Characterisation of cortical subplate neurons

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

Abstract

Building the brain is like erecting a huge complex tower or bridge. The construction requires a dynamic scaffold which is built and modified along with the final permanent structure. After the completion of the construction the scaffold has to be dismantled at the right places and at the right time. The subplate, the earliest generated and largely transient cortical neurons is the foundation of the brain, and disruption of these cells may be the source of many developmental flaws, and therefore a fundamental topic to study. Cerebral cortical developmental disorders (schizophrenia, autism, attention deficit/hyperactivity disorder, ADHD) and perinatal hypoxic injuries (periventricular leucomalacia, PVL) involve cells of the subplate. The Molnar group has been investigating the integration of subplate cells into the intracortical and extracortical circuitry, their neurochemical properties and physiological characteristics over the last 15 years. The major hindrance of progress in the understanding of the role of this enigmatic cell population in cortical development and disease is the lack of reliable markers for these cells. In view of the selective vulnerability of this cell population and their important role in cortical development we propose to identify specific gene expression patterns in subplate and exploit this knowledge for further molecular and genetic approaches to study their role and vulnerability. These approaches require much specialised skills, which are beyond the scope of a single research group. The proposed collaboration will foster the interactions between a molecular and genetic laboratory and a cellular and anatomical group within the same Department of the same University and will open opportinities for collaboration with practising clinicians to initiate clinical applications in neuro-imaging, psychiatry, ophthalmology and neuropathology.

Technical Summary

This proposal addresses the development of cortical circuits which is important for the understanding of many disorders such as childhood epilepsy, schizophrenia, autism and cerebral palsy. Subplate neurons are amongst the earliest generated neurons of our brain and lay the foundation of our developing cerebral cortex. They integrate into the developing intra and extracortical circuitry, providing vital support for critical developmental steps. After subserving these functions, the majority of subplate neurons die and give way to the permanent cortical circuits. The lack of the molecular characterisation and selective markers hinders the progress in this field. We will combine neuroanatomical (Molnar) with molecular genetic (Davies) techniques to identify markers for this cell population. We have generated pilot data which suggests that our approach will work, enabling us to make a significant contribution to this field. We propose the further comparisons in gene expression between layer VI and subplate cells at various developmental time points in different cortical regions (putative primary somatosensory cortex and visual cortex) using microarray analysis. Our E18 and P8 screens have already identified candidate genes which are selectively expressed or expressed at a higher level in subplate cells than in the neighbouring layer VI cells. In this proposal we (1) wish to extend the gene expression analysis to additional stages (E15 and adult); (2) study selected mouse mutants (including CTGF and Nkx2.2 KOs); (3) relate gene expression patterns to cortical circuitry; (4) generate two transgenic mice lines (one with reporter gene expression and one conditional KO); (5) investigate comparative aspects of subplate in rodent and human and (6) start to use the markers in the study of rodent models of pathological conditions (including reeler mouse, cdk5 KO and Scrambler mouse). It is our intention to start to use the new subplate markers in clinical diagnosis and we have set up collaborations with the groups of Harrison, Rutherford and Ragge to exploit these new molecular tags in the clinicopathological analysis of brain developmental disorders.

Publications

10 25 50
 
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 Art of Anatomy Exhibition - St John's College, Oxford (July 2018) 
Description Art of Anatomy Exhibition, The Barn, June-July, 2018 Professor Clive Lee (Royal College of Surgeons in Ireland & Royal Hibernian Academy of Arts) Dr Sarah Simbler (Tutor of Anatomy at the Ruskin School of Art, University of Oxford) Dr Tian S. Liang (Early Career Leverhulme Fellow, St John's College) Professor Zoltán Molnár (Tutor of Human Anatomy, St John's College, Oxford) This exhibition will explore the artistic representation of anatomy during different historic periods and in different parts of the world. It will coincide with the Summer Meeting of the Anatomical Society and the Editor of Journal of Anatomy has invited papers from the anatomists and artists involved (1). Anatomy Transformed Professor Clive Lee is Professor of Anatomy at the Royal College of Surgeons in Ireland and the Royal Hibernian Academy of Arts, Visiting Professor of Biomechanics at Trinity College Dublin and has applied to be a Visiting Researcher at St John's College during Trinity Term 2018. In medicine and engineering, anatomy is applied, but in art it is transformed. Transformation by distortion is examined by comparing masterpieces, such as Ingres' La Grande Odalisque, estimated to have 3 extra lumbar vertebrae, with anatomically accurate computer images generated by Oscar winning engineer, Anil Kokaram (2,3). The balance between accuracy and artistry is explored in a triptych from passport photo to photographic portrait, by Amelia Stein RHA, to a portrait in oils by Mick O'Dea, President of the Royal Hibernian Academy of Arts www.rhagallery.ie The biomechanics of beauty will explore the practicalities of aesthetic ideals from an engineering standpoint. Finally, Anatomists, Engineers & Artists is a video installation showing the creation of an on-line 3D surface anatomy course: www.rcsi.ie/surfaceanatomy Science, History, Art Dr Sarah Simblet is a fine artist, writer, broadcaster and anatomist, Tutor in Anatomy at the Ruskin School of Art (BFA) and she teaches Short Courses in Anatomy, Botany and Drawing on the Summer School Programme (4). She is author of Anatomy for the Artist (2001), The Drawing Book (2005), Botany for the Artist (2010) and co-author of The New Sylva (2014). Sarah is dedicated to sharing and encouraging visual intelligence in others through her drawings, teaching and broadcasting worldwide. www.rsa.ox.ac.uk/people/sarah-simblet Anatomising the Body: Art, Science and the Humanities in Modern China Dr Tian S. Liang is a Leverhulme Fellow at St John's College and co-editor of Hong Ling: A Retrospective. Taipei: Soka Art (2016). She specialises in modern and contemporary East Asian art and explores understandings of human anatomy and its relations to artistic representations of the human body in China between 1851 and 1949 (5). By placing the knowledge of human anatomy at the centre of a broader nexus of artistic, medical, educational, publishing and humanitarian contexts, this project will provide the first history of the ways in which the 'body' was scientifically assessed and artistically represented across different visual media - painting, sculpture, print, woodcut and photography. https://www.leverhulme.ac.uk/awards-made/awards-focus/anatomising-body-art-science-and-humanities-modern-china-1851%E2%80%931949 Cerebral Art Professor Zoltan Molnar is Tutor of Human Anatomy at St John's College Oxford, Professor of Developmental Neuroscience at Department of Physiology, Anatomy and Genetics. His main research interest is in the development of the cerebral cortex. He has been running and organising the Neuroanatomy Practicals since 2000 at the University of Oxford. He can see art in the structure of the brain, in its histology, images. He has a huge collection of microscopic images. For some examples see (6) and for journal covers selected from Molnár Laboratories illustration see: https://www.dpag.ox.ac.uk/research/molnar-group/publications-front-covers/journal-covers 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2018 
Impact This exhibition will explore the artistic representation of anatomy during different historic periods and in different parts of the world. It will coincide with the Summer Meeting of the Anatomical Society and the Editor of Journal of Anatomy has invited papers from the anatomists and artists involved. 
URL https://www.sjc.ox.ac.uk/college-life/art/
 
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 cerebral cortical development
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description Senior Founding Member of the University of Oxford Cortex Club
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact The Cortex Club connects researchers at the University of Oxford with world-leading neuroscientists through a unique educational forum dealing with cutting-edge topics and significant challenges in neuroscience. Our events range from small intense debates with up-and-coming scientists to large discussion sessions led by internationally prominent speakers, followed by the opportunity to ask them questions over drinks.
URL http://cortexclub.com
 
Description ZM is regularly teaching on Courses organized by the European Confederation of Neuropathological Societies (EURO-CNS) CME
Geographic Reach Asia 
Policy Influence Type Influenced training of practitioners or researchers
Impact I contribute to the training of Paediatric Neuropathologists by lecturing on Courses organised by the European Confederation of Neuropathological Societies (EURO-CNS) CME and the The Royal College of Pathologists Continuing Professional Development.
URL http://www.euro-cns.org/events/cme-training-courses/
 
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 NEUROBID FP7-HEALTH-2009 No:241778- "Neuroscience on Barriers in Development"
Amount £200,000 (GBP)
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 Improved protocols for laser capture microdissection 
Description We have developed a simple, flexible, and low-cost method for simultaneously producing RNA from discrete cell groups in embryonic day 15 mouse brain. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact BMC Mol Biol. 2009 Jul 6;10:69. High quality RNA from multiple brain regions simultaneously acquired by laser capture microdissection. Wang WZ, Oeschger FM, Lee S, Molnár Z. 
URL http://www.ncbi.nlm.nih.gov/pubmed/?term=High+quality+RNA+from+multiple+brain+regions+simultaneously...
 
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 Murine subplate markers for E15, E18, P8 ages 
Description We performed microarray analysis to identify markers expressed in the murine subplate at various ages. http://europepmc.org/abstract/MED/19008461 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact Various neuropathology laboratories have approached us after the publication of: PMID: 19008461 for probes. We are very happy to see that these markers are useful for the wider community (including human neuropathologists). 
URL https://molnar.dpag.ox.ac.uk/subplate/
 
Title Subplate markers for human pathological analysis 
Description We identified several new subtype specific biomarkers for subplate neurons. These can be used in human pathology and in animla models of human pathology (e.g. periventircular leucomalachia). 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact These markers will have impact on neuropathological diagnosis (selective loss of subplate neurons) and perhaps in psychiatry. The markers will enable us to detect subtle neuropathological abnormalities. 
URL http://www.ncbi.nlm.nih.gov/pubmed/21368089
 
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 database on layerspecific cortical transcriptome: http://genserv.anat.ox.ac.uk/layers 
Description This new resource (http://genserv.anat.ox.ac.uk/layers) greatly extends currently available resources, such as the Allen Mouse Brain Atlas and microarray data sets, by providing quantitative expression levels, by being genome-wide, by including novel loci, and by identifying candidate alternatively spliced transcripts that are differentially expressed across layers. 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact http://genserv.anat.ox.ac.uk/layers It is difficult to judge at present, too early, but we noticed that our paper PMID: 21867878 had the highest download in the journal of NEURON after a few weeks of publication. 
URL http://genserv.anat.ox.ac.uk/layers
 
Title A Transcriptomic Atlas of Mouse Neocortical Layers - supplementary website for Belgard, et al. (2011) 
Description A transcriptomic atlas of mouse neocortical layers. Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, García-Moreno F, Molnár Z, Margulies EH, Ponting CP. Neuron. 2011 Aug 25;71(4):605-16. We sequenced transcriptomes from layers 1-6b of different areas (primary and secondary) of the adult (postnatal day 56) mouse somatosensory cortex to understand the transcriptional levels and functional repertoires of coding and noncoding loci for cells constituting these layers. A total of 5,835 protein-coding genes and 66 noncoding RNA loci are differentially expressed ("patterned") across the layers, on the basis of a machine-learning model (naive Bayes) approach. Layers 2-6b are each associated with specific functional and disease annotations that provide insights into their biological roles. This new resource (http://genserv.anat.ox.ac.uk/layers) greatly extends currently available resources, such as the Allen Mouse Brain Atlas and microarray data sets, by providing quantitative expression levels, by being genome-wide, by including novel loci, and by identifying candidate alternatively spliced transcripts that are differentially expressed across layers. 
Type Of Material Database/Collection of data 
Year Produced 2011 
Provided To Others? Yes  
Impact This is the first website that describe the layer-specific transcriptome of the adult mouse cortex using deep sequencing method. This enables the study of splice variants and non-coding transcripts. 
URL http://genserv.anat.ox.ac.uk/layers
 
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/
 
Title Web resource for adult forebrain expression in mouse and chicken at http://genserv.anat.ox.ac.uk/brainevo. 
Description We explored which genes are actively transcribed in the regions of controversial ancestry in a representative bird (chicken) and mammal (mouse) at adult stages. We conducted four analyses comparing the expression patterns of their 5,130 most highly expressed one-to-one orthologous genes that considered global patterns of expression specificity, strong gene markers, and coexpression networks. we provide a Web resource for adult forebrain expression in mouse and chicken at http://genserv.anat.ox.ac.uk/brainevo. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact This dataset not only will enable insights into telencephalic gene expression evolution, but also can facilitate future functional investigations. For example, the cross-species marker lists for striatum and hippocampus can readily be expanded using the advanced search feature on the website. 
URL http://genserv.anat.ox.ac.uk/brainevo
 
Description Analysis of the Golli-tau-eGFP mouse model. 
Organisation University of California, Los Angeles (UCLA)
Department Neuropsychiatric Institute UCLA
Country United States 
Sector Academic/University 
PI Contribution Almost entire analysis of this model has been performed in our laboratory with the help of our collaborators. Some of the surgery has been done at UCLA.
Collaborator Contribution The Golli-tau-eGFP model enabled my group to start to analyse the integration of the subplate into the intra and extracortical circuitry. We received constructs to generate our Golli-Cre model, which will be exploited in our future work on selective subplate modulation.
Impact 19289548J Physiol. 2009 May 1;587(Pt 9):1903-15. Epub 2009 Mar 16. Dynamic integration of subplate neurons into the cortical barrel field circuitry during postnatal development in the Golli-tau-eGFP (GTE) mouse. Piñon MC, Jethwa A, Jacobs E, Campagnoni A, Molnár Z.
Start Year 2006
 
Description Comparative aspects of subplate neurons 
Organisation University of Melbourne
Department Department of Pharmacology
Country Australia 
Sector Academic/University 
PI Contribution We performed all analysis on the marsupial brain samples.
Collaborator Contribution We received Marsupial brain samples for further analysis.
Impact Multidisciplinary: Anatomy, comparative neurobiology, genomicsComparative aspects of subplate zone studied with gene expression in sauropsids and mammals. Wang WZ, Oeschger FM, Montiel JF, García-Moreno F, Hoerder-Suabedissen A, Krubitzer L, Ek CJ, Saunders NR, Reim K, Villalón A, Molnár Z. Cereb Cortex. 2011 Oct;21(10):2187-203. Epub 2011 Mar 2. PMID: 21368089
Start Year 2009
 
Description Comprehensive spatiotemporal map of the primate brain transcriptome - adviser to Allen Brain Research Institute 
Organisation Allen Institute for Brain Science
Country United States 
Sector Charity/Non Profit 
PI Contribution My laboratory has been involved in the planning and the analysis of this large transcriptomic analysis of the developing macaque brain. In particular we advised on the laser dissection of embryonic cortical layers and on the analysis and interpretation of the data. The paper is under review in Nature, I pasted the abstract below: The detailed transcriptional underpinnings of brain development and neuropsychiatric disease are poorly understood, particularly in humans and closely related primate model organisms. To fill this gap, we describe a comprehensive spatiotemporal transcriptional atlas of rhesus monkey brain development that combines dense pre- and postnatal temporal coverage with fine anatomical parcellation of cortical and subcortical regions associated with human neurological and psychiatric disease. Using these data, we show high rates of expression change throughout prenatal and early postnatal development that taper off sharply during childhood, which are of comparable magnitude in both dividing precursors and maturing postmitotic neurons. Prenatal patterning varies dramatically from postnatal stages, while acquisition of adult-like molecular profiles for cortical layers and areas occurs gradually but surprisingly late in postnatal life. Different cell populations show discrete but overlapping expression profiles and show evidence for differences in developmental timing but also an unexpected degree of synchrony of specific developmental processes. Comparing rhesus gene expression trajectories to human, rat and mouse reveals large-scale differences between primates and rodents and a number of genes with human-specific temporal patterning. This transcriptional map, along with corresponding neuroimaging reference and cellular resolution gene expression data, provide a rich, freely accessible resource for understanding spatiotemporal transcriptional dynamics of primate and human brain development.
Collaborator Contribution All experiments and tissue processing was done by the Allen Brain Research Institute.
Impact The output will be published on the appropriate website for the DEVELOPING non-human primate developing atlas, similarly to the adult website: http://www.blueprintnhpatlas.org/
Start Year 2014
 
Description Detailed transcriptome analysis in the the adult mouse cortical layers. 
Organisation National Institutes of Health (NIH)
Department National Human Genome Research Institute (NHGRI)
Country United States 
Sector Public 
PI Contribution We are driving the project through the biological questions and we are responsible completely for the tissue dissection, RNA processing etc.
Collaborator Contribution NHGRI is underwriting all the costs for sequencing and provide huge support for the analysis. MRC FGU Oxford is collaborating with us on the rest.
Impact The production of the first batch of samples has been completed and the first sequences are in our possession. We are closely collaborating with bioinformatics experts at NIH and FGU Oxford on the analysis. We are particularly interested in comparing the subplate and layer 6 expressions.
Start Year 2008
 
Description I helped with the new edition of the brain part of the Kaufman's Atlas of Mouse Development. 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Brain Development Z Molnár, DJ Price Kaufman's Atlas of Mouse Development Supplement: With Coronal Sections, 239
Collaborator Contribution Brain Development Authors Zoltán Molnár, David J Price Publication date 2015/9/23 Journal Kaufman's Atlas of Mouse Development Supplement: With Coronal Sections Pages 239 Publisher Academic Press Description This chapter is divided into several sections that follow the chronological development of the mammalian brain (Goffinet and Rakic, 2000). It starts with a discussion of the specification of future neural tissue and the early types of signaling that contribute to the regionalization of the central nervous system (CNS)(E5-E12). Then, focusing mainly on the cerebral cortex, the text describes in detail how different cell types are generated and sets out some general principles underlying the layered structure of the mature neocortex (E12-P8). The mature ... Scholar articles Brain Development Z Molnár, DJ Price - Kaufman's Atlas of Mouse Development Supplement: , 2015 Related articles
Impact https://books.google.co.uk/books?hl=en&lr=&id=U-GcBAAAQBAJ&oi=fnd&pg=PA239&ots=rC3BP_nnya&sig=dq96eq2DhH-R89_Zbo2O29gICGM#v=onepage&q&f=false
Start Year 2015
 
Description Microarray screen on the gene expression of cerebral cortical layers 
Organisation Medical Research Council (MRC)
Department MRC Functional Genomics Unit
Country United Kingdom 
Sector Public 
PI Contribution Our tem drove this project through almost entirely, but the processing and the analysis of the microarrays were done by OXION and MRC FGU, Oxford.
Collaborator Contribution The MRC FGU Oxford (Director Kay Davies) helped us to process and analyse the gene expression in subplate neurons by using their core facilities for microarray analysis. The Wellcome Trust funded OXION Program (Fran Ashcroft) further provide core support for such work.
Impact Publications: 19580671 and 19008461 Also see review: PMID: 18494261
Start Year 2007
 
Description Molecular characterisation of adult subplate 
Organisation National Institutes of Health (NIH)
Department National Human Genome Research Institute (NHGRI)
Country United States 
Sector Public 
PI Contribution We proposed the project. Contributed to the planning, my team collected the brain samples, performed the dissection of layers and performed the RNA extraction. We also played role in the histological validation and interpretation of the results.
Collaborator Contribution Our NIH Collaborators funded all the sequencing reported in our recent publication PMID: 21867878. We continue this collaboration for some comparative work (avian - mammalian comparisons) and again NIH shall fund all the costs of these as well.
Impact Multidisciplinary - Anatomy, Genetics, Genomics and Bioinformatics A transcriptomic atlas of mouse neocortical layers. Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, García-Moreno F, Molnár Z, Margulies EH, Ponting CP. Neuron. 2011 Aug 25;71(4):605-16. PMID: 21867878
Start Year 2009
 
Description Production of the conditional Snap25 KO mouse model. 
Organisation University of New Mexico
Country United States 
Sector Academic/University 
PI Contribution We shall use this model in combination with other transgenic models to selectively eliminate regulated synaptic vesicle release in (1) subplate, (2) dorsal thalamus or (3) layer 4 in the cerebral cortex. These experiments shall help us with the dissection of cortical circuits.
Collaborator Contribution We shall receive the mouse line with floxed Snap25 from the university of New Mexico for our experiments.
Impact We have already published in this collaboration (PMID: 11753414 and PMID: 12451131), but the above described experiments could lead to a very productive approach in dissecting functional cortical interactions.
 
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 Subplate Gene Expression Atlas 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution The Subplate Gene Expression Atlas illustrates the cortical expression patterns of 426 selected genes. These genes were identified by both microarray/RNA seq and in situ hybridization studies as preferentially expressed in subplate at at least one developmental age (E15, E18, P4/P7/P8 and Adult). The expression patterns illustrated in the Atlas are derived from published or publicly available in situ hybridization images. Expression levels were categorized for the illustration according to two criteria: abundance of cells (abundant vs sparse) and expression level (no labeling detected vs weak labeling vs strong labeling).
Collaborator Contribution A microarray based approach was used to identify genes expressed at a higher level in the mouse subplate compared to overlying cortical plate at embryonic ages E15.5 and E18.5 and subplate compared to overlying layer 6a at postnatal P8 (Affymetrix Gene ST1.0 at E15, Affymetrix 430 2.0 for E18.5 and P8). Data was RMA normalized and putatively differential gene expression (>1.5-fold higher in subplate, nominal p<0.05) determined. High-throughput sequencing data was used to identify genes expressed at a higher level (>1.5 fold) in the adult mouse subplate/layer 6b compared to the adjacent layer 6a. In total, 1642 genes were identified as potentially SP enriched at least at one age. Of these, 426 genes could be confirmed as SP enriched using published or publicly available databases including Allen Mouse Brain Atlas (Adult), Allen Developing Mouse Brain Atlas (E15.5, E18.5, P4 and P14), Genepaint.org (E14.5, P7 and Adult) and or our own in situ hybridization or immunohistochemistry experiments. The schematic results of this are presented here in the "Subplate Gene Expression Atlas". Genes with uniform or no labelling, or for which no images could be found, were not included. Using the above approach, we selected against genes that are subplate expressed, but are additionally expressed in layer 6a at equal or higher levels. Furthermore, there may be subplate specific or enriched genes not identified by the microarrays. Thus, genes important for the differentiation of the deep cortical layers or those relevant in the specification of subplate prior to E15.5 may not be included here. This Subplate Gene Expression Atlas is an ongoing project and over time more genes identified by other sources may be added if there is convincing evidence of their subplate enriched expression at the above time points.
Impact Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia. Hoerder-Suabedissen A, Oeschger FM, Krishnan ML, Belgard TG, Wang WZ, Lee S, Webber C, Petretto E, Edwards AD, Molnár Z. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3555-60.
Start Year 2012
 
Description Subplate in a rat model of preterm hypoxia-ischemia 
Organisation Lausanne University Hospital (CHUV)
Country Switzerland 
Sector Hospitals 
PI Contribution Division of Neonatology, Department of Pediatrics, University Hospital Center and University of Lausanne, Lausanne, Switzerland
Collaborator Contribution The group of Professor Truttmann provided us with a hypoxia model and brains for analysis. P2 rats underwent permanent occlusion of the right common carotid artery followed by a period of hypoxia. P8 rats were perfused and all subsequent analysis using immuno- histochemistry; subplate and deep layers cells were performed in Oxford. We quantified and compared cortical neuron numbers in various areas with sham-operated case.
Impact Subplate in a rat model of preterm hypoxia-ischemia. Authors: Chika Okusa, Franziska Oeschger, Vanessa Ginet, WeiZhi Wang, Anna HoerderSuabedissen, Tomohiro Matsuyama, Anita C Truttmann, Zoltán Molnár. Publication date 2014/9/1 Journal: Annals of Clinical and Translational Neurology Volume 1, Issue 9, Pages: 679-691.
Start Year 2010
 
Description Subplate transcriptome analysis in macaque and human 
Organisation Allen Institute for Brain Science
Country United States 
Sector Charity/Non Profit 
PI Contribution We are currently analysing data (that is very similar to our original description of the subplate-specific transcriptome in mice - see Hoerder-Suabedissen et al., 2009; Oeschger et al., 2013) in macaque in collaboration with the Allen Brain Institute, Seattle, USA.
Collaborator Contribution We defined layers on cytoarchitectonic distinctions, advised ABI on the location and numbers of dissected areas. Provided our data for the mouse - macaque comparisons.
Impact http://www.blueprintnhpatlas.org/
Start Year 2012
 
Description Validation, characterisation and the use of Snap 25 CONDITIONAL knock out mouse line 
Organisation University of New Mexico
Country United States 
Sector Academic/University 
PI Contribution The Molnar Laboratory (Dr Anna Hoerder-Suabedissen) was leading the validation of the Snap25 cKO mouse. The newly generated Snap25-fl/fl has been validated for silencing in cell culture and gives rise to a barrel phenotype when layer 4 neurons are silenced.
Collaborator Contribution Professor Michael Wilson generated the Snap25-fl/fl mouse and started its initial validation.
Impact Hoerder-Suabedissen A et al., (2014) FENS Abstr. 3536
Start Year 2010
 
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 BBC on a publication on brain fording in Nature Physics by Tuomas Tallinen, a soft matter physicist at the University of Jyväskylä in Finland and a co-authors. 
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 Interview to BBC on a publication on brain fording in Nature Physics by Tuomas Tallinen, a soft matter physicist at the University of Jyväskylä in Finland and a co-authors.
I discussed research with Dr Jonathan Webb, Science reporter, BBC News and my comments were used in the Science and Environment BBC Website: http://www.bbc.co.uk/news/science-environment-35438294
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/news/science-environment-35438294
 
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 Lecture for the Oxford Medical Lecture Club on 28th January 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Oxford Medical Lecture Club is for the Retired Clinical Professionals of University of Oxford. The members organise the meetings and invite lecturers. My lecture was on the History of Neuroscience in Oxford (with special attention to Willis and Sherrington). https://www.facebook.com/molnarlab/posts/768407353351984 The members of the group were encouraged to contribute to the History of Medical Sciences Project website with their memories and conserve historic letters, manuscripts with general importance.
Year(s) Of Engagement Activity 2018
URL https://www.facebook.com/molnarlab/posts/768407353351984
 
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 The 2015 Brain Awareness Week Lecture at Museum of the History of Science, Oxford 19th March 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The 2015 Brain Awareness Week Lecture at Museum of the History of Science, Oxford 19th March 2015.
This lecture was part of the Brain Awareness Week activities at Oxford.
The lecture was entitled: "Neuroscience in Oxford: Four Centuries of Discovery" and was aimed at the general public. The lecture was recorded and now available on: https://history.medsci.ox.ac.uk/seminars/history-of-medical-sciences-seminar-series/prof-zoltan-molnar-neuroscience-in-oxford-four-centuries-of-discovery/
Year(s) Of Engagement Activity 2015
URL https://history.medsci.ox.ac.uk/seminars/history-of-medical-sciences-seminar-series/prof-zoltan-moln...
 
Description The 2015 Brain Awareness Week Lecture at Museum of the History of Science, Oxford 19th March 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The lecture was hosted by the History of Science Museum and it was entitled: "Neuroscience in Oxford: Four Centuries of Discovery".
The lecture theatre was completely full and the lecture was recorded and posted to: https://history.medsci.ox.ac.uk/seminars/history-of-medical-sciences-seminar-series/prof-zoltan-molnar-neuroscience-in-oxford-four-centuries-of-discovery/
Year(s) Of Engagement Activity 2015
URL https://history.medsci.ox.ac.uk/seminars/history-of-medical-sciences-seminar-series/prof-zoltan-moln...
 
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