ACTIVITY-DIFFUSION COUPLING IN NEURAL SIGNALLING

Lead Research Organisation: University College London
Department Name: UNLISTED

Abstract

Physiological interpretation of changes detected with diffusion-weighted MRI in the human brain remains an outstanding medical issue. We believe that the proposed project will provide important insights into this problem and thus will assist in understanding the underlying neural pathologies. Furthermore, a better understanding of the mechanisms that regulate cortical excitability will give us an insight into new approaches to the treatment of epilepsy. MCW frequently appears at public meetings organised by the National Society for Epilepsy and Epilepsy Action, and has helped the BBC establish an information resource on epilepsy (http://www.bbc.co.uk/health/epilepsy/).

Technical Summary

Diffusion-weighted magnetic resonance imaging (DW-MRI) detects physiological changes in the brain by highlighting alterations in local water diffusivity. However, the causal relationship between diffusivity and neural activity is poorly understood. Synaptic physiology studies have suggested that extracellular diffusion influences the occupancy of high-affinity synaptic receptors by remotely released neurotransmitter molecules. In this project we develop a novel two-photon photobleaching method to estimate extracellular diffusivity in brain tissue at high spatial resolution. We explore how regional differences in extracellular diffusivity influence the extent of extrasynaptic signalling. We also apply these methods to determine how extracellular diffusion of neurotransmitters is altered in epileptic tissue. The expected results will provide important clues to (a) the role of high- versus lower- affinity synaptic receptors in extrasynaptic signalling (and possibly seizure initiation) within distinct hippocampal circuitries and (b) the physiological interpretation of diffusivity changes in the brain detected with DW-MRI.

Publications

10 25 50
 
Description European Commission Panel of Experts (Awarding Panel in Neurosciences, 2005-2006)
Geographic Reach Asia 
Policy Influence Type Influenced training of practitioners or researchers
Impact Influenced science funding policy in neuroscience and neurology across Europe.
 
Description Wellcome Trust Senior Fellowhip (Renewal)
Amount £1,350,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2013
 
Title Single-bouton recordings and imaging 
Description A technique to carry out patch-clamp recording and and simultaneously image Ca2+ in small axonal boutons 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Publications and new techniques 
 
Title point-source line-scan diffusion measurement 
Description A new point-source line-scan imaging technique has been developed to assess extracellular molecular mobility (diffusivity) in brain tisssue. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This technique has allowed measurements of extracellular molecular mobility in the hippocampus providing an important alternative to the only existing technique. 
 
Title A large scale biophysical computer model of synaptic microenvironment 
Description A large scale biophysical computer model of synaptic microenvironment is designed for Monte-Carlo simulations of rapid molecular evemts inside and outside the synaptic cleft, ion 3D brain tissue. 
Type Of Material Computer model/algorithm 
Year Produced 2010 
Provided To Others? Yes  
Impact High-impact publications. 
 
Description Fluctuations in release probability 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Electrophysiological data
Collaborator Contribution Simulation data
Impact artilce in Nature Neuroscience
 
Description GABA signalling in neurogliaform cells 
Organisation University of Oxford
Department MRC Anatomical Neuropharmacology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Specifci research ideas, experiments and designs
Collaborator Contribution Specific experiments
Impact Two papers in the Journal of Neuroscience
Start Year 2006
 
Description LTP and D-serine release from astrocytes 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Academic/University 
PI Contribution Dr Stephane Oliet, INSERM Bordeaux, France.
Collaborator Contribution Provided electropohysiological data
Impact Christian Henneberger, Thomas Papouin,3, Stéphane H. R. Oliet, & Dmitri A. Rusakov. Nature (in press).
Start Year 2006
 
Description NMDA receptor function 
Organisation University College London
Department Centre for Clinical Pharmacology & Therapeutics
Country United Kingdom 
Sector Academic/University 
PI Contribution Caried out imaging experiments
Collaborator Contribution Supplied mouse model
Impact Article in EMBO Journal
Start Year 2006
 
Title A large-scale Monte-Carlo model of synaptic environment 
Description A library of programs for Monte Carlo simulations of rapid molecular events inside and outside the synaptic cleft. Written by Drs L Savtchenko and K. Zheng. 
Type Of Technology Software 
Year Produced 2007 
Impact Several high-profile publications 
 
Title A large-scale computer model environment for exploring realistic neuronal networks 
Description A large-scale computer model environment for exploring realistic neuronal networks. Allows inclusion of >100,000 individual NEURON-type cells. Enabled for parallel computing on the cloud. 
Type Of Technology Software 
Year Produced 2013 
Impact High-impact publications reflecting some fundamental scientific observations. 
 
Title Dedicate 64-core computer cluster 
Description A dedicated in-house 64(+) computer cluster (parallel computing enabled) for biophysical and neural network modelling including computational environment. Designed and built by Dr K. Zheng. 
Type Of Technology e-Business Platform 
Year Produced 2008 
Impact High-profile publications reflecting several scientific discoveries. 
 
Title Fluorecence anisotropy imaging 
Description An image analysis tool allowing to translate two FLIM signals (parallel and perpendicular) into local rotation correlation parameter across the imaged region of interest. Applied to map local instantaneous molecular diffusion. 
Type Of Technology Software 
Year Produced 2010 
Impact Book chapter. Being implemented to gauge molecular diffusivity at nanoscale. 
 
Description International lectures at major research conferences and university deprtments 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talks were noted internationally.

This question and example are not serious.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014
 
Description Membership of international advisory bodies and reviewing panels: 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Decisions made

Influencing science policy and funding
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014
 
Description Peer-reviewing for major funding bodies 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact N/A

Decision made
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014
 
Description Peer-reviewing for top-tier science journals 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Publications

N/A
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014