Investigating the mechanisms of structural plasticity in mouse visual cortex in vivo using chronic two-proton imaging

Lead Research Organisation: University College London
Department Name: Neuroscience Physiology and Pharmacology

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Circuits in the brain have the ability to adapt to novel experiences and environments. These changes are facilitated through a combination of functional plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), and structural changes, such as the addition or subtraction of boutons and spines, the putative pre- and postsynaptic components of the synapse. While both aspects of plasticity are important, the study of long-term structural plasticity in vivo has only recently become feasible with the advent of two-photon microscopy. In this proposal, I outline a series of experiments that investigate the mechanisms of structural plasticity using chronic in vivo two-photon and intrinsic signal imaging techniques in combination with molecular tools. Previously, we developed a retinal lesion paradigm in mice that induces massive functional and structural plasticity in both excitatory and inhibitory cortical neurons. Because the plasticity occurs in the visual cortex, optical imaging and/or electrophysiology in combination with visual stimulation can be used to measure the degree of functional plasticity. I will utilize this paradigm as a tool to investigate the mechanisms that drive structural changes at the single cell level. In the first set of experiments, I will investigate the degree to which activity drives structural plasticity (as suggested by in vitro experiments, as well as my own data). Using molecular tools, such as the genetically encoded calcium indicator TN-XXL, which allows for the chronic measurement of structural and functional dynamics in a single cell, I will measure the functional and structural changes that occur after the retinal lesion plasticity paradigm. Then, using channel rhodopsin 2, a light-gated algal channel that reliably generates action potentials when stimulated with blue light, I will stimulate cells in control animals with the previously measured activity patterns to determine the degree to which activity drives structural plasticity. In a second set of experiments, I will investigate the role of molecular signaling in structural plasticity. I will first investigate the role of Otx2, a molecule known to be important in functional plasticity, using Otx2 knock-out mice. Using the same molecular tools described above, I will determine the degree to which structural plasticity is altered in these transgenic mice. In the long term, after characterizing mechanisms of structural plasticity, I plan to investigate which of these mechanisms are deficient in disease states with altered structural dynamics, such as Fragile X syndrome and Alzheimer’s disease.

Publications

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Chen JL (2013) Imaging neuronal populations in behaving rodents: paradigms for studying neural circuits underlying behavior in the mammalian cortex. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Keck T (2017) Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions in Philosophical Transactions of the Royal Society B: Biological Sciences

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Lyamzin DR (2015) Nonlinear transfer of signal and noise correlations in cortical networks. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Sammons RP (2015) Adult plasticity and cortical reorganization after peripheral lesions. in Current opinion in neurobiology

 
Description pz
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description rsa
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description European Research Council Starting Grant
Amount € 1,494,474 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 01/2013 
End 12/2017
 
Description King's international studenship
Amount £30,000 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 10/2013
 
Description Wellcome Senior Research Fellowships
Amount £1,568,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 08/2023
 
Description royal society researach grant
Amount £14,932 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 08/2012
 
Description Butz 
Organisation Free University of Amsterdam
Department Center for Neurogenomics and Cognitive Research
Country Netherlands 
Sector Academic/University 
PI Contribution We collaborate with computational neuroscientists on the mechanisms of structural plasticity. Their computational models suggest potential molecular mechanisms, which we have begun to check in experimental preparations.
Collaborator Contribution Our partners have modeled aspects of our data to gain insights into the mechanisms underlying our findings.
Impact This collaboration has lead to work presented at the meeting of the organization of computational neuroscience in 2011. We presented the experimental neuroscience and our collaborators presented the computational models of this data.
Start Year 2010
 
Description Georg Keller 
Organisation Friedrich Miescher Institute for Biomedical Research (FMI)
Country Switzerland 
Sector Academic/University 
PI Contribution We have provided structural imaging and electrophysiology data to projects in this collaboration.
Collaborator Contribution They have provided in vivo functional imaging data related to projects in this collaboration.
Impact Multiple publications have resulted from this collaboration (Barnes et al., 2015, Keck et al., 2013). This is not multi-disciplinary.
Start Year 2010
 
Description Presented neuroscience research at United Nations Office in Bangkok 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Third sector organisations
Results and Impact I visited the United Nations Office in Bangkok to explain our research findings.
Year(s) Of Engagement Activity 2016
 
Description student did internship in lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact we had a 15 year old pupil visit the lab for two weeks and work on a small research project. she has since reported interest in studying neuroscience at university.
Year(s) Of Engagement Activity 2016
 
Description student internship in lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact A student from a low-income background did a research project in the lab for two weeks.
Year(s) Of Engagement Activity 2014
 
Description visit Harrow School for Boys 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 40 pupils in the local science club (ages 14-17) attended a my presentation on neuroscience research. It led to an extended discussion afterward.
Year(s) Of Engagement Activity 2015