Thalamocortical interactions during development

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

The human brain is made up of individual units- nerve cells (or neurons) and glial cells. One of the most important questions in the field is to understand how these neurons establish connections with each other to form functional circuits in different areas in the brain with distinct functions. Sensory organs send information they receive from the environment to the specialised visual, auditory and somatosensory cortical regions in the brain through a relay centre called the thalamus. How are the connections linking these regions formed? To understand this mechanism we must study early stages of development and look for the factors and elements that control their correct formation. Recent studies on genetically modified mice have identified families of molecules that are involved in early stages of thalamic development. Using these mice major recent advances have been made, implicating genes in the direct control of area identities in early stages development. We will use advanced techniques to test other candidate molecules and examine the influence of thalamic input on the development of the cortical cells. Moreover, we shall further investigate the mechanisms by which specific thalamic nerve fibres connect to a particular cortical area. It has been suggested that in addition to these factors, how neurons communicate with each other is also crucial for a correct formation and maintenance of connections. Several mutant mice lacking specific proteins involved in neural communication are also available. We are planning to study these mutant mice in order to elucidate the precise role of neuronal communication in generating a correctly assembled mature brain. This research is important to establish how environmental factors interact with genetic information to produce a correctly wired brain.

Technical Summary

The cerebral cortex constitutes half the volume of the human brain and is presumed to be responsible for the neuronal computations underlying such complex phenomena as perception, thought, language, attention, episodic memory and voluntary movement. While some components of the cerebral cortical areal specialization are determined by differential patterns of commitment at an early stage, there is considerable evidence that developing cortex is partly multipotential and that a localized extrinsic signal is needed as an epigenetic cue to determine the ultimate differentiation of each area. The thalamic projections, which arrive early to the cortex, are strong candidates for this extrinsic signal. We propose to investigate the various forms of interactions between the thalamic fibres and different compartments of the developing mouse cortex at well defined periods of thalamocortical development as thalamic projections accumulate within the subplate layer below the developing cortical plate and while they invade the cortex and start to recognize their ultimate target cells in layer 4. The proposed projects present unique opportunities to address fundamental questions. (1) We shall examine whether or not thalamic projections influence cortical neurogenesis. (2) We shall investigate the role of the earliest functional connections in the delivery and layerspecific targeting of thalamocortical projections. We wish to examine the contribution of the various forms of transmission (regulated, spontaneous, paracrine vesicle release) in thalamocortical and cortical development using Snap-25 and Munc-18 KO mice and in paradigms created in organotypic co-cultures. (3) Using selected mutants (Sema6A KO, L1 KO and reeler mutant mice and Shaking Rat Kawasaki) we are particularly interested in further investigating the mechanisms by which thalamic projections home into a particular cortical region and layer. The proposal would start to identify ontogenetic programs responsible for key developmental events whose disruption could lead to numerous malformations and devastating diseases such as childhood epilepsy, schizophrenia and autism. We are in a competitive position to perform the experimental work since we have already made contributions to the field, accumulated a large volume of pilot data and key collaborations are in place. I have had a long standing interest in cerebral cortical development and application of in vitro methods, including organotypic co-culture and thalamocortical slice preparations. In addition the proposals are particularly timely since some of the technologies and transgenic animals have just became available. The MRC support would enable me to consolidate my position in this exciting and growing field.

Publications

10 25 50
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Abdel-Mannan O (2008) Evolution of cortical neurogenesis. in Brain research bulletin

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Bystron I (2006) The first neurons of the human cerebral cortex. in Nature neuroscience

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Cheung AF (2007) Comparative aspects of cortical neurogenesis in vertebrates. in Journal of anatomy

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Guillemot F (2006) Molecular mechanisms of cortical differentiation. in The European journal of neuroscience

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Hanashima C (2006) Building bridges to the cortex. in Cell

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Hoerder-Suabedissen A (2008) Thalamocortical maturation in mice is influenced by body weight. in The Journal of comparative neurology

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Hoerder-Suabedissen A (2009) Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. in Cerebral cortex (New York, N.Y. : 1991)

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Jeans AF (2007) A dominant mutation in Snap25 causes impaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse. in Proceedings of the National Academy of Sciences of the United States of America

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Molnár Z (2006) Comparative aspects of cerebral cortical development. in The European journal of neuroscience

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Molnár Z (2006) Foreword to reviews on molecular and cellular basis of cortical development (CONCORDE). in The European journal of neuroscience

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Molnár Z (2007) Genes involved in the formation of the earliest cortical circuits. in Novartis Foundation symposium

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Métin C (2007) Conserved pattern of tangential neuronal migration during forebrain development. in Development (Cambridge, England)

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Price DJ (2006) The development of cortical connections. in The European journal of neuroscience

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Rakic S (2006) Role of p35/Cdk5 in preplate splitting in the developing cerebral cortex. in Cerebral cortex (New York, N.Y. : 1991)

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Stubbs D (2009) Neurovascular congruence during cerebral cortical development. in Cerebral cortex (New York, N.Y. : 1991)

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Tuoc TC (2009) Selective cortical layering abnormalities and behavioral deficits in cortex-specific Pax6 knock-out mice. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Title Artworks generated by pupils and audience after neuroscience lectures 
Description https://history.medsci.ox.ac.uk/art/activities/brain-portraits/A resource for teaching Science, art and creativity Resource of new ideas to spark the imagination for teaching science through art with downloadable activities Nobel prize winning scientist, Sir Charles Scott Sherrington, was a neuroscientist who was passionate about teaching. He was an extraordinary man - a curious, creative scientist who expressed and explored his wonder at life through writing and poetry. Scientist-turned-artist, Dr Lizzie Burns, has used Sherrington's words and ways of looking at the world to create cross-curricular resources for primary, secondary schools and beyond The website is generated in collaboration with Dr Burns and the History of Medical Sciences website (Dr Damion Young and Dr Zoltan Molnar and colleagues). 
Type Of Art Artefact (including digital) 
Year Produced 2013 
Impact We received feedback on our website: https://history.medsci.ox.ac.uk/art/feedback/, indicating that the audience was engaged. 
URL https://history.medsci.ox.ac.uk/art/activities/brain-portraits/
 
Title The Oxford Science and Ideas Festival - The consciousness field 
Description https://www.dpag.ox.ac.uk/news/the-oxford-science-and-ideas-festival http://www.theconsciousnessfield.com/index.html Once again researchers from across our Oxford Neuroscience Community pulled all the stops out for the Oxford Science and Ideas Festival. Extensive programmes of activities were run by the Nuffield Department of Clinical Neurosciences and the Department of Experimental Psychology. In addition, the Department of Physiology, Anatomy and Genetics' Zoltan Molnar in collaboration with Colin Blakemore and St John's College put on a holographic presentation 'The Consciousness Field' created by artist Maria Lopez. 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2018 
Impact The exhibition was very well attended and the general public had the chance to ask questions from researchers and artists. http://www.theconsciousnessfield.com/index.html 
URL https://www.dpag.ox.ac.uk/news/the-oxford-science-and-ideas-festival
 
Description Emphasized the human specific differences in cortical development
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
URL http://www.ncbi.nlm.nih.gov/pubmed/20979582
 
Description Regularly lecture on Neuropathology Courses in Europe and in the Royal College of Pathologists
Geographic Reach Asia 
Policy Influence Type Influenced training of practitioners or researchers
Impact The Royal College of Pathologists Continuing Professional Development and European Confederation of Neuropathological Societies (EURO-CNS) CME regularly ask me to give lectures on their courses on basic cerebral cortical development. These interactions help with the translation of basic research directly to the clinic. Neuron-specific markers (cortical subplate neurons) are beginning to be evaluated after hypoxic ischaemia in human currently in collaboration with several groups. My latest meeting was: Joint Meeting of the Paediatric Pathology Society and the Society of Pediatric Pathology 4-6 Sep 2014 in Birmingham
URL http://www.paedpath.org/news.php?readmore=95
 
Description BBSRC Project Grant
Amount £600,000 (GBP)
Funding ID BB/F003285 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2007 
End 04/2010
 
Description John Fell Fund (Oxford Uni)
Amount £15,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start  
 
Description MRC Project Grant
Amount £600,000 (GBP)
Funding ID G0700377 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2007 
End 09/2010
 
Description NEUROBID FP7-HEALTH-2009 No:241778- "Neuroscience on Barriers in Development"
Amount £200,000 (GBP)
Funding ID 241778 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start  
 
Title High quality RNA from multiple brain regions 
Description We established and optimised a method for the collection of high quality RNA from multiple brain regions, which were simultanelously acquired by laser capture microdissection. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact The publication (PMID:19580671) has been requested from us by numerous groups even before its publication. 
URL http://europepmc.org/abstract/MED/19580671
 
Title Modern tracing methods with carbocyanine dyes. 
Description We optimised conditions for the use of multiple fluorescent carbocuanine dyes in various systems and species (including human postmortem specimen). The advantage of this method is that it can be used on fixed material, therefore it is contributing to 3Rs! 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact We published the summary of our methods: Molnár Z, Blakey D, Bystron I, Carney R, (2006) Tract-tracing in developing systems and in post-mortem human material. Neuroanatomical Tract-Tracing 3: Molecules - Neurons - Systems, Springer/Kluwer/Plenum, NY, (Editors: L Zaborszky, FG Wouterlood, JL Lanciego). Chapter 12:336-393. 
URL http://books.google.co.uk/books?id=-vPcRekAT6oC&pg=PA362&lpg=PA362&dq=L+Zaborszky,+FG+Wouterlood,+JL...
 
Title Subplate neuronal markers - P8 
Description We performed microarray analysis on postbatal 8 days old mouse subplate and layer 6. This data has been published: PMID: 19008461 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. Hoerder-Suabedissen A, Wang WZ, Lee S, Davies KE, Goffinet AM, Rakic S, Parnavelas J, Reim K, Nicolic M, Paulsen O, Molnár Z. Cereb Cortex. 2009 Aug;19(8):1738-50. 
URL http://europepmc.org/abstract/MED/19008461
 
Title Online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. 
Description Here we present gene expression evidence for distinct roles of the mouse subplate across development as well as unique molecular markers to extend the repertoire of subplate labels. Performing systematic comparisons between different ages (embryonic days 15 and 18, postnatal day 8, and adult), we reveal the dynamic and constant features of the markers labeling subplate cells during embryonic and early postnatal development and in the adult. This can be visualized using the online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. We also identify embryonic similarities in gene expression between the ventricular zones, intermediate zone, and subplate, and distinct postnatal similarities between subplate, layer 5, and layers 2/3. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Our database (https://molnar.dpag.ox.ac.uk/subplate/) help the general research community to find suitable markers to reveal subplate, the early generated, largely transient cell population. 
URL https://molnar.dpag.ox.ac.uk/subplate/
 
Description Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex 
Organisation Max Planck Society
Department Max Planck Institute for Experimental Medicine
Country Germany 
Sector Public 
PI Contribution We analysed the connections in the Satb2 KO and participated in gene expression analysis.
Collaborator Contribution The group gave access to various mouse mutants to test some of our ideas on brain development.
Impact 18255031 16519651
Start Year 2006
 
Description Snap 25 KO analysis 
Organisation Medical Research Council (MRC)
Department MRC Functional Genomics Unit
Country United Kingdom 
Sector Public 
PI Contribution We performed all the analomical and hystopathological analysis of the Snap25 mutant and compared this result to the Snap25 KO.
Collaborator Contribution The MRC FGU helped us with behavioural analysis and with gene expression analysis (microarray work).
Impact 17283335
Start Year 2006
 
Description Study cortical development in the conditional Pax6 KO 
Organisation Max Planck Society
Department Department of Molecular Cell Biology
Country Germany 
Sector Public 
PI Contribution We performed most of the histological and gene expression analysis. We traced the early connectivity in the mutant and imaged and documented the results.
Collaborator Contribution We have been examining the laminar and areal differentiation of the cerebral cortex in the absence of Pax6.
Impact 19571125 18753373
 
Description Thalamocortical development in Sema6A KO 
Organisation Max Planck Society
Department Department of Molecular Cell Biology
Country Germany 
Sector Public 
PI Contribution Our group is expert in the study of thalamocortical and corticofugal development in embryonic and postnatal stages. We analysed these pathways in the Sema6A KO model.
Collaborator Contribution We jointly studied the Sema6A KO mouse model. This model was generated and maintained at Dublin.We have studied the cortical layer specification and arealization in the Pax6 conditional KO mouse. The partnership started on a previous EU Grant, but has been ongoing for more then 10 years.We have used the Golli-tau-eGFP transgenic mouse model to study the integration of the subplate neurons into the intra and extracortical circuitry in the mouse barrel cortex.The group helped us to study the Tbr2 KO model, which helped us to get a functional insight into the possible functions of the different cortical progenitors.
Impact 19402755
 
Description Thalamocortical development in Sema6A KO 
Organisation Trinity College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution Our group is expert in the study of thalamocortical and corticofugal development in embryonic and postnatal stages. We analysed these pathways in the Sema6A KO model.
Collaborator Contribution We jointly studied the Sema6A KO mouse model. This model was generated and maintained at Dublin.We have studied the cortical layer specification and arealization in the Pax6 conditional KO mouse. The partnership started on a previous EU Grant, but has been ongoing for more then 10 years.We have used the Golli-tau-eGFP transgenic mouse model to study the integration of the subplate neurons into the intra and extracortical circuitry in the mouse barrel cortex.The group helped us to study the Tbr2 KO model, which helped us to get a functional insight into the possible functions of the different cortical progenitors.
Impact 19402755
 
Description Thalamocortical development in Sema6A KO 
Organisation University of California, Los Angeles (UCLA)
Department Neuropsychiatric Institute UCLA
Country United States 
Sector Academic/University 
PI Contribution Our group is expert in the study of thalamocortical and corticofugal development in embryonic and postnatal stages. We analysed these pathways in the Sema6A KO model.
Collaborator Contribution We jointly studied the Sema6A KO mouse model. This model was generated and maintained at Dublin.We have studied the cortical layer specification and arealization in the Pax6 conditional KO mouse. The partnership started on a previous EU Grant, but has been ongoing for more then 10 years.We have used the Golli-tau-eGFP transgenic mouse model to study the integration of the subplate neurons into the intra and extracortical circuitry in the mouse barrel cortex.The group helped us to study the Tbr2 KO model, which helped us to get a functional insight into the possible functions of the different cortical progenitors.
Impact 19402755
 
Description Thalamocortical development in Sema6A KO 
Organisation University of Oxford
Department Sir William Dunn School of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Our group is expert in the study of thalamocortical and corticofugal development in embryonic and postnatal stages. We analysed these pathways in the Sema6A KO model.
Collaborator Contribution We jointly studied the Sema6A KO mouse model. This model was generated and maintained at Dublin.We have studied the cortical layer specification and arealization in the Pax6 conditional KO mouse. The partnership started on a previous EU Grant, but has been ongoing for more then 10 years.We have used the Golli-tau-eGFP transgenic mouse model to study the integration of the subplate neurons into the intra and extracortical circuitry in the mouse barrel cortex.The group helped us to study the Tbr2 KO model, which helped us to get a functional insight into the possible functions of the different cortical progenitors.
Impact 19402755
 
Description 15 BM lectures/year 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact I give about 15 lectures (to 150-200 medical students) and give over 50 hours of practicals (75 students present at the time) and about 140 hours of tutorials (1-6 students present). In this capacity I educate the future generation of medical practitioners about important aspects of basic research and their translation to the clinic.

Several of my students started distinguished research and clinical career within UK or elsewhere.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
Description 3 FHS and 4 MSC lectures/year 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact I dedicate 3 FHS lectures (to 3rd year medical students) and 4 MSC lectures directly related to my own research program.

The medical students and the MSC graduate students highly appreciate to be able to hear the latest research results related to cortical development.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Brain Diaries Exhibition - Museum of Natural History, University of Oxford 
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 Extract from the introduction from the exhibition website: Baby, child, teenager, adult
Throughout your life, your brain undergoes extraordinary changes.
Fascinating physical developments in your brain unlock each new chapter as you grow. And with billions of neurons and trillions of connections, it responds to your experiences to make you the person you are.
What does the latest research tell us about how
our brains work, from the minute we are conceived to the moment we die?
Explore the Brain Diaries to find out....http://www.oum.ox.ac.uk/braindiaries/
Year(s) Of Engagement Activity 2016
URL http://www.oum.ox.ac.uk/braindiaries/
 
Description C'est quoi la neurocience? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I gave a presentation (in French) to 10-12 years old students at the International "European" School at Culham. The presentation took 2 hours and received very enthusiastic response form pupils, teachers and subsequently from parents.

The school asked me to do this presentation again every year.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Computer Assisted Learning Sessions on Oxford University's Weblearn Site 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Oxfor University's Medical Division has a Computer Assisted Cearning Program (CAL - Weblearn). I contributed to the design, photography, content of the Neuroanatomy pages. These include direct links to RESEARCH and basic research questions.

I received very positive feedback from students, my peers and from IT professionals.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL https://weblearn.ox.ac.uk/portal/hierarchy/medsci
 
Description Interview to the OX Magazine on Brain Awareness Week 2017 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact From the 10th March the Museum of Natural History are opening an exhibition and series of events on the mysteries of neurological development - Brain Diaries. I was approached by the OX Magazine to give an interview and discuss the highlights of this exhibition and also my own research. This was produced for the general public in Oxfordshire.
The interview can be accessed on: http://oxhc.co.uk/Brain-Diaries-In-conversation-with-Professor-Zoltan-Molnar.asp
Year(s) Of Engagement Activity 2016
URL http://oxhc.co.uk/Brain-Diaries-In-conversation-with-Professor-Zoltan-Molnar.asp
 
Description Molnar Laboratory FaceBook Page with over 200 followers 
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 The Molnar Laboratory has its own Facebook page: https://www.facebook.com/molnarlab/
There are over 200 followers. The FB page advertises seminars, lectures, conferences and keeps in touch with alumni of the laboratory.
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019
URL https://www.facebook.com/molnarlab/
 
Description Open day presentation on medicine and neuroscience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I usually do about 5 Open Day presentations a year. They each take less then an hour, but the attendance is excellent (20-40 pupils an each occasions).

Numerous medical students reported that the open day presentations influenced their career decisions (towards medicine and research).
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Professor Molnar has a Twitter Account with Science Focus 
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 Professor Molnar has a Twitter Account (https://twitter.com/ZoltanMolnar64) that has outreach function. Seminars, lectures and conferences are advertised. It also draws attention to recent publications and presentations. There are over 300 followers.
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019
URL https://twitter.com/ZoltanMolnar64
 
Description Professor Zoltán Molnár features in BBC programme 'How the NHS Changed our World' 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact https://www.dpag.ox.ac.uk/news/professor-zoltan-molnar-features-in-bbc-programme-how-the-nhs-changed-our-world

The BBC recently visited Zoltán Molnár, Professor of Neuroscience here in DPAG, to discuss the research undertaken by Sir Charles Scott Sherrington, during his time in the Laboratory of Physiology, as part of a new series on 'How the NHS Changed our World'.

Sherrintgon kept hundreds of of microscope slides in a specially constructed Histological Box, which has been preserved and is now kept by Zoltán here in the Department.

In the interview, Zoltán sheds light on how Sherrington and his colleagues would shed their skin for the sake of scientific research. Sherrington's notes reveal how popular self-experimentation was in those days.

The interview can be viewed here and you can also watch the whole episode on iPlayer.
Year(s) Of Engagement Activity 2018
URL https://www.dpag.ox.ac.uk/news/professor-zoltan-molnar-features-in-bbc-programme-how-the-nhs-changed...
 
Description http://www.neuroscience.ox.ac.uk/directory/zoltan-molnar 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact I receive applications from around the World from postdoctoral fellows and graduate students.

I received one Japanese and one Australian postdoctoral fellow to my laboratory (they brought their own funding) due to the website. I receive Fullbright and Rhodes Scholars to my laboratory triggered through the website.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL http://www.neuroscience.ox.ac.uk/research_directory/m-p/zoltan-molnar