Information processing within the input layers of the cerebellum and barrel cortex

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

Abstract

The question of how the brain processes information about the body and the surrounding world is one of the most exciting and challenging problems in science today. It also has important implication for health because it is difficult to design treatments for diseased states when
it is not understood how brains function normally. In this study we will examine the mechanisms underlying information processing in two major brain regions involved in motor function: the cerebellum and cortex. The cerebellum and cortex are made up of several layers with each layer being made up of many cells (neurons). Since processing occurs roughly sequentially through the layers we will study the input layers of these brain structures, where the earliest stages of processing occur, because understanding their function is essential for understanding subsequent processing. We will use a combination of newly developed methods including laser-based imaging of cellular activity, electrical measurements and computer modelling to understand how the electrical properties of individual cells and their connections contribute to the complex and dynamic processing of signals within the neuronal network.

Technical Summary

An important objective in neuroscience is to understand how information is processed in various brain regions, thereby laying a basis for understanding brain function and how the properties of neural networks are disrupted during disease. Recent application of the patch-clamp method to in vivo preparations has allowed recordings from small cells for the first time, together with accurate subthreshold voltage measurements and relatively unbiased cell selection. This has provided a more complete picture of the input properties and activity of single cells within cerebellar and cortical networks under physiological conditions. However, these new insights have highlighted our lack of knowledge of the signal processing being performed, in particular, the way in which signals are transformed at the synaptic and cellular level. We will use in vitro slice preparations, which are amenable to experimental manipulations, combined with physiologically realistic excitation, derived from in vivo recordings, to examine the synaptic and cellular basis of signal processing in the input layers of cerebellum and barrel cortex. By collaborating with in vivo experimentalists, and by using rapid 2-photon calcium imaging, localized neurotransmitter uncaging and dynamic clamp techniques in vitro, together with biologically realistic network modeling we will bridge the gap in our knowledge between in vivo descriptions of neuronal activity and the synaptic, cellular and network mechanisms that underlie it.

Publications

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DiGregorio DA (2007) Desensitization properties of AMPA receptors at the cerebellar mossy fiber granule cell synapse. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Kanichay RT (2008) Synaptic and cellular properties of the feedforward inhibitory circuit within the input layer of the cerebellar cortex. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description ANR-BBSRC SysBio Initiative
Amount £320,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2008 
End 06/2011
 
Description ERC Advanced grant
Amount € 2,500,000 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 03/2012 
End 02/2017
 
Description Wellcome Trust Biomedical resources Award (Development and standardization of biologically realistic neural network models through an open source database)
Amount £1,048,732 (GBP)
Funding ID 086699 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2008 
End 11/2013
 
Description Wellcome Trust Principal Research Fellowship
Amount £2,700,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2016
 
Title AOD based high speed 3D 2-photon microscopy 
Description Measuring neuronal activity at physiologically relevant time scales within a 3D network of neurons is essential for understanding how information is processed in the brain. Unfortunately, the best methods currently available for measuring neural activity in networks are very limited. For this reason we have developed a new type 2-photon microscope that can focus and scan at high speed. This technology, which is based on acousto-optic devices, has submicrometer spatial resolution and measurement bandwidth of >30kHz. Preliminary data from our prototype microscope demonstrates that this method will allow the activity of many tens of neurons distributed in 3D space to monitored at kilohertz rates. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact We have filed 3 patent applications on this technology and published a detailed paper on the microscope design (20588506). I have also presented our results at microscopy conferences (UK, Netherlands and France) and at conferences on imaging in neuroscience (UK, France). It has generated a lot of interest and we are presently writing up a series of papers describing this new technology and its application to imaging neural networks. 
 
Title Multiple-Probability Fluctuation Analysis (Variance-mean analysis) 
Description Multiple-Probability Fluctuation Analysis (Variance-mean analysis) is a fluctuation analsyis method for determining the functional (quantal) properties of central synapses. We have continued to improve Multiple-Probability Fluctuation Analysis by developing a new statisical approach for esimating errors in the variance-mean plot. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? Yes  
Impact This quantitative analysis method is widely used by groups working on synaptic transmission across the world. The latest developments in this method have been published in this reporting period (16376992 and 18828002) 
 
Title NeuroConstruct 
Description Computer models of neuronal networks can help us understand how synaptic and cellular mechanisms underlie brain function in health and disease. However, these complex models are difficult to develop and are inaccessible to most neuroscientists. To overcome this we have developed a new software tool, neuroConstruct, for constructing, visualising and analysing conductance-based neural network models in 3D space. A user friendly interface and automated code generation for existing neuronal simulators allow models to be built, modified and run without specialist programming knowledge, making it suitable for experimentalists, theoreticians and teaching. The 3D nature of the models generated, and the powerful inbuilt connectivity algorithms allow models of greater biological realism to be created and verified and enable direct comparison with imaging experiments. Neuroconstuct is freely available form neuroConstruct.org. 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact Since neuroconstruct was released in 2007 upon publication (17442244) it has been downloaded by 1500 users across the world. It is used as core software on courses on computational Neuroscience. It has also been used in several published studies both from our lab (19145233) and from other labs around the world. 
URL http://www.neuroconstruct.org/
 
Title NeuroML: a language for describing data driven models of neurons and networks 
Description Biologically detailed single neuron and network models are important for understanding how ion channels, synapses and anatomical connectivity underlie the complex electrical behavior of the brain. NeuroML (NeuroML.org) is an XML based language for specifying data driven models of neurons and networks with a high degree of biological detail. NeuroML facilitates the exchange of complex neural models across specialist simulators, allowing greater transparency, validation and accessibility of models. There are a growing number of applications with support for NeuroML. 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact NeuroML is an international collaborative effort that has been recognized by the INCF as a potential standard for computational neuroscience. We have built a website for this open source project, which provides information and validation tools for this initiative. The development of NeuroML is actively ongoing. The first version of NeuroML can be used to define and store a wide range of existing computational neuroscience models. We are also currently working with simulator developers to make their software NeuroML complaint. 
URL http://www.neuroml.org/
 
Title NeuroMatic 
Description NeuroMatic is a software application built in the Igor Pro environment for analyzing and acquiring electrophysiological data. It is freely available from www.neuromatic.thinkrandom.com. By allowing users to organize their data into Sets and Groups, NeuroMatic makes it relatively easy to compute transformations and perform statistical analysis on their data, including scaling, alignment averaging, baseline subtraction, spike detection, stationarity analysis, rise-time computations, etc. Being open source and of a modular design, NeuroMatic also allows users to develop their own analysis functions that can be easily incorporated into NeuroMatic's framework. This software is written by a single member of my lab but includes algorithms developed by others in the Silver Lab. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact This software has been downloaded by over 2000 users worldwide and is widely used in electrophysiology labs across the world. 
URL http://www.neuromatic.thinkrandom.com/Install.html
 
Description Determinants of information processing in Cerebellum 
Organisation Hungarian Academy of Sciences (MTA)
Department Institute of Experimental Medicine
Country Hungary 
Sector Academic/University 
PI Contribution Provide electrophysiology, imaging and modelling to the project.
Collaborator Contribution Contibute quantitative anatomical studies.
Impact Rapid desynchronization of an electrically coupled interneuron network with sparse excitatory synaptic input. Neuron. 2010 Aug 12;67(3):435-51. Gap junctions compensate for sublinear dendritic integration in an inhibitory network. Science. 2012 Mar 30;335(6076):1624-8.
Start Year 2006
 
Description Development of NeuroML 
Organisation Arizona State University
Country United States 
Sector Academic/University 
PI Contribution We have been the main contributor and developer of the NeuroML initiative.
Collaborator Contribution The Crook Lab collaborates with my Lab on the open source NeuroML project (NeuroML.org), which is developing a model description language for single neuron and network models in computational neuroscience.
Impact A description of the part of NeuoML that deals with neuronal morphologies was published in 2007 (Pubmed ID 17873371). A website describing this initiative, together with software tools is available at (NeuroML.org). NeuroML: a language for describing data driven models of neurons and networks with a high degree of biological detail. PLoS Comput Biol. 2010 Jun 17;6(6):e1000815.
Start Year 2006
 
Description Simulating cerebellar function 
Organisation Okinawa Institute of Science and Technology
Country Japan 
Sector Academic/University 
PI Contribution A member of my lab, who was the first author on this study, carried out the extensive computer simulations for this mainly theoretical study. We also provided intellectual input and all contributed to writing the paper.
Collaborator Contribution Collaborative project on cerebellar Purkinje cell function.
Impact We published a paper in Neuron entitled Cerebellar LTD and pattern recognition by Purkinje cells (17408582). This generated considerable interest and was featured in a Comment article entitled 'Pauses as neural code in the cerebellum' . Determinants of synaptic integration and heterogeneity in rebound firing explored with data-driven models of deep cerebellar nucleus cells. J Comput Neurosci. 2010
Start Year 2006
 
Title IMAGING APPARATUS AND METHODS 
Description Design details of a compact 3D 2-photon scanhead based on acousto-optic deflectors. This includes the properties of the crystals, their arrangement and the way they can be driven to point and scan a laser beam over a 3D volume. It also includes a design for correcting chromatic aberrations within the system. 
IP Reference WO2008032061 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact These designs form the basis of our prototype microscope. We are currently in discussions with microscope manufactures regarding the possibility of commercialization.
 
Title OPTICAL BEAM DEFLECTION APPARATUS AND METHODS 
Description This patent extends our previous patent on 3D 2-photon imaging by combining it with galvanometer scanning, thereby allowing larger volumes to be imaged. 
IP Reference WO2009087392 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact The inventions in this patent may be used in any commercialization of the microscope.
 
Title AOL microscope 
Description We have developed a new type of 2-photon microsope that uses a novel acousto-optic lens to scan and focus a laser beam. This allows rapid processes to be monitored in 3D space. We are using this technology to study rapid distributed signalling in neuronal dendrites and neurona populations. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2010
Development Status Actively seeking support
Impact This provides a new tool for neuroscience research. 
 
Description BA Science festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact A member of my lab was a science and engineering ambassador and was involved in science demonstrations at the BA Science festival in Liverpool.

Enhancing science awareness and encouraging school children to pursue science.
Year(s) Of Engagement Activity 2008
 
Description Software Release 
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 We made the software application neuroConstruct freely available from neuroConstruct.org upon publication of the companion paper.

To date we have had 1500 user downloads from over 40 countries worldwide. Several of these downloads are from the interested public.
Year(s) Of Engagement Activity 2007
 
Description Software release 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Release of computer language for describing biologically detailed models of neurons and networks. Also several models made available in this format.

Software resources.
Year(s) Of Engagement Activity 2010