Cellular and neurophysiological mechanisms of sensory-driven behaviour

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

Our senses are our brains' window to the world - they are also the scientists' window to understanding the brain. By investigating how information about the external world is processed by networks of neurons, we aim to elucidate how the brain performs its variety of tasks.
Specifically, we use the sense of smell of mice to explore how networks of neurons in the olfactory system process information endowing the animal with the ability to discriminate, identify and memorize odours. Based on detailed anatomical and functional models we perform targeted opto- and pharmakogenetic modifications. We probe the resultant alterations using physiological and imaging techniques as well as quantitative behavioural paradigms. Thus, with continuous refinement of our models of sensory processing we will get quantitative insight into how neural circuits compute in the healthy brain. Moreover, in particular behavioural paradigms in social environments together with detailed models of brain function will give us the tools at hand to efficiently and sensitively detect when and how this information processing is perturbed in cognitive disease.

Technical Summary

Understanding how complex behaviour emerges from the properties of molecules, cells and ensembles of cells is one of the key challenges in Neuroscience. Our work tackles this question employing the olfactory system of mice as a model system.
To understand how smells are processed we modify specific selected groups of neurons in the first relay station of the olfactory system, the olfactory bulb. Cellular specificity is achieved by combining transgenic mice, engineered to express Cre recombinase in defined groups of cells. This will be combined with injections of viruses conditionally expressing a variety of pharmako- and optogenetic tools into the olfactory bulb. Subsequently, we investigate how such targeted manipulations affect odour related behaviour, such as odour detection, identification, discrimination or memory. To this end we develop a variety of highly automatized and quantitative behavioural paradigms tailored to sensitively detect small perturbations. To unravel the cellular and network mechanisms underlying behavioural alterations we employ in vitro and in vivo physiological approaches where whole-cell patch recordings are used to map odour response properties of individual neurons and imaging techniques are employed to study the spatial distribution of activity. Previously, we have found that genetic modifications to the synapses between principal projection neurons (mitral cells, MC) and the dominant group of interneurons (granule cells, GC) resulted in sensitive alterations to odour discrimination ability: Increasing calcium influx at the MC-GC synapse through targeted ablation of the glutamate receptor subunit GluA2 increased inhibition and reduced discrimination times, i.e. the time needed in a behavioural experiment to accurately discriminate two similar odorants. Conversely, ablating the NMDA receptor subunit resulted in decreased Ca influx, decreased inhibition and slowed down odour discrimination. Our current research aims to identify the mechanisms behind this bidirectional alteration of odour discrimination by employing inducible (optogenetic) modifications to GCs during physiological recordings in behaving mice in vivo, thus providing a mechanistic link between cellular properties and behaviour.
Combining these genetic, physiological and behavioural techniques with computational modelling approaches we aim to elucidate the cellular basis of olfactory behaviour and ultimately more general complex behaviours. This will provide us with the tools and concepts necessary to tackle the question how circuit function might be altered in complex cognitive disease such as autism spectrum disorders or schizophrenia.
 
Description HFSP Grant
Amount $750,000 (USD)
Funding ID RGP0048 
Organisation Human Frontier Science Program (HFSP) 
Sector Charity/Non Profit
Country France
Start 09/2013 
End 08/2017
 
Title AutonoMouse 
Description Tool for efficient behavioural analysis for groups of mice in social, home-cage setting 
Type Of Material Technology assay or reagent 
Year Produced 2019 
Provided To Others? Yes  
Impact Mice can be trained in a stress-free social environment (group=housed) for periods of up to 18 months performing automatic operant conditioning tasks. This method was publised and shared with several groups and is no in operation in >5 research labs around the world (Germany, UK, USA). 
URL https://pubmed.ncbi.nlm.nih.gov/30840676/
 
Description Biomimetic nanoelectrodes for stable intracellular neural recordings 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Electrophysiological evaluation of novel biomimetic nanoelectrodes
Collaborator Contribution Devleopment of biomimetiv nanoelectrodes
Impact Multidisplinary: Surface science, materials engineering, neuroscience, physiology Publication: Angle et al, 2014, US Patent filed 14/937,740 filed on Nov 10, 2015 (joined with Melosh, Angle, Hanna - Stanford)
Start Year 2012
 
Description Higher-order feature detection in olfactory bulb 
Organisation Cornell University
Country United States 
Sector Academic/University 
PI Contribution Experimental analysis of olfactory bulb connectivity and integration using optogenetic and electrophysiological tools
Collaborator Contribution Models of olfactory bulb function and behavioural tests
Impact Two distinct channels of olfactory bulb output Fukunaga I, Berning M, Kollo M, Schmaltz A, Schaefer AT. Neuron. 2012 Jul 26;75(2):320-9. PMID:22841316 Multidisplinary: Theoretical neuroscience, experimental psychology, physiology
Start Year 2010
 
Description Mechanisms of inhibitory processing in the olfactory bulb 
Organisation Heidelberg University
Country Germany 
Sector Academic/University 
PI Contribution Developed automated conditioning system and behavioural tasks, implement optogenetic probes to investiagte role of interneurons, in vivo physiological analysis, modelling of OB function.
Collaborator Contribution Devise viral molecular targeting strategies, in vitro physiological analysis
Impact Maintaining accuracy at the expense o speed: stimulus similarity defines door discrimination time in mice. Abraham NM, Spors H, Carleton A, Margrie TW, Kuner T, Schaefer AT. Neuron. 2004 Dec 2;44(5):865-76. PMID: 15572116 Synaptic inhibition in the olfactory bulb accelerates door discrimination in mice. Abraham NM, Egger V, Shimshek DR, Renden R, Fukunaga I, Sprengel R, Seeburg PH, Klugmann M, Margrie TW, Schaefer AT, Kuner T. Neuron. 2010 Feb 11;65(3):399- PMID: 20159452 Kuner & Schaefer 2012 Multidisplcinary: Molecular biology, behavioural neuroscience, physiology
 
Description Olfactory Bulb connectomics 
Organisation Max Planck Society
Department Center of Advanced European Studies and Research
Country Germany 
Sector Charity/Non Profit 
PI Contribution Acquire data and analyse data from Olfactory bulb connectomics.
Collaborator Contribution MPI: Provide support for analysing large data sets (>100 TB) NIH / Caesar: Help with development of specific histoogical protocols and advise on data acquisition
Impact Publications expected but not yet occurred.
Start Year 2015
 
Description Olfactory Bulb connectomics 
Organisation Max Planck Society
Department Max Planck Institute for Brain Research
Country Germany 
Sector Academic/University 
PI Contribution Acquire data and analyse data from Olfactory bulb connectomics.
Collaborator Contribution MPI: Provide support for analysing large data sets (>100 TB) NIH / Caesar: Help with development of specific histoogical protocols and advise on data acquisition
Impact Publications expected but not yet occurred.
Start Year 2015
 
Description Olfactory Bulb connectomics 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Acquire data and analyse data from Olfactory bulb connectomics.
Collaborator Contribution MPI: Provide support for analysing large data sets (>100 TB) NIH / Caesar: Help with development of specific histoogical protocols and advise on data acquisition
Impact Publications expected but not yet occurred.
Start Year 2015
 
Description ''Neuroscience and Illusion' at Crick 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
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Primary Audience Schools
Results and Impact Activity: Part of the 'Summer Youth Project': Crick outreach team supports a local group of teenagers so they will participate in the Crick's autumn film festival "science on screen".

Impact: Raised interest on neuroscience on young teenagers, channeled questions from common illusions into the reasoned work, managed them to have fun while thinking on scientific reasoning.
Year(s) Of Engagement Activity 2007,2018
 
Description ''The Place Cell game' at Crick Late, Deconstructing Patterns 
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Impact: Making the game fun was a very interesting bit. It not only had to work technically (live feed on two TVs, two arenas so people competed against each other, video tracking custom software on bonsai) it also had to be fun. Fine tuning of the reward scheme led to a quick (1+1min) game, easy to play, easy to explain. Then in 5 min one could introduce the game and raise interest on the research behind. The "how does it actually relate to your work" question was a recurrent one, so matching performance with real research is an important job.
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URL https://www.crick.ac.uk/whats-on/about-our-public-events/crick-lates/
 
Description Art and Neuroscience Social 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Activity: Exhibition of the tapestries "The fabric of thoughts" at an Arts and Neuroscience social satellite event to the Neuroscience 2018 conference in San Diego (30k attendees).

Impact: Collected good feedback and impressions about the artwork and scope of the project.
Year(s) Of Engagement Activity 2018
URL https://www.facebook.com/plugins/post.php?href=https%3A%2F%2Fwww.facebook.com%2Fcdmtextil%2Fposts%2F...
 
Description Art of Neuroscience - award 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Activity: tapestries depicting EM landscapes of the mouse olfactory bulb.
Broadcasted in different supports (Scientific American report online, international newspapers).
It closed a product that has been exposed in later occasions (SfN 2018 San Diego, Fabrics Museum Terrassa 2018, 2 planned exhibitions in 2019).

Impact: developing a logic to convert images into patterns compatible with a jacqard loom with digital thread control. Woven tapestries are really beautiful - hence the honorable mention in this contest. That consolidated the result, leading to a 3-month exhibition in the Fabrics Museum in Terrassa. It also secured the collaboration - now focused on both exhibiting current work and to showcase future results.
Year(s) Of Engagement Activity 2018
URL https://aon.nin.knaw.nl/index.php/portfolio/2018/
 
Description Bright Lights, Crick Circuits 
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Part Of Official Scheme? No
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Results and Impact Hands-on activity about designing your own neural circuit and engaging in discussion about neuroscience at the Crick during the first Crick late. Most important impact: Excited many people about the research in the Neurophysiology of Behaviour lab.
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URL https://www.crick.ac.uk/whats-on/about-our-public-events/crick-lates/
 
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Results and Impact Activity: Carried out a playful experiment with volunteers by recording and stimulating muscle activity. The goal was to depict possibilities of e.g. brain machine interfaces.

Impact: Demonstrating relevance of neuroscience carried out at the Crick.
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Description Crick Late (Crick, activity delivery), London. By PhD Cristina Marin. 
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Part Of Official Scheme? No
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Results and Impact Crick Late (Crick, activity delivery), London. By PhD Cristina Marin.
Year(s) Of Engagement Activity 2019
 
Description Digital Neurons 
Form Of Engagement Activity Participation in an activity, workshop or similar
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Primary Audience Public/other audiences
Results and Impact Activity: We used simulated neurons (run on customized cheap microcomputers) to demonstrate how neurons work through their electrical currents and how neurons interact in neural networks. Participants were able to control the inputs to a simulated neuron and observe the effects of their action in a series of games.

Impact: Engaging in conversation with members of the public about our progress in improving neuronal recording techniques and what this might mean for the future of medicine, technology and society at large.
Year(s) Of Engagement Activity 2019
URL https://www.crick.ac.uk/whats-on/crick-late-making-science-happen
 
Description ICON season 2 (2018) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Activity: informal talk series given by GLs on a Friday afternoon, aimed to generate a relaxed atmosphere where to discuss science and foster interaction between members of different labs.

Impact: better organised - we started the talks once the calendar was closed. Still retrieving very good feedback from audience and speakers. Talk format now more established - close to a chalk-talk, but with the same spirit.
Year(s) Of Engagement Activity 2018
 
Description In and Out - of a neural circuit 
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 Activity: submitted image to the Wellcome Photography Prize 2019

Impact: ongoing evaluation. So far, it helped planning new projects for 2019.
Year(s) Of Engagement Activity 2018
URL https://wellcome.ac.uk/what-we-do/our-work/photography-prize
 
Description Introduction to... How a mouse senses its world - Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact One hour talk on how our research helps understand the field of neuroscience using olfaction as a template. Most important impact: Excited many people about the research in the Neurophysiology of Behvaiour Lab
Year(s) Of Engagement Activity 2010,2017
URL https://www.crick.ac.uk/
 
Description Marques d'aigua 
Form Of Engagement Activity Participation in an activity, workshop or similar
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Results and Impact Activity: Exhibition of the work behind "The fabric of thoughts" at the Fabrics Museum of Terrassa (Catalonia, Spain).

Impact: Settled the project and highlighted specific needs for museum exhibits.
Year(s) Of Engagement Activity 2018
URL http://cdmt.cat/event/marques-aigua-obres-francesca-pinol-espai-
 
Description Meet a Scientist 
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Primary Audience Undergraduate students
Results and Impact Activity: Explaining my research to a group of UCL first year biology students and assessing their performance in presenting a research paper provided by me in advance.

Impact: Giving young students insight into the daily life of a neuroscientist at the Crick and challenge them to think about and understand a recent and exciting question in the field of neuroscience.
Year(s) Of Engagement Activity 2019
 
Description Neuroscience of Perception at Decoding Sensations - Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Symposium with brief talks from philosophy, neuroscience and art on the topic of 'perception'. Starter of a 4-day multidisciplinary art exhibit. Most important impact: being able to organise an event with professionals from the arts scene was very interesting. I found very useful to understand a bit what is required to mix well art & science. People showed great interest in the dichotomy of perception vs reality. Good feedback.
Year(s) Of Engagement Activity 2017
URL http://homeofart.org/2017/03/decoding-sensations-curious-brew-art/
 
Description Science Art workshop 
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Results and Impact 'Winter workshop' Science art workshop for primary school children in Kings Cross, London
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Description Technical training in electrophysiological and bio-photonic instrumentation 
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Part Of Official Scheme? No
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Primary Audience Postgraduate students
Results and Impact Postgraduate students and postdoctoral researchers in physiology often have insufficient technical background to understand the instrumentation used in research and its limitations. To address this, two annual residential workshops each provide two weeks training in electronics, instrumentation, optical methods and microscopy for 20 UK, European and international students. Both courses have 40-50 applicants each year internationally.
'Microelectrode Techniques for Cell Physiology'runs each September since 1984 at the Marine Biological Association in Plymouth. It comprises 25 lectures and 60 hours of hands on practical work and demonstrations. As well as the MBA, it is sponsored by BBSRC, the Physiological Society and the Company of Biologists. Around 50 instructors teach electronic and optical methods with support from instrumentation companies. All are engaged in research or development. Webpage www.mba.ac.uk/microelectrode-techniques-cell-physiology
'Electrophysiological recording and Optical Imaging in Neuroscience' runs each spring at the Universite Paris Descartes and Ecole Normale Superieure in Paris since 2009. The emphasis is more with biophotonics applied in neuroscience than the Plymouth cell physiology version. There are 25 lectures and 40 hours practical and demonstrations. Many instructors teach both courses and support is from instrumentation and optical companies and local institutions. Web: www.parisneuro.ovh
Feedback from both courses is overwhelmingly positive. Major benefits for students are in meeting peers at a similar stage in career and contact with experts in particular techniques. Supervisors comment on the confidence students aquire after attending the workshops. Around 800 students have taken part in one or other workshop since 1984. For the instructors and instrument makers the workshops are a focus for technical developments.
Year(s) Of Engagement Activity 2017,2018
URL http://www.parisneuro.ovh
 
Description The Infinite Brain - Public Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact 500 - 1000 people attended a A table-top public activity to explore what the connectome is and how The Crick studies it. Impact: first contact of people with what The Crick is (they had lived with the plans & construction for long, but scientists hadn't moved in yet).
Year(s) Of Engagement Activity 2016
URL http://somerstownart.org/
 
Description You are electric at Crick Discovery day - Public event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Registering nerve stimulation from you and driving those impulses onto your friend allows kidnapping your partner's fist, which will close on your will. Most important impact: very interactive activity, interesting and fun. People enjoyed, both kids and adults.
Year(s) Of Engagement Activity 2018
URL https://www.crick.ac.uk/whats-on/upcoming-events/2017/06/17/crick-discovery-day/
 
Description Your reality is Broken at Wellcome Friday Spectacular 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact object-oriented standing small talk. Neuroscientists were scattered along the venue holding an object that related to their research. That would be used as a spark to engage in conversations with attendees about our research. Other activities were taking place simultaneously (dance, talks, ...). Most important impact: very interactive activity, the proximity to the public drives the conversation to a more personalised field. Being scattered, out-of-focus of the event's attention leads people to feel less shy, to ask more. Then the performance becomes personalised.
Year(s) Of Engagement Activity 2017
URL https://www.mas-productions.org/your-reality-is-brokenthe-wellcome-trust/
 
Description Zoetropes of Discovery - Art Science Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Combining art and science by building zoetropes depicting animations such as cell duplications or immune responses. Most important impact: Making science available and building interest in research to local school kids.
Year(s) Of Engagement Activity 2017
URL https://www.crick.ac.uk/whats-on/upcoming-events/2017/07/20/zoetropes-of-discovery-20-july/