Developing brain networks act locally to build globally
One of the outstanding mysteries of the cerebral cortex is how individual neurons develop the proper synaptic connections to form large-scale, distributed networks. Now, an international team of scientists including researchers from Goethe University and the FIAS have gained novel insights from spontaneously generated patterns of activity by local networks in the early developing visual cortex. Apparently these form the basis for long-range neural connections that are established through brain activity over the course of cortical development.
Now, as published in Nature Neuroscience, scientists at the Max Planck Florida Institute for Neuroscience, Frankfurt Institute for Advanced Studies, Goethe University of Frankfurt, and the University of Minnesota have investigated the visual cortex of the ferret, an ideal model system to explore the early development of networks in the cortex. These are composed of thousands of neurons and are distributed over millimetres of the cortical surface. In the visual cortex, network activity encodes specific features of the visual scene like the orientation of edges and the direction of object motion.
By using calcium imaging techniques, the scientists were able to visualize with unprecedented resolution spontaneous activity patterns, i.e. patterns not produced by visual input. To their great surprise, the spontaneous activity patterns were highly correlated between distant populations of neurons – and in fact were so highly correlated that the activity of small populations of neurons could reliably predict coincident network activity patterns millimetres away, and these correlation patterns beautifully predicted the patterns of network activity evoked by visual stimulation.
In their next step, the researchers used this remarkable correspondence of spontaneous and visually-evoked network patterns to find out how the interaction of networks developed in the immature brain. By looking at the state of spontaneous activity patterns prior to eye opening, they expected to see a striking difference in the patterns of spontaneous activity because the long-range cortical connections that are thought to be the basis for distributed network activity patterns are absent in the immature cortex. To their surprise, they discovered robust long-range patterns of correlated spontaneous activity prior to eye opening, and found that they extended over distances comparable to what was seen in the mature brain.
Confronted with this paradox, the researchers first considered whether the correlated activity patterns could be spreading through chains of local cortical connections, similar to a forest fire. To test this intriguing possibility, Matthias Kaschube, Professor for Computer Science at Goethe University and Fellow at the Frankfurt Institute for Advanced Studies (FIAS), and his doctoral student Bettina Hein, built a computational model of the neural circuitry in the early visual cortex. They found that by using a set of parameters that are consistent with the organization of local cortical connections, the model could precisely reproduce the patterns of spontaneous long-range correlations they had observed experimentally, without the need for long-range connections.
Taken together, these results suggest that long-range order in the early developing cortex originates from neural activity driven by short-range connections. In other words, local connections build a network activity scaffold. Following the well-accepted plasticity rule ‘what fires together wires together’, activity mediated by local connections can then guide the subsequent formation of long-range network connections. In a twist of the oft-used phrase, ‘think globally, act locally’, developing cortical circuits act locally to achieve global effects. Future studies will test the prediction that activity dependent plasticity mechanisms shape the structure of long-range connections based on the instructive activity patterns derived from local cortical connections.
Gordon B Smith, Bettina Hein, Dave E Whitney, David Fitzpatrick, Matthias Kaschube: Distributed network interactions and their emergence in developing neocortex (2018) Nature Neuroscience. http://www.nature.com/articles/s41593-018-0247-5
An image can be downloaded here.
Caption: Spatial patterns of spontaneous correlation (example in figure on the left) in the immature visual cortex prior to eye-opening are distributed across several millimeters and resemble the layout of the response properties (example on the right) of visual cortex after eye-opening; Data: Max Planck Florida Institute.
Credit: Bettina Hein
Further information: Professor Matthias Kaschube, Institute for Computer Science and Frankfurt Institute for Applied Sciences, Riedberg Campus, Tel. +49 69 798-47521, email@example.com.
Researchers decode structure and function of docking domains in the biosynthesis of peptide natural products
FRANKFURT. Microorganisms often assemble natural products similar to industrial assembly lines. Certain enzymes, non-ribosomal peptide synthetases (NRPS) play a key role in this process. Biotechnologists at Goethe University have now been able to discover how these enzymes interact with each other. This brings them one step closer to their goal of engineering the production of such peptide natural products.
Many important natural products such as antibiotics, immunosuppressants, or cancer drugs are derived from microorganisms. These natural products are often small proteins or peptides which are generated in the cell by NRPS enzymes similar to a modern automobile factory: at each station additional parts are added to the basic structure until finally a completed automobile leaves the factory. With regard to the NRPS, a specific amino acid is incorporated and processed at each station (module), so that in the end peptides emerge that can be linear, cyclic or otherwise modified including unusual amino acids.
If larger peptides are generated by these systems, often several NRPS enzymes – or assembly lines – operate successively. The order in which this happens is determined by docking domains. These are small regions at the end of the assembly lines that fit with the next NRPS enzyme in line like a key in a lock. Although the basic principles of these NRPS interactions have been known for a long time, the structure of the docking domains was unknown until now. The research groups led by Professor Jens Wöhnert form the Institute of Molecular Biosciences and Professor Helge Bode from Molecular Biotechnology at Goethe University have now been able to successfully explain this.
“We were able to determine the structures of individual docking domains and, for the first time, an NRPS docking domain pair as well,” explains Carolin Hacker, who is a PhD student in Jens Wöhnert’s group. “This made it possible to clarify the rules for the interaction of the docking domains and to change them in such a way that new natural products will be generated,” adds Xiaofeng Cai, postdoctoral researcher in Helge Bode’s group.
“We are only at the beginning of our research: We need structures of additional and structurally diverse docking domains so that in the end we can utilise them like building blocks. Our goal is to connect various biosynthesis pathways and create totally new substances” Wöhnert explains. “Nature has been quite inventive in this area, and there are apparently numerous different ways to mediate the interaction of these complexes,” adds Bode.
Research in this area continues in both groups as part of the LOEWE research cluster MegaSyn. The first results on the structures of additional docking domains are quite promising.
Publication: Carolin Hacker, Xiaofeng Cai, Carsten Kegler, Lei Zhao, A. Katharina Weickhmann, Jan Philip Wurm, Helge B. Bode, Jens Wöhnert: Structure-based redesign of docking domain interactions modulates the product spectrum of a rhabdopeptide-synthesizing NRPS, Nature Communications, https://www.nature.com/ncomms/, DOI: 10.1038/s41467-018-06712-1
You can download an image at: www.uni-frankfurt.de/74390329
Caption: 3D structure of an NRPS docking domain pair. The docking domains of NRPS B (green) connects to the fitting docking domain of NRPS C (magenta) via a β-leaflet.
Further information: Professor Jens Wöhnert, Institute for Molecular Biosciences, Faculty 15, Riedberg Campus, Tel. +49 69 798-29785, firstname.lastname@example.org
Professor Helge B. Bode, Molecular Biotechnology, Faculty 15, Riedberg Campus, Tel.: +49 69 798-29557, email@example.com
Barry Eichengreen appointed Visiting Professor for Financial History 2019
FRANKFURT. Barry Eichengreen, University of California, Berkeley, will hold the Visiting Professorship of Financial History at Goethe University Frankfurt’s House of Finance next year. The professorship is endowed by Metzler Bank and Friedrich Flick Förderungsstiftung.
Barry Eichengreen is George C. Pardee and Helen N. Pardee Professor of Economics and Political Science at the University of California, Berkeley. His research focuses on the history and current operation of the international monetary and financial system.
His most recent books include The Populist Temptation: Economic Grievance and Political Reaction in the Modern Era (2018), How Global Currencies Work: Past, Present, and Future with Livia Chitu and Arnaud Mehl (2017), Hall of Mirrors: The Great Depression, the Great Recession, and the Uses – and Misuses – of History (2015), and Exorbitant Privilege: The Rise and Fall of the Dollar and the Future of the International Monetary System (2011) (shortlisted for the Financial Times and Goldman Sachs Business Book of the Year Award in 2011). One of the best known books by Barry Eichengreen is Golden Fetters: The Gold Standard and the Great Depression, 1919–1939 (1992) which argues that a main cause for the world depression of the 1930ies was the structurally flawed and poorly managed international gold standard. In his most widely cited paper (with Tamim Bayoumi in 1993) he argued that the European Union was less suitable as a Single Currency Area than the United States.
Professor Eichengreen was educated at Yale University in New Haven, CT (M.A in Economics, M.Phil. in Economics, M.A. in History and a Ph.D. in Economics) and the University of California, Santa Cruz (B.A. in Economics and Political Science). He is a Research Associate at NBER (National Bureau of Economic Research) and a Research Fellow at CEPR (Centre for Economic Policy Research). He received a doctor honoris causa from the American University in Paris and, in 2010, the Schumpeter Prize from the International Schumpeter Society. Eichengreen has been named one of Foreign Policy Magazine's 100 Leading Global Thinkers, and he is a past president of the Economic History Association (2010-11 academic year).
During his stay in Frankfurt in May 2019, Barry Eichengreen will head a workshop for young scholars on the occasion of the 50th anniversary of the IBF (Institut für Bank- und Finanzgeschichte) on “Financial History – Reflections on the Past to Tackle Today’s Key Finance Questions” and deliver the keynote address in an international research conference at Goethe University. He will also give a seminar titled “Topics in Macroeconomic History” in the Ph.D. program of the University’s Graduate School GSEFM at the House of Finance.
Professor Eichengreen is the fifth holder of the Goethe University Visiting Professorship of Financial History. In the context of this professorship, distinguished international experts in banking and financial history are invited to share their research insights and methods with researchers, students and the interested public in Frankfurt. Cooperation partners are the Research Center SAFE at the House of Finance and the Institut für Bank- und Finanzgeschichte. Previous Visiting Professors were Benjamin Friedman, Harvard University (2015), Caroline Fohlin, Emory University, Atlanta (2016), Hans-Joachim Voth, University of Zurich (2017) and Harold James, Princeton University (2018). The Visiting Professorship was initially endowed by Metzler Bank and Edmond de Rothschild Group in 2014 on the occasion of Goethe University’s centennial. Since 2018 it is sponsored by Metzler Bank and Friedrich Flick Förderungsstiftung.
Picture material may be downloaded at: http://www.muk.uni-frankfurt.de/74041865?
Further Information: Dr. Stephanie Collet, Research Center SAFE, House of Finance, Campus Westend, Tel. +49 69 798-30041, firstname.lastname@example.org
Excellence strategy: Joint project between Justus-Liebig-University, Goethe University and Max-Planck-Institute clears the last hurdle
FRANKFURT/GIESSEN. With their joint application for an excellence cluster, Goethe University Frankfurt and Justus-Liebig-University Giessen asserted themselves successfully against strong competition. The German Research Foundation announced on 27th September, that the “Cardiopulmonary Institute” (CPI) application, along with 56 other Excellence Cluster projects nationwide, will receive funding for the next seven years.
University President Professor Birgitta Wolff says: “Congratulations to our colleagues in Frankfurt, Giessen and Bad Nauheim, who fought with great success for their scientific ideas and concepts with an excellent application amid a field of strong competitors. The culture of cooperation that has emerged over the course of nearly twelve years among the partners was undoubtedly a decisive moment for this achievement. The formal foundation as an interuniversity institute is new, as is a more developed substantive approach. This latest achievement demonstrates that the effort and investment put into university cardiovascular research paid off.”
Professor Stefanie Dimmeler, lead scientist for Goethe University, emphasizes: “We are thrilled about this huge success which would not have been possible without the support of our great team. The funding of the ‘Cardiopulmonary Institute’ will allow us to create a centre that is unique worldwide with the goal of better understanding heart and lung diseases and identifying new therapeutic options.”
Heart and lung diseases are among the most frequent causes of death worldwide, with multiple interactions between the two organs and challenges in treatment that have yet to be resolved. A coherent understanding of the molecular biology of the individual and cooperative cellular processes, which constitute the foundation of these organs’ homeostasis and their failure in the course of disease, is lacking along with the knowledge of how these processes could be used for new, individualized therapy concepts.
The consortium of the three partners consisting of basic and medical scientists and clinicians has already made fundamental contributions to cardiovascular research and therapeutic developments within the framework of the previously funded Excellence Cluster Cardio-Pulmonary System (ECCPS). The newly approved institute pursues new structural and programmatic paths with the vision of precision biology being the motor for precision medicine. This success is simultaneously an important signal for the sustained development of research strategy at Goethe University.
The joint institute is an interuniversity facility in accordance with §47 of the Hessen Higher Education Act. Within a short time, several new professorships and junior research groups will be set up to further strengthen work in future fields of cardio-vascular research. The CPI will finance cutting edge technologies and flexible innovation programs. The CPI Academy supports research-oriented teaching and promotes academic career development, such as a “science track” for medical students, support of MD and PhD programmes, the financing of career programmes for basic, medical and clinical researchers, and a mentoring programme.
With the new Excellence Cluster, the three partners also strengthen the scientific profile of the region, further enhancing its status in the area of cutting-edge medical research.
Cardiovascular Researcher Dr. Nuno Guimarães Camboa founds a junior research group at Goethe University with €1.25m
FRANKFURT. Following ten years at the renowned University of California San Diego (UCSD), cardiovascular researcher Dr. Nuno Guimarães Camboa is coming to Goethe University. He was lured by the DZHK (German Centre of Cardiovascular Research), which has 28 locations in Germany, one of which is Goethe University. The native Portuguese has been awarded a DZHK junior research group grant and will receive € 1.25m in the next five years to create a research group dedicated to basic research on cardiovascular diseases.
A transcription factor is at the centre of Dr. Nuno Guimarães Camboa’s work. This is a protein which supports the copying of the DNA of the genetic code, “translating” it to RNA. From his previous research projects at the University of California, the junior researcher knows that a specific transcription factor, TBX18, is typically present in three cell types: smooth muscle cells that are found in vessel walls, pacemaker cells in the sino-atrial node (the structure responsible for setting the rhythm of cardiac contraction), and activated connective tissue cells in the injured heart. All three cell types are involved in dangerous cardiovascular diseases: dilations of the aorta (aortic aneurysms), cardiac arrhythmias and morbid proliferation of connective tissue in the heart (cardiac fibrosis).
“We believe that TBX18 affects these cells’ functions”, says Guimarães Camboa. “This factor could therefore play a role in certain cardiovascular diseases.” With his DZHK junior research group at the Goethe University Frankfurt, he wants to investigate which genes are regulated by the transcription factor. The biologist is also planning the targeted inactivation of TBX18 in the relevant cell types. The consequences of this inactivation on the function of the cells will subsequently be closely analysed. “We thus want to better understand the signalling networks active in specific types of cardiovascular disease and hope to thereby improve their early detection and treatment”, explains Guimarães Camboa.
Guimarães Camboa is coming to the DZHK partner site at Goethe University after ten years in the US. He both completed his doctorate and carried out a four-year PostDoc at the University of California. He previously concentrated on the heart’s formation during embryonic development.
With the junior research groups, the DZHK wants to attract talented and qualified young scientists from Germany and abroad, and provide them with scientific independence early on. In addition to leading a research group, the young scientists also have teaching duties, so that they can qualify for a professorship.
Further information: Dr. Nuno Guimarães Camboa, Institute for Cardiovascular Regeneration, University Hospital Frankfurt, email@example.com .
Image may be downloaded at: www.uni-frankfurt.de/73850305