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.
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.
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.
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.
Publications
Boyd-Gibbins N
(2021)
Turnover and activity-dependent transcriptional control of NompC in the Drosophila ear.
in iScience
Boyd-Gibbins N
(2020)
Turnover and Activity-Dependent Transcriptional Control of NompC (=TRPN1) in the <i>Drosophila</i> Ear
in SSRN Electronic Journal
Bryant D
(2022)
The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.
in JCI insight
Bullen A
(2020)
Ultrastructural defects in stereocilia and tectorial membrane in aging mouse and human cochleae.
in Journal of neuroscience research
Daudet N
(2020)
Notch Signalling: The Multitask Manager of Inner Ear Development and Regeneration.
in Advances in experimental medicine and biology
Forge A
(2020)
Restoring the balance: regeneration of hair cells in the vestibular system of the inner ear
in Current Opinion in Physiology
Gonçalves AC
(2019)
Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity.
in Scientific reports
Heard G
(2019)
TRPV4 Receptors as Multimodal Sensors of Inner Ear Fluids.
Keder A
(2020)
Homeostatic maintenance and age-related functional decline in the Drosophila ear.
in Scientific reports
Lezirovitz K
(2020)
A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.
in Human molecular genetics
Loh YM
(2023)
The auditory efferent system in mosquitoes.
in Frontiers in cell and developmental biology
Nolan LS
(2020)
Conference Poster
Nolan LS
(2022)
Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice.
in Scientific reports
Prades S
(2021)
Functional P2X7 Receptors in the Auditory Nerve of Hearing Rodents Localize Exclusively to Peripheral Glia.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Requena T
(2022)
A Drosophila model for Meniere's disease: Dystrobrevin is required for support cell function in hearing and proprioception.
in Frontiers in cell and developmental biology
Smith KE
(2021)
Divergent membrane properties of mouse cochlear glial cells around hearing onset.
in Journal of neuroscience research
Smith KE
(2020)
Olfactory ensheathing cells from the nasal mucosa and olfactory bulb have distinct membrane properties.
in Journal of neuroscience research
Su MP
(2018)
Sex and species specific hearing mechanisms in mosquito flagellar ears.
in Nature communications
Zak M
(2021)
A gradient of Wnt activity positions the neurosensory domains of the inner ear.
in eLife
| 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 | Biogenic amines in malaria mosquitoes: from hearing to swarming behaviour |
| Amount | £55,327 (GBP) |
| Funding ID | ISSF3/ H17RCO/NG21 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 12/2021 |
| 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 | Defining the molecular mechanisms underlying sex-differences in the maintenance of hearing. |
| Amount | £3,273,631 (GBP) |
| Funding ID | 225443/Z/22/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 07/2022 |
| End | 07/2030 |
| Description | Future Leaders Fellowship |
| Amount | £1,127,491 (GBP) |
| Organisation | United Kingdom Research and Innovation |
| Department | Future Leaders Research Fellowship |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2019 |
| End | 04/2023 |
| 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 | Metabolic refinement of sensory cell development |
| Amount | £727,794 (GBP) |
| Funding ID | BB/V006371/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2021 |
| End | 04/2024 |
| Description | Prosensory signals: from discovery to application using inner ear organoids |
| Amount | £848,846 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2022 |
| End | 02/2025 |
| 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 | To turn it up or to turn it down? Characterising the role of different levels of Wnt and Hedgehog signalling activity in the formation of auditory and vestibular hair cell types |
| Amount | £120,000 (GBP) |
| Funding ID | PA27 |
| Organisation | Action on Hearing Loss |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2021 |
| End | 09/2023 |
| 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 | Conference presentation - ANTI-Vec Net annual meeting 2023 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Investigating the molecular basis of disease-transmitting mosquito hearing and swarming behaviour for mosquito control; Oral presentation; Ellis D, Freeman E, Bagi J, Tytheridge S, Terrazas D, Andres M; ANTI-Vec Net annual meeting; February 26-March 1 2023; Kifili, Kenya. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Conference presentation - EMBO Conference "Molecular and Population Biology of Mosquitoes and Other Disease Vectors" 2022 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | 2022, EMBO Conference "Molecular and Population Biology of Mosquitoes and Other Disease Vectors", Julio 23-28, Kolymbari, Grecia: Neuromodulation of malaria mosquito hearing and swarming behaviour. Presentación oral, session chair. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Crick Institute - Neuroscience Interest Group |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Interest group based at the Crick Institute. We participate as associate members. The group meets every two weeks to discuss different neuroscience topics based on the research performed by the participating groups. |
| Year(s) Of Engagement Activity | 2020,2021 |
| 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 | Seminar presentation - University of Leicester 2023 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | Neurogenetics seminar, University of Leicester, United Kingdom: Auditory neuromodulation in malaria mosquitoes. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Seminar presentation - University of Nagoya 2022 (online) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | University of Nagoya YLC Salon. Online seminar: Octopamine as a key neuromodulator of malaria mosquito hearing. |
| Year(s) Of Engagement Activity | 2022 |
| 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 |