A number of award winning art-science images have been produced.
First Year Of Impact 2018
Sector Education,Other
Impact Types Cultural

 
Description Bogue Research Fellowship
Amount £3,690 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 02/2020 
End 03/2020
 
Description Can we prevent hearing loss by manipulating the stress granule pathway?
Amount £96,726 (GBP)
Funding ID R581/0517 
Organisation The Dunhill Medical Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2017 
End 11/2019
 
Description Medical Research Council
Amount £637,945 (GBP)
Funding ID 177392 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2018 
End 11/2021
 
Description Taiwan Partnering Award: Mosquito Research - From Sensory Biology to Vector Control
Amount £25,284 (GBP)
Funding ID BB/R021007/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2018 
End 05/2020
 
Description The life course of neuronal microdomains regulating excitability of the auditory nerve
Amount £59,979 (GBP)
Funding ID JAHL/2 
Organisation The Dunhill Medical Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2020
 
Description Wellcome Institutional Strategic Support Fund
Amount £21,831 (GBP)
Funding ID 174320 
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 06/2019
 
Description Zhiyong Liu 
Organisation Chinese Academy of Sciences
Country China 
Sector Public 
PI Contribution Host laboratory for team of Dr Zhiyong Liu as part of Newton Fellowship funded project to develop new Crispr/Cas9 tools for genome editing in the chicken embryo
Collaborator Contribution Training to Crispr/Cas9 techniques
Impact - Newton Fellowship awarded to Dr Liu (Royal Society and Chinese Academy of Sciences)
Start Year 2020
 
Description collaboration Marta Ibanes 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution Initiation of a collaboration to perform collaborative work into the mechanisms of hair cell fate decisions. Our lab provided data (functional studies, role of Atoh1 and Id4) and intellectual input to this project, which is still in progress.
Collaborator Contribution The partner is a mathematician using computational models of Notch signalling. In this project, Dr Ibanes will use a model of lateral inhibition to study the impact of the autoregulation of Atoh1 expression on the dynamics of hair cell fate decisions. We could also in the future extend this work to study in silico the interactions between different types of bHLH (including Id4) in this context.
Impact this is a multidisciplinary collaboration, in which my lab provides functional data from in vivo and in vitro studies (expression patterns of some of the factors studied, gain and loss of function studies) and the lab of Dr Ibanes uses computational model to study the interactions between factors controlling hair cell fate decisions in silico.
Start Year 2017
 
Description BRC Hearing Theme 2nd Anniversary Event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Participation in the BRC Hearing Theme event for colleagues, external partners, charities, funders, patients and the public. Aim to explain research activities and encourage engagement. Images were used by PhD students undertaking engagement activities at the event.
Year(s) Of Engagement Activity 2019
 
Description Featured lab on The Science Times (www.instagram.com/thesciencetimes/), May 2018. 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Featured lab on The Science Times. Contributed confocal image & description.
Year(s) Of Engagement Activity 2018
URL http://www.instagram.com/thesciencetimes/
 
Description Invited speaker - Translational Hearing Research Summit: Biological and Pharmacological Approaches 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Translational Hearing Research Summit: Biological and Pharmacological Approaches 22 March 2018, Wellcome Collection, London, UK
A unique, one-day summit that brings together opinion leaders and stakeholders from around the world to share and discuss the biggest challenges and opportunities in the translation of hearing loss and tinnitus research.
The summit, organised by Action on Hearing Loss, the UCL Ear Institute and the NIHR UCLH BRC Deafness and Hearing Loss theme is a full-day meeting consisting of presentations, networking sessions and a panel-led discussion. The programme brings together academia, industry, investors, commissioners, clinicians and patients to discuss strategies to accelerate the development of pharmaceutical and biological treatments for hearing loss and tinnitus.
Year(s) Of Engagement Activity 2008,2018
URL https://www.actiononhearingloss.org.uk/finding-cures/translational-research-initiative-for-hearing/t...
 
Description Pint of Science Talk - Hear Me Out 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk given to general public about hearing research as part of the Pint of Science event. Intended for public engagement and dissemination of research.
Year(s) Of Engagement Activity 2019
 
Description Scientific American, Editor's Pick: "The Brain in Images", July 2019. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Image included in article selecting the best neuroscience images of 2019, published in Scientific American.
Year(s) Of Engagement Activity 2019
URL http://www.scientificamerican.com/article/the-brain-in-images-top-entries-in-the-art-of-neuroscience...
 
Description collaborative, cross-project visit at the Ludwig Maximilian University (LMU) of Munich 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact During a 4-day visit at the Ludwig Maximilian University of Munich, Prof Albert explored the collaborative potential across three ongoing (or recently ceased) grants:
Award References: BB/L02084X/1 + BB/M008533/1 + BB/R021007/1 + ERC-consolidator grant Clock mechanics (648709), S34, BB/R000549/1, 1206383, 1336457

The visit included a central seminar with the LMU's neurolunch series and meetings with various group leaders and internationally leading PIs in animal evolution, neuroscience and health (e.g. Prof Benedikt Grothe, Prof Axel Borst, Prof Nicolas Gompel, Prof Peter Becker, Prof Till Roenneberg and Prof Martha Merrow). The aim of this visit was to present the recent data of the involved projects just prior to submission for publication and to explore how the overlaps between the different projects can be harvested by new collabrations with experts in the respective fields. Examples include the exploitation of circadian clock function and auditory homeostasis (Profs Becker, Grothe and Merrow), or the evolution of sensory modality and submodality (Profs Borst + Gompel). The short-term goal will be to apply for larger national (e.g. Wellcome Trust collaborative awards) or international (e.g. European Research Council) follow-up grants! The LMU is a centre of German academic excellence, which is of strategic interest for UCL.
Year(s) Of Engagement Activity 2018