Neuroplasticity and Disease

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

In Vivo Imaging of Synaptic Reorganization in the Healthy and Diseased Brain||We are trying to understand which changes in the adult brain accompany cognitive processes such as learning and neuropathologies including brain injury and neurodegeneration. Our ultimate goal is to use this knowledge to guide the development of novel therapies for neurological diseases.||Synapses, the micro-connections between nerve cells, are vulnerable targets in numerous diseases including Alzheimers and stroke. Also, synaptic changes have long been implicated in learning and memory. However, despite their importance, many fundamental aspects of synaptic function remain mysterious: for example, whether synaptic reorganization occurs upon learning and repair from injuries is poorly understood. This is mainly due to the lack of tools to study the intact brain at cellular resolution.||To overcome these limitations we use animal models of common brain disorders and in vivo 2-photon microscopy. This technique enables the detection of fluorescently-labelled synaptic elements deep below the surface of the intact brain. Cellular structures, previously invisible to ordinary microscopes, can thus be repeatedly visualized in living animals over a wide range of temporal scales, from seconds to several months. This novel approach offers the prospect of discovering synaptic defects at early stages of disease that could be used as therapeutic targets.

Technical Summary

The goal of our programme is to understand at the molecular and cellular level the mechanisms of synaptic plasticity and their relevance to the proper function and neuropathology of the adult mammalian brain.||Central issues in neuroscience are to define the neural substrates of adaptation to experience, learning and memory and ultimately of common brain disorders. Synapses, microstructures that allow interconnection of neural circuits, play a key role in all these processes. In particular, there is ample evidence that synaptic plasticity underlies cognitive functions such as learning and memory and various neuropathologies including Alzheimers and stroke.||However, to date, many fundamental questions about synaptic function and plasticity, despite their importance, remain unanswered. In fact, while functional imaging studies can reveal the brain areas involved in disease, cellular events such as modifications of specific neural circuits and synaptic signalling have remained largely inaccessible to existing approaches in intact mammals. For example, are synaptic sites in the adult brain fixed or can learning and memory change them? Which cellular signalling pathways underlie the stability or modification of neuronal connections and how can they be manipulated to design new therapies for neurological diseases?||Given the extraordinarily complex properties of synaptic networks our contribution towards tackling these issues will be interdisciplinary. We will combine behavioural and advanced molecular genetic, optical and anatomical techniques in mice. We plan to investigate the adaptive modifications of neural circuits especially in the context of defined behavioural paradigms and central nervous system dysfunction.||Specifically, one major avenue of research will be to study the dynamics of identified axonal networks in animal models of common brain disorders with in vivo 2-photon microscopy. This optical tool enables the detection of fluorescently-labelled cellular compartments in scattering tissue up to several hundred microns below the surface of the intact brain. We have recently tracked the dynamics of single axons, individual synapses and even synaptic molecule clusters in living animals over a wide range of temporal scales, from seconds to several months.||This provides a novel way of looking at the cellular and synaptic basis of biological processes such as learning and common pathologies such as fragile-X syndrome and brain injury. We hope this approach will lead to the discovery of synaptic and circuit phenotypes at early stages of disease that could be used as therapeutic targets.

Publications


10 25 50
Allegra Mascaro AL (2013) In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex. in Proceedings of the National Academy of Sciences of the United States of America
Canty AJ (2013) Synaptic elimination and protection after minimal injury depend on cell type and their prelesion structural dynamics in the adult cerebral cortex. in The Journal of neuroscience : the official journal of the Society for Neuroscience
 
Title Damage Limitation 
Description Image created to illustrate our work on antipsychotic medication and inflammation (Bloomfield et al. Submitted) 
Type Of Art Image 
Year Produced 2012 
Impact Increased visibility of the group and Institute. 
URL http://bpod.mrc.ac.uk/archive/2012/9/4
 
Title Growing Again 
Description Image created to illustrate our work on synaptic alterations after laser axotomy (Canty et al. Nat Communications 2013) 
Type Of Art Image 
Year Produced 2013 
Impact Increased visibility of the group and Institute. 
URL http://bpod.mrc.ac.uk/archive/2013/7/28
 
Title Unstable Connections 
Description Image created to illustrate our work on synaptic alterations during ageing (Grillo et al. PNAS 2013) 
Type Of Art Artefact (including digital) 
Year Produced 2013 
Impact Increased visibility of the group and Institute. 
URL http://bpod.mrc.ac.uk/archive/2013/5/25
 
Description Ageing 1
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
 
Description Ageing 2
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description Human neuron grafts
Geographic Reach North America 
Policy Influence Type Gave evidence to a government review
 
Description Next Generation Optical Microscopy to Tackle Neurodiseases
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description BAP training membership/bursary 2014
Amount £200 (GBP)
Organisation British Association for Psychopharmacology 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 07/2014 
End 08/2014
 
Description BSF student bursary 2013
Amount £300 (GBP)
Organisation British Science Association 
Sector Learned Society
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2013 
End 10/2013
 
Description ECNP young scientist award 2013
Amount £500 (GBP)
Organisation European College of Neuropsychopharmacology (ECNP) 
Sector Learned Society
Country European Union (EU)
Start 03/2013 
End 04/2013
 
Description ERASMUS
Amount £4,500 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 04/2010 
End 06/2010
 
Description ERASMUS
Amount £4,500 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 03/2012 
End 05/2012
 
Description Interdisciplinary approaches to life sciences
Amount £4,500 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 04/2009 
End 06/2009
 
Description International Outgoing Fellowship (Cooper-Int Award)
Amount £9,000 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 06/2013 
End 09/2013
 
Description MRC Interdisciplinary Cross Campus PhD Studentship
Amount £102,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2012 
End 10/2015
 
Description MRC imaging call
Amount £957,000 (GBP)
Funding ID MR/K015834/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2013 
End 02/2017
 
Description Wellcome ISSF
Amount £150,000 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2012 
End 09/2013
 
Title Organotypic slice cultures 
Description Preparation of organotypic brain slice cultures for long-term live imaging, elctrophysiology and pharmacology (De Paola et al. 2003 Nat Neurosci). 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact We are currently replacing animals using this technology. 
 
Description Antipsychotic medication in brain inflammation and structure 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we proposed the project
Collaborator Contribution they will provide key expertise
Impact a PhD student is working on the project. A temporary post-doc generated preliminary data which will be used for a grant.
Start Year 2011
 
Description ES cell derived interneurons in vivo 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Monitored the integration of ES cell derived interneurons in the living brain
Collaborator Contribution Set up the in vitro assays to generate the interneurons
Impact Paper published: Cambray et al, Nature Communications 2012
Start Year 2011
 
Description Human derived neuron and organoid grafts 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We proposed the collaboration
Collaborator Contribution The lab of Dr. Rick Livesey will provide key expertise
Impact Invited talk at Keystone Symposium, Axons: form cell biology to pathology, Santa Fe, USA, January 2016
Start Year 2015
 
Description Imaging optical chemical sensors using FRET-FLIM in vivo 
Organisation Faculty of Engineering
Department Department of Bioengineering
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we proposed the project
Collaborator Contribution they will provide key expertise
Impact A PhD student has been recruited
Start Year 2012
 
Description Imaging optical chemical sensors using FRET-FLIM in vivo 
Organisation Faculty of Natural Sciences
Department Department of Physics
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we proposed the project
Collaborator Contribution they will provide key expertise
Impact A PhD student has been recruited
Start Year 2012
 
Description Imaging optical chemical sensors using FRET-FLIM in vivo 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we proposed the project
Collaborator Contribution they will provide key expertise
Impact A PhD student has been recruited
Start Year 2012
 
Description Optogenetic Manipulation of Injured Neural Circuits 
Organisation Faculty of Engineering
Department Department of Bioengineering
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we provide the in vivo imaging expertise to monitor and manipulate injured neural circuits
Collaborator Contribution they provide new key tools
Impact new staff is being appointed
Start Year 2012
 
Description Pharmaco-genetic stimulation of cholinergic pedunculopontine nucleus (PPN) neurons in a Parkinson's model 
Organisation Faculty of Medicine
Department Brain Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We helped with the initial set up (PPL, GM forms, ordering, logistics), the design and strategy (opto vs DREADD, animal group design, virus work, behaviour, ephys, immunocytochemistry), to the execution (behaviour, virus, immuno) of the experiments. Moreover, we helped to obtain key reagents for the project, e.g. the Chat-cre rats, obtained under my HO PPL, and the DREADD virus, which my team amplified, sequenced, checked and bought.
Collaborator Contribution They performed the behavioural, electrophysiological and virus experiments.
Impact Paper published in Molecular neurodegeneration
Start Year 2013
 
Description Sesn3 in human epilepsy 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Functional validation of sesn3 as a regulator of a gene network in mammalian neurons
Collaborator Contribution Identification of Sesn3 as a master regulator of a gene network underlying human epilepsy.
Impact Paper published in Nature Communication
Start Year 2012
 
Title EPBscore 
Description Novel method for computer-assisted analysis of axonal structure and dynamics. 
Type Of Technology Software 
Year Produced 2011 
Open Source License? Yes  
Impact - One paper published in PNAS (Grillo et al., 2013). - Other labs worldwide are using this tool. 
 
Company Name Koniku 
Description the company takes advantage of real neurons in a robust, reproducible and addressable way in order to define an architecture that is capable of tackling problems in visual processing, data processing, and pattern recognition. 
Year Established 2014 
Impact attracted venture capital
Website http://www.koniku.uk/
 
Description AC mentoring 
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 One member of my group also participated in an online mentoring scheme.

One student has been adviced on career paths in medicine after discussing our own research.
Year(s) Of Engagement Activity 2010
 
Description Big Neuron (Cambridge/ London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact The purpose of these events was to encourage collaboration, and participation of people working on the topic of 3D neural reconstructions, and analysis of the 3D reconstructions. The aim is to make automated tools available and open-source online, so that anyone will be able to analyse neuron data. Also, this will standardize analysis methods between different labs/ groups. A landmark paper on this topic is in progress.
Year(s) Of Engagement Activity 2015,2016
URL http://www.alleninstitute.org/article/bigneuron-project-launched-advance-3d-reconstructions-neurons
 
Description British Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Peter Bloomfield in my group gave a talk on the changes in the brain in schizophrenia.
Year(s) Of Engagement Activity 2015
 
Description British Science Festival Birmingham 2014 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact to be updated
Year(s) Of Engagement Activity 2014
URL http://www.britishscienceassociation.org/science-society/public-engagement-resources-0
 
Description British Science Festival, Newcastle 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Peter Bloomfield attended as an Imperial College bursary award student and talked about his scientific interests and project.

Increased visibility for the group and CSC/Imperial.
Year(s) Of Engagement Activity 2013
 
Description CSC newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact One of my lab members, Kat Papadoupolou, has written commentaries on scientific papers which are used together with a striking image to explain in simple terms novel scientific discoveries.
Year(s) Of Engagement Activity 2016
URL http://bpod.mrc.ac.uk/
 
Description Deutsche welle interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact This was a phone interview to comment on research on the brain of London taxi drivers

An article summarizing the interview has been published in
http://www.dw.de/dw/article/0,,15586568,00.html
Year(s) Of Engagement Activity 2012
URL http://www.dw.de/dw/article/0,,15586568,00.html
 
Description Ethical review panel meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact About 25 members of the ethical review panel attended my 25 min talk followed by 15' discussion.

The CERP was visibly pleased by the discussion and left with a better understanding of the impact of mouse work to treat neurological injury.
Year(s) Of Engagement Activity 2009
 
Description FG University of the 3rd Age 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 30 senior citizens from the University of the 3rd Age, which promotes lifelong learning, mainly among retirees attended a talk on 'neural plasticity and ageing' given by my group.

University of the third age senior citizens enjoyed the talk on 'neural plasticity and ageing'. During and after the talk there were numerous questions and a long discussion on learning during ageing.
Year(s) Of Engagement Activity 2011
 
Description Imperial Festival 2015 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact As a cohort we were involved in devising and presenting two exhibits in the Brain Zone of the Imperial Festival 2015. The festival is annual event held at Imperial College London, which aims to share with a wide audience the research being carried out at the college and get the public excited by science. We ran two activities: "Mind Control" required participants to control the height of a drone using an EEG headset and included a creative area encouraging children to design their own "Mind Machine". "Brain Chain" demonstrated the difference between pathological & normal electrical transmission in motor neurons and included a "Build a Brain" competition, challenging visitors to assemble a model brain as quickly as possible. The exhibits provided information about how brain waves can be recorded and analysed, about the nervous system and how disease affects the path of neurological signals, and about basic brain anatomy. Whilst on the stands, we answered questions from a wide range of visitors about the exhibits, about neuroscience in general, about the work that the students at the CDT for Neurotechnology are engaged in, and the impact of these activities. The stands were popular (especially with children) and attracted over 500 visitors over two days, of varying ages and education level.
Year(s) Of Engagement Activity 2015
URL https://www.imperial.ac.uk/be-inspired/festival/about/festival-2015/
 
Description MRC miroscopy workshop with kids 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact >50 pupils attended a microscopy workshop where one of my students, Peter Bloomfield, and one post-doc, Kat Papadoupolou, both participated. This sparked questions and discussions.
Year(s) Of Engagement Activity 2016
 
Description NETT International Conference on System Level Approaches to Neural Engineering 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The aim of the International Conference on System Level Approaches to Neural Engineering (ICSLANE) is to bring together theoretical and experimental neuroscientists and roboticists to discuss the state of the art in the field of Neural Engineering. This three day long event is part of a series of training events organised by the Marie Curie Initial Training Network NETT (Neural Engineering Transformative Technologies).
Year(s) Of Engagement Activity 2015
URL http://www.neural-engineering.eu/BarcelonaConference2015/index.html
 
Description Native scientist talks 
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 Two members of my lab, Raquel real, MD and Kat Papadoupolou, PhD, gave science talks to school children aged 7-10 in an attempt to engage immigrant communities.
Year(s) Of Engagement Activity 2015
URL http://www.nativescientist.com/
 
Description Skeptics in the pub 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact One of my students gave a talk on the changes in the brain in schizophrenia
Year(s) Of Engagement Activity 2015
 
Description Strictly Science 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact This event was very well attended.

Increased visibility for the group.
Year(s) Of Engagement Activity 2013
URL http://www.centenary.mrc.ac.uk/strictlyscience/today/
 
Description Synaptic plasticity and Repair twitter page 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact We have started our own twitter page where we post articles and comments related to our work on synaptic connectivity and human stem cells.
Year(s) Of Engagement Activity 2016
URL https://twitter.com/DePaola_Lab
 
Description media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was interviewed by the new scientist regarding a recent Nature paper on the role of complement protein in Schizophrenia and synaptic elimination.
Year(s) Of Engagement Activity 2016
 
Description mentoring 
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 I mentored one student as part of an online mentoring scheme

The student has been advised on career paths after discussions on the research in my MRC group.
Year(s) Of Engagement Activity 2010