Development of the Layer 5 Pyramidal Neuron Subgroup Expressing Er81

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

Abstract

In the developing cerebral cortex, pyramidal neurons are generated in the germinal zones and migrate into the developing cortical plate, with the earliest generated occupying the deepest layers, and the last generated the more superficial layers. Within the germinal zones the type of pyramidal neuron generated is controlled by differential regulation of gene expression, some of which have been identified. We do not yet know how expression of particular genes leads to particular patterns of axon outgrowth, target selection, or physiological properties. Er81 is expressed at early stages of cortical development in the ventricular zone in dividing cells and then later in post-mitotic L5 neurons in the cortical plate. In both Pax6 mutants and Ngn2 mutants the expression of Er81 is disrupted, implying Er81 is regulated by both of these genes. This suggests an early role for Er81 in neuronal differentiation and cortical lamination/migration, similar to its role in olfactory bulb development. At later stages, most L5 Er81 expressing neurons also express Ctip2 but not Otx1. Ctip2 controls the formation of corticospinal axon outgrowth, whilst Otx1 controls outgrowth of collicular/pontine projections. Whilst some studies have shown ER81 to be down-stream of Ctip2, our preliminary microarray and qPCR data show that Er81 controls Ctip2, which is confirmed by the up-regulation of Ctip2 seen in the Er81 KO. Loss of Ctip2 results in a loss of CST axons, whilst reduced expression results in mis-specification of cortical pyramidal neurons, suggesting that Ctip2 and Er81 control the processes of axonal specification and collateral withdrawal of L5 projections. Outside the cortex, Er81 is expressed specifically in target nuclei of L5 neurons, such as the superior colliculus and inferior olive, offering an exciting avenue for investigation of specification of cortical connectivity. A similar role has been shown for Er81 in formation of circuitry in the spinal cord where ER81 is expressed by specific motor and sensory neurons and there are defects in the formation of these interconnections in mutants. Er81 and Ctip2 are both regulated by Fezf2. In Fezf2 mutants there is a mis-specification of the L5 Ctip2 expressing cells, which instead express Tbr1 and Satb2, migrate to L6 and send axons through the anterior commissure/corpus callosum. Satb2 is expressed in L5 callosal projection neurons and represses the expression of Ctip2. In the Er81 KO mouse we showed an increase in the number of Ctip2-expressing neurons with callosal projections suggesting that Er81 controls Ctip2 by suppressing Satb2. Er81 can be seen to play a central role in the establishment of cortical connectivity. In the last few years our understanding of the molecular control of cortical neuronal specification has improved and we have produced some very exciting preliminary data underpinning the proposed experiments. Whilst this complex network of genes regulates the development of particular pyramidal cells, we have very little idea about how changes in these networks allow for specific regional connectivity which is a fundamental process of brain wiring. As clinically related studies of brain development identify new gene associations with developmental disorders that result in altered brain function, it is essential to understand the details of the normal transcriptional networks. Whist it is perhaps premature to suggest that knowledge of how specific genes influence cortical wiring could enable future therapies, this will be essential if we are ever to use cell based therapies in brain repair. Current research has focused almost exclusively on the generation of identifiable neuronal cell classes from both innate and experimentally induced stem cells, no understanding of how such cells might be controlled in terms of their connectivity has yet been made.

Technical Summary

Characterisation of L5 Er81 neurons Using the Er81-GFP mouse the expression pattern of Er81 during the developmental stages of neuronal genesis and migration, dendritic elaboration, axonal outgrowth, and refinement of connections will be described. This will corroborate previous studies but also allow the correlation of Er81 expression with other L5 marker genes, using in situ hybridisation (ISH) and immuno-histochemistry (IHC). Combining these studies with axon tracing, (viral eGFP will optimise details of cell morphology), we will characterise the different molecular subclasses of pyramidal cells with axonal projection targets. Role of Er81 in the transcriptional network Using microarrays on Er81 KO mice cortex at specific stages of development, we will look for genes regulated by Er81. Er81 linked genes in cortex will be compared with those previously identified in DRGs by our collaborator Silvia Arber. These target genes will be validated by ISH, qPCR and IHC. Using slice cultures candidate genes will be screened to show linked changes in expression following Er81 over-expression or knockdown. Further analysis will be made using ChIP-seq to discover Er81 interacting partners. Using ChIP-PCR the link between Er81 and Ctip2 and other candidate genes, such as the recently identified L5 gene Tshz2. For Tshz2 we can further characterise L5 neurons in Tshz2-GFP and Tshz2 KO mice. Role of Er81 in L5 neuron identity Using the Er81-LacZ KO mice, the expression of Er81 target genes, and the changes in dendritic morphology/axonal projections of null-Er81 cells will be determined. Er81 will be locally over-expressed in cortex using in utero electroporation and changes in pyramidal cell connectivity, somatodendritic morphology and gene expression will be detailed.

Planned Impact

This research addresses fundamental questions about normal brain development. There are several important levels at which this work will be of major benefit in the short and long term. Recently our understanding of CNS development has improved dramatically, in particular molecular techniques and the ability to manipulate genes has revolutionized our understanding of the controls of brain development. At a scientific level, no one would doubt the fascination in understanding how the brain develops, in particular how the myriad of different neurons classes are generated in specific places and ratios and then link in a highly specific fashion to form the amazing connectivity which underpins brain function. Our experience of discussion with scientific and clinical colleagues, students and school children, and with lay audiences testifies to the widespread interest in this area of research. A deeper and intriguing aspect of this research is how changes in these regulatory patterns must underpin subtle changes in circuit formation, which form the basis of all differences in personality, intelligence, and performance. Whilst the brains of all species are remarkably similar at a gross level, the subtle changes in development of the precise patterns of circuitry underpin individual differences. In man this accounts for the different abilities of the mathematical, genius, the concert pianist or professional sportsman, and even world leaders. Tentative steps towards an understanding of the development of the brain and how this accounts for such differences are clearly of huge public interest. The subtle changes in the process of brain wiring which generate positive differences in abilities can also have tragic negative outcomes. With the advent of new molecular techniques and clinical screening programmes, many candidate genes and genomic interactions have been identified which are linked to brain abnormalities. In some cases these are severe malformations, resulting in major functional impairment, whilst in others they are subtle changes which affect only certain functions, such as dyslexia. As candidate genes are identified, finding out how they fit into the regulatory networks, such as those highlighted in this proposal, will be the obvious progression. This will certainly be of interest to clinicians, who diagnose and define the potential outcomes associated with such abnormalities. Patients and patient groups will naturally have a keen interest in understanding such conditions. Indeed the specific charities and support groups commonly focus on such research as the key to understanding the nature of the disability and the implications for sufferers. Commercial concerns will also be interested in the development of diagnostics and in the longer term for therapies. Increased longevity and concomitant increase in the number of patients diagnosed with CNS degenerative diseases, is a major global health problem. Stem cell research is currently one of the best hopes for curing such disorders. The ability to harness innate stem cells from the brain, or from elsewhere in the body, to generate neurons is a key strategy for the potential repair of CNS disorders. Similarly the use of embryonic of other donor stem cells to form specific neuronal subtypes is a major area of translational research. In stroke or CNS injury the promotion of regeneration and plasticity, or generation of new neurons from intrinsic stem cells, is key to functional repair. Unless we understand the normal controls on neuronal development and in particular connectivity, it is unclear how any realistic therapy could be achieved. Indeed mis-wiring the CNS from grafted or regenerating neurons could have even more problematic consequences. This work will inform the vast field of basic and clinically related research in this area and again be of enormous interest to patient groups, funding agencies and pharmaceutical and biotechnology companies in this area.

Publications

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Abe P (2015) Intermediate Progenitors Facilitate Intracortical Progression of Thalamocortical Axons and Interneurons through CXCL12 Chemokine Signaling. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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García-Moreno F (2015) Subset of early radial glial progenitors that contribute to the development of callosal neurons is absent from avian brain. in Proceedings of the National Academy of Sciences of the United States of America

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Grant E (2016) The Regulation of Corticofugal Fiber Targeting by Retinal Inputs. in Cerebral cortex (New York, N.Y. : 1991)

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Grant E (2012) Development of the corticothalamic projections. in Frontiers in neuroscience

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Hoerder-Suabedissen A (2013) Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia in Proceedings of the National Academy of Sciences

 
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-turne 
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 Joint Cortex Club Session on Brain Modelling with Dr Lizzie Burns 
Description Dr Lizzie Burns (https://history.medsci.ox.ac.uk/art/dr-lizzie-burns/) featured in Cortex Club (http://cortexclub.com/about/). 
Type Of Art Artwork 
Year Produced 2014 
Impact The modelling session made the participants to think about brain anatomy, more global issues of neuroscience, while creating artwork (https://history.medsci.ox.ac.uk/art/dr-lizzie-burns/). 
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 Our project set out three main aims.

1. Define the genesis, migration, dendritic and axonal development of the population of L5 Er81 neurons and correlate this morphology with differential gene expression.

2. Define the role of Er81 in the transcriptional network that regulates the development of a sub-population L5 pyramidal neurons

3. To establish the role of Er81 in the connectivity of L5 neurons.

We made progress in all three areas over the last 1-1.5 years and we shall soon be in a position to summarise the details in publications. The project is progressing according to the original plans, but these are still early days to provide comprehensive and final summaries for these questions.



1. Basic developmental studies of Er81 expression and characterisation of the L5 sub-population is progressing well and nearing completion. We are currently investigating the somatodendritic morphology of layer 5 neurons. The retrograde tracing and immunohistochemistry part of the project is completed for adult.

2. The analysis of Er81 KO by immunohistochemistry has begun. We had difficulties to breed the Er81 KO colony, but now we have sufficient numbers to complete the study. We used viral tracing methods to dissect the circuits formed by Er81 positive layer 5 neurons and Er81 positive ventral horn motorneurons.

3. The molecular studies to elucidate the genes that are regulated by Er81 by over-expressing Er81 in the developing cortex in vitro has been completed and we also completed the microarray-based expression analysis. We completed the validation of selected candidate genes by qPCR, in situ hybridisation and immunohistochemistry. Similar analysis is ongoing of the KO mouse. Some of the ChIP-PCR studies are completed, but others are still ongoing. Validation of candidate genes will start this year.

4. Identifying Er81 target genes is on-going, the investigation of the Tshz2 KO mouse started, but not completed.

These experiments shall lead to the findings that we shall publish openly in the literature in due course.
Exploitation Route Our research is primarily concerned with basic developmental neurobiology, but the implications could be very general in due course. Er81 is a key gene that is involved in the generation and differentiation of upper (layer 5 cortical) and lower (ventral horn spinal cord) motorneurons. Understanding Er81 action can have very general implications, including devastating human pathologies.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.dpag.ox.ac.uk/academic_staff/zoltan_molnar/molnar_research
 
Description Pathways to impact - Molnár and Taylor Communication and engagement with the wider community This research addresses fundamental questions about normal brain development. There is a widely held fascination in understanding how the brain develops, in particular how the myriad of different neurons classes are generated in specific places and ratios and then link in a highly specific fashion to form the amazing network of connections which underpins brain function. There is now almost a daily item in the national press relating to work that forms the focus of this research. This highlights the importance society attaches to work in the field of brain science and in particular developmental disorders affecting human behaviour and function. Transfer of Knowledge to Future Generations Given the strong underlying relevance of this work to clinical science, it is essential that future clinicians are both aware and understand the research and its implications. Oxford is one of the highest ranked medical schools internationally and we are privileged to teach highly motivated medical students and to attract undergraduate researchers to help with project work related to this proposal. This exposure seeds the imagination of future generations of clinicians, many of whom will continue in clinical research fields with a high level and essential understanding of the complexities of CNS development. Further, both JT and ZM are deeply involved in the Internationally rated Graduate Training Programme in Neuroscience at Oxford, which has generated a world class group of alumni, many of whom are now leading Neuroscience researchers. It is this initial educational impact, which ensures the future exploitation and maximization of the impact of this research. Academic and Commercial Impact Our work will be published in leading open access scientific journals and present our findings at National and International meetings which is the conventional and established means of communication of the major findings of the research outlined in this programme. We will always seek to publish in highest impact journals thus ensuring the widest audience of researcher within the wider fields of Development and Neuroscience. Although we have no current plans for direct commercial exploitation of this work, public presentation and publication is the essential mechanism for generating interest in our work from Biotechnology and Pharmaceutical industries. We have requested the funding to ensure that this function of our scientific work is efficiently and optimally achieved. It is through such links that collaborations with clinicians, biotechnology companies and other researchers are fostered. If commercially exploitable finding are made, we will use the University ISIS innovations to ensure that this is maximised. Communication to Policy Makers and the Wider Public Both PIs are involved in communication of science to the wider community, through access and outreach programmes for Schools and through continuing education programmes. Significant findings will be publicised both in scientific journals and via Departmental and University WebPages and through these links, to the wider audience through the press. We will continue our work with the outreach programmes and seek to enhance our general public engagement. Both PIs also play important roles in the Development of Research strategy for the Medical Sciences Division in Oxford, and through this to the University and directly linking to both Government and charitable funding bodies. Collaboration and coproduction Our impressive and enthusiastic collaborators attest to the wide interest and potential of this research project. We will endeavour to continue to build on these international collaborations through meetings and laboratory exchanges in which we will promote the training and transfer of knowledge. Indeed Dr Cheung has just returned from an extensive visit to a collaborator in Japan to learn the technique of intrauterine electroporation. In terms of active collaborations with clinical science ZM has a long standing link to clinical neurology and neuropathology and regularly presents his findings to a clinical audience. Exploitation and Application Oxford now has a Stem Cell research initiative and we intend to link to this programme and with the laboratories involved in neuronal stem cell work. A fundamental part of attempts to use cell based therapies to repair the CNS is to ensure that the connections formed by transplanted cells are appropriate and effectively restore function. Our deep understanding of this field and the knowledge generated from the work outlined in this proposal will be of essential interest to Pharmaceutical and Biotechnology companies in this area. Whilst we currently have no commercial exploitation plans, any finding that do have potential will be exploited through Oxford ISIS Innovations. JT has followed this route with ISIS Innovations based upon similar work on neuronal cell survival. Capacity and involvement Both PIs undertake certain public engagement activities as outlined above. These include school visits, open days, science festivals, as well as academic conferences which enable us to both formally and informally disseminate our research. We will also use the University of Oxford Press Office to ensure maximum public impact of our notable research findings. Impact ability, deliverables and milestones Whilst this work does not have immediate commercial goals, our hope is that the finding from this research will inform the wider scientific and specific biotechnology communities involved in brain development and repair. From previous experience, the progress from initial discussion of invention to engagement with potential commercial partners is within the time frame of this proposal. If such opportunities present we would hope that a five year period for commercial exploitation would be realistic. Resource for the activity We do not seek additional funding for potential exploitation or specific avenues for communication, as our current activities and the normal plans for public engagement can be met within the outlined budget. Any resultant commercial exploitation or wider publicity would be provided by ISIS Innovation and the University Press Office without cost.
First Year Of Impact 2014
Sector Education,Healthcare
Impact Types Cultural,Societal

 
Description Advisor for Allen Brain Institute Non-Human Primate Developmental Brain Atlas
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
Impact We were invited to advise Allen Brain Institute on the layer-specific transcriptome analysis based on our previous publications in this field: Wei-Zhi Wang*, Franziska Oeschger*, Sheena Lee and Zoltán Molnár (2009) High quality RNA from multiple brain regions simultaneously acquired by laser capture microdissection. BMC Molecular Biology 10(1):69. Hoerder-Suabedissen A*, Wang WZ*, Lee S, Davies KE, Goffinet AM, Rakic S, Parnavelas J, Reim K, Nicolic M, Paulsen O, Molnár Z. (2009) Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. Cereb Cortex. 19(8):1738-50. Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, García-Moreno F, Molnár Z*, Margulies EH*, Ponting CP*. (2011) A transcriptomic atlas of mouse neocortical layers. Neuron. 71(4):605-16. (*co-corresponding authors) Oeschger FM, Wang WZ, Lee S, García-Moreno F, Goffinet AM, Arbonés ML, Rakic S, Molnár Z. (2011) Gene Expression Analysis of the Embryonic Subplate. Cereb Cortex. 22(6):1343-59.
URL https://www.alleninstitute.org/
 
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 Emphasized the human-specific differences in cerebral cortical development
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
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 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. News release on the establishment of the cortex club: https://www.dpag.ox.ac.uk/news/cortex-club-celebrates-10-years-of-student-run-talks-and-discussions-for-oxfords-neuroscience-community
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 Fondation Philippe Wiener - Maurice ANSPACH Foundation Collaborative Research Grant
Amount £51,500 (GBP)
Organisation Wiener-Anspach Foundation 
Sector Charity/Non Profit
Country Belgium
Start 10/2014 
End 09/2016
 
Description Newton Advanced Fellowship (ref: NA140246) to support collaboration with with Dr Xiaoqun Wang, Institute of Biophysics, Chinese Academy of Science, China.
Amount £111,000 (GBP)
Funding ID NA140246 
Organisation Royal Society of Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 03/2018
 
Description Newton International Exchanges (NI140073) with Dr Paul Manger (South Africa) Project title: "The thalamocortical projection in large brained mammals"
Amount £6,000 (GBP)
Funding ID NI140073 
Organisation Royal Society of Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2015 
End 04/2016
 
Description Newton International Exchanges Dr Patricia Garcez (Brazil) (2015/R1, NI150133) Project title: "Transcriptional control of Neuronal migration"
Amount £1,740 (GBP)
Funding ID NI150133 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2015 
End 08/2015
 
Description The Academy of Medical Sciences Newton Advanced Fellowship
Amount £111,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Department Newton Advanced Fellowship
Sector Academic/University
Country United Kingdom
Start 03/2017 
End 02/2020
 
Title Allen Brain Research Institute - Non Human Primate Developmental Transcriptome Database 
Description The Allen Brain Institute contacted us to advise them on the collection and analysis of the developmental transcriptomic atlas in macaque cerebral cortex. The approach is similar that we developed previously - Hoerder-Suabediessen et al., 2009 - PMID: 23401504 and 2013 - PMID: 23401504; Oeschger et al., 2013 - PMID: 21862448; Belgard et al., 2010 - PMID: 21867878 
Type Of Material Biological samples 
Year Produced 2014 
Provided To Others? Yes  
Impact Our work that was supported by MRC lead to establishing methodologies and approaches that now used by the Allen Brain Institute. We were invited to advise the recent project on Macaque Brain Development Transcriptome where we shall lead the analysis of the subplate layer. This is based on - Hoerder-Suabediessen et al., 2009 - PMID: 23401504 and 2013 - PMID: 23401504; Oeschger et al., 2013 - PMID: 21862448; Belgard et al., 2010 - PMID: 21867878 
URL http://www.alleninstitute.org/science/public_resources/nhp_atlas.html
 
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 In Utero Electroporation Methods in the Study of Cerebral Cortical Development 
Description Electroporation or electropermeabilization is a method that uses electric pulses to deliver molecules into cells and tissues. The in utero electroporation method has enabled the field to administer plasmids to these neural progenitors, allowing temporal and cell type-specific control for the manipulation of gene expression. My laboratory shared our methodological expertise with the field in a book chapter: Protocol Prenatal and Postnatal Determinants of Development; Volume 109 of the series Neuromethods pp 21-39 In Utero Electroporation Methods in the Study of Cerebral Cortical Development Authors Isabel Martínez-Garay, Fernando García-Moreno, Navneet Vasistha, Andre Marques-Smith, Zoltan Molnar Publication date 2016 Journal Prenatal and Postnatal Determinants of Development Pages 21-39 Publisher Springer New York 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Research in the field of cortical development has benefited from technical advances in recent years, and tools are now available to label, monitor, and modulate cohorts of cerebral cortical neurons using in vivo approaches. Substantial populations of cerebral cortical neurons are generated in a specific sequence by the radial glia progenitors that line the ventricular surface during development. These radial progenitors self-renew and generate intermediate progenitors or neurons in a precisely choreographed fashion. in utero electroporation has become a central technique in the study of key aspects of neural development, such as progenitor proliferation, neurogenesis, neuronal migration, and circuit formation. This method has also facilitated the exploitation of cell lineage and optogenetic techniques in various species from chick to gyrencephalic higher mammals. This chapter provides a description of the method and gives some examples for its utility in the study of cerebral cortical development and evolution. 
URL http://link.springer.com/protocol/10.1007/978-1-4939-3014-2_2
 
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 The History of Medical Sciences University of Oxford Project 
Description The History of Medical Sciences Project, University of Oxford. Our project aims to preserve and bring to life the rich history of science through the followings streams: 1. Seminars, given by experts in their field, on the history of important discoveries and the individuals behind them 2. Digitisation and display of historical microscope slides used for research and teaching and associated letters, notes and other documents, 360° photography of historical models and instruments 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Pur historic repository helped to preserve unique letters, histological preparations, scientific instruments and models. The historic repository attracted several international scholars to further study the life and work of outstanding Oxford research academics, including Sherrington, Eccles, Fitzgerald. 
URL https://history.medsci.ox.ac.uk/
 
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 Comprehensive spatiotemporal map of the primate brain transcriptome - adviser to Allen Brain Research Institute 
Organisation Allen Institute for Brain Science
Country United States 
Sector Academic/University 
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 Connectional Analysis of Motor Circuits Using Pseudorabies Virus 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution Transcription factors (TFs) Er81 and Otx1 label distinctive populations of cortical layer 5 neurons and ventral horn motor neurons within the spinal cord. It is known that both TF populations project to the spinal cord. Functional motor circuits can be traced by inoculating pseudorabies virus (PRV152) into a muscle. Tracing was done by our partners.
Collaborator Contribution Our contribution was the histological analysis. Our hypothesis is that the first cohorts of back-labelled CST and LMNs would show similar a bias towards Er81 or Otx1. Our study investigates whether within a hierarchical trans-synaptically retrograde-labelled motor circuit shortly after its formation, a similar proportion of CST and LMNs express the transcription factors Er81 and Otx1.
Impact Manuscript is under preparation: Connectional Analysis of Motor Circuits Using Pseudorabies Virus Joseph Hutchinson1, Amanda Cheung1, Cindy T.J. van Velthoven2, Jeremy S. Taylor1, Zoltán Molnár1* 1Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. 2 University Medical Center Utrecht NIDOD Laboratory KC03.069.0 Lundlaan 6, 3584 EA Utrecht The Netherlands (C.vanVelthoven-2@umcutrecht.nl)
Start Year 2012
 
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 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 transcriptome analysis in macaque and human 
Organisation Allen Institute for Brain Science
Country United States 
Sector Academic/University 
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 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-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014
 
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 2006,2007,2008,2009,2010,2011,2012,2013,2014
 
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
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 2006,2007,2008,2009,2010,2011,2012,2013,2014
 
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 2006,2007,2008,2009,2010,2011,2012,2013,2014
URL https://weblearn.ox.ac.uk/portal/hierarchy/medsci
 
Description Exhibition: 'Revelaing the Brain' Museum of History of Science, Oxford 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Zoltan Molnar was part of the team who organised the exhibition called Revealing the Brain, which run until Sunday, June 2 2013, featuring videos and artefacts from the History of Science Museum, Oxford.

Oxford University's Department of physiology, anatomy and genetics is supporting the exhibition. "Exhibits show publications and objects that helped to establish some fundamental concepts behind our understanding of the brain.

"The exhibition gave a flavour of Oxford neuroscience since the time of Thomas Willis in the 17th century, and Nobel Prize winner Sir Charles Sherrington in the 20th century, right through to the latest discoveries made today by leading groups at Oxford University."

The exhibition was well attended, there was media and web coverage in Oxford.
http://www.neuroscience.ox.ac.uk/news/exhibition-revelaing-the-brain
http://www.mhs.ox.ac.uk/exhibits/revealing-the-brain/
http://www.neuroscience.ox.ac.uk/news/oxford-neuroscience-brain-exhibition-now-online
Year(s) Of Engagement Activity 2013
URL http://www.oxfordtimes.co.uk/news/10279737.Visitors_to_rack_brains_over_how_mind_works/
 
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 Interviews on the Evolution of the Human Neocortex: How Unique Are We? The Company of Biologists workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviews on the "Evolution of the Human Neocortex: How Unique Are We?" The Company of Biologists workshop Wiston House, Steyning, West Sussex, UK, September 2013.

The video and my meeting report on "Evolution of the Human Neocortex: How Unique Are We?" generated strong interest in comparative neurobiology from colleagues, schools and rom the general public.
Year(s) Of Engagement Activity 2013,2014
URL http://www.youtube.com/watch?v=vsbVby7PKPA
 
Description Molnar Lab hosted student in The Oxford/HBI Summer Student Exchange scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Supporters
Results and Impact Zoltan Molnar was invited to the HBI Year Opening Ceremony where he gave a brief talk to general audience including benefactors of HBI in Calgary. This followed with a seminar that was attended by over 200 students.

Several students would like to apply to the scheme and consider working in labs at Oxford.
Year(s) Of Engagement Activity 2013
URL http://www.neuroscience.ox.ac.uk/news/rose-florence-fricker-awarded-the-2013-john-w-griffin-award/th...
 
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 Molnar Laboratory has its own FaceBook page 
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 2015,2016,2017,2018,2019,2020
URL https://www.facebook.com/molnarlab/
 
Description New Theories on the Origin of Cerebral Cortical Convolutions 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact New Theories on the Origin of Cerebral Cortical Convolutions


http://www.neuroscience.ox.ac.uk/about/news/new-theories-on-the-origin-of-cerebral-cortical-convolutions/

no actual impacts realised to date
Year(s) Of Engagement Activity 2012,2013,2014
URL http://www.hfsp.org/frontier-science/awardees-articles/new-theories-origin-cerebral-cortical-convolu...
 
Description News Release on: Unexpected origin of the subplate neurons (Pedraza et al., PNAS 2014) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Our interview helped to release the following news in english and in Spanish (http://www.madrimasd.org/informacionidi/noticias/noticia.asp?id=60258?igen=notiweb&dia_suplemento=martes
and in:
http://www.abc.es/ciencia/20140429/abci-nuevos-hallazgos-corteza-cerebral-201404281708.html

A collaborative study between the groups of Professor Juan De Carlos (Instituto Cajal, C.S.I.C., Madrid, Spain) and Professor Zoltán Molnár (Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford UK) has provided evidence for a new source of the earliest generated cerebral cortical cells, the subplate. In their recent publication in the journal Proceeding of the National Academy of Science USA (Pedraza et al., 2014) they describe that a considerable proportion of these early generated cells (known as the subplate) originate from an unusual and unexpected source, in the anterior and medial part of the telencephalon, outside the cerebral cortex itself. Previously, it had been generally accepted that they originate locally from the germinal zone of the cortical neuroepithelium.

These subplate cells in the embryonic cerebral cortex are particularly interesting for clinicians concerned with brain developmental abnormalities, since they provide a transient scaffold for the developing cerebral cortex and assist in the development of cortical connectivity, effectively providing the foundation of the adult structure. Indeed, the first synaptic contact in the cerebral cortex is established between subplate cells and the first thalamic fibers that reach the neuroepithelium. Disruption or damage to these early cells could be the source of flaws that lead to cerebral cortical developmental disorders, such as cerebral palsy, schizophrenia and autism. The discoveries that these scaffold cells arrive after a longer and more arduous journey might be significant to understand developmental disorders, because the process of their migration could be vulnerable and could be the cause of some cortical developmental abnormalities. If the scaffold is not assembled in the right time at the right place, then other aspects of the building work of making a brain can suffer which may only manifest in later life. This makes the discovery of this unusual origin and migration of the subplate neurons important for the developmental neurobiology and clinical neurology community.

The team in Madrid, led by Professor De Carlos noticed that some subplate cells originate from an unusual anterior and medial location (rostral medial telencephalic wall) and migrate tangentially through long routes to the cerebral cortex. The team at Oxford studied a selective subgroup of subplate cells expressing Lpar1 (Edg2) which had similar distribution and characteristics to the labeled cells found by De Carlos and his team (Molecular diversity of early-born subplate neurons. Hoerder-Suabedissen A, Molnár Z. Cereb. Cortex. 2013 Jun;23(6):1473-83). When the two teams compared their results on a meeting they decided to use cell-tracker to label rostral medial telencephalic wall in the mouse strain with fluorescently labeled Lpar1-positive cells. These experiments showed a very good match and clearly demonstrated that indeed this subset of labeled subplate cells originated from this unexpected and unusual anterior-medial source in mice.

The layer of subplate cells is in the Cerebral Cortex of all mammals, but their size varies between species, being wider in humans and primates. This suggests that subplate cells are not a vestige of early neuronal structures, but a fundamental structure involved in early stage of cortical development. For this reason it will be important to study this source also in humans and hence, it will be imperative to study abnormalities of this particular subplate cell population in human cognitive disorders. It has been previously found that many of the schizophrenia and autism associated genes were expressed transiently in subplate during development (Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia. Hoerder-Suabedissen et al., Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3555-60). Studying the way that nerves develop and connect this network can reveal where things can go wrong and trigger diseases such as the mentioned cerebral palsy, autism or schizophrenia.

This work was supported by the Spanish Ministerio de Ciencia e Innovación and by the Medical Research Council of the United Kingdom. Please visit the Proceedings of the National Academy of Sciences website for the full article (Pedraza et al., 2014)

After the publication of these news releases, I received more approaches from Spain (from students and postdocs).
Year(s) Of Engagement Activity 2013,2014
URL http://www.dpag.ox.ac.uk/news/unexpected-origin-of-the-subplate-scaffold-cells-of-our-developing-bra...
 
Description News release on: Autism and Schizophrenia May Develop During Short Period of Time in Infancy 
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 News release was helped by our work and our interview:

http://healthland.time.com/2013/02/12/autism-and-schizophrenia-may-develop-during-short-period-of-time-in-infancy/
http://www.sciencedaily.com/releases/2013/02/130211162223.htm
http://www.genengnews.com/gen-news-highlights/autism-and-schizophrenia-genes-show-early-fleeting-activation/81247981/
http://www.enn.com/health/article/45586
http://scicasts.com/gene/2029-functional-genomics/5417-study-shows-autism-and-schizophrenia-genes-only-active-in-developing-brains/
http://medicalxpress.com/news/2013-02-genes-autism-schizophrenia-brains.html
http://www.myscience.org/news/2013/genes_for_autism_and_schizophrenia_only_active_in_developing_brains-2013-imperial
http://www.sify.com/news/genes-for-autism-and-schizophrenia-only-active-in-developing-brains-news-international-ncmp5rcadic.html

Genes connected to the two disorders may only be active for a brief window of time.
The study, while in mice, could provide clues about how the developmental disorders develop. Focusing on a region of the brain known as the subplate, where the first nerve cells develop, researchers at the University of Oxford, King's College London and Imperial College London found that genes linked to autism and schizophrenia were only active in these regions during early stages of brain development.

Neurons in the subplate region form the foundation for the network of neural connections that eventually crisscross the brain. Studying the way that nerves develop and join this network can reveal where the growth can go wrong and trigger diseases such as autism or schizophrenia.

I regularly advise journalists on publications related to autism and schizophrenia and on general issues on brain development.
These news releases gave us public exposure.
Year(s) Of Engagement Activity 2013,2014
URL http://healthland.time.com/2013/02/12/autism-and-schizophrenia-may-develop-during-short-period-of-ti...
 
Description Open Day - Medical Division Oxford 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact My College, St John's Oxford receives one of the highest number of applicants for medical and biomedical sciences course at Oxford. The open days are very popular and they often continue with discussions about my research activities. I host 5 open days a year and 30-40 pupils attend them (5x30-40/year).

St John's have one of the highest numbers of medical and biomedical applicants. The quality of medical and biomedical intake is high (as it is measured from subsequent distinctions, and exam results).
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014
 
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 2006,2007,2008,2009,2010,2011,2012,2013,2014
 
Description Oxford - McGill Mini Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact https://www.mcgill.ca/brain/international-partners/oxford-university/oxford-neuroscience-news

On 14th January 2014 a mini Symposium organised by Andrew King and Zoltán Molnár served as the first joint cluster meeting between the systems and cellular neuroscience groups of the DPAG. The meeting covered a wide range of topics focussed around "Mammalian cerebral cortical circuits".

The joint cluster meeting brought together groups who are experts in the field of cerebral cortical circuit formation and plasticity in mammals. Their expertise extends from neurogenesis and neuronal migration to the establishment and plasticity of connections. These groups use various techniques: laser-scanning photo stimulation, 2-photon microscopy, confocal microscopy, electrophysiology and behavioural testing. Their aim is to understand how mammalian cortical neurons control cortical development and plasticity and how they are integrated into functional cortical circuitry responsible for some of the most sophisticated sensory and motor processing.

The cluster meeting was linked to the visit of Professor Anne Mc Kinney, Vice Chair of McGill's Brain Institute, who delivered a keynote lecture on "Dendritic spines, autism and epilepsy". Her laboratory has made a great contribution to the insights into synapse maintenance and plasticity in the mammalian cerebral cortex and hippocampus.

The symposium gave an excellent opportunity to continue to build links between McGill and Oxford Neuroscience.
Year(s) Of Engagement Activity 2013,2014
URL https://www.mcgill.ca/brain/international-partners/oxford-university/oxford-neuroscience-news
 
Description Prepared a website and video with Oxford Sparks for pupils (12-14 yo) to explain basics of movement control 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Schools
Results and Impact The website (http://www.oxfordsparks.net/video/youve-got-nerve) has been viewed over 500 people just 3 days after publishing.

I already received e-mails from schools to do some more presentations - based on the video.
Year(s) Of Engagement Activity 2014
URL http://www.oxfordsparks.net/video/youve-got-nerve
 
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 2015,2016,2017,2018,2019,2020
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 School visit London and Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact About 150 pupils attended the presentation and the seminar was followed with intense discussions.

The impact is difficult to measure, but I am sure that the interest in biology and awareness of neuroscience and the brain increased.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014
 
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 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 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 2006,2007,2008,2009,2010,2011,2012,2013,2014
URL http://www.neuroscience.ox.ac.uk/research_directory/m-p/zoltan-molnar