EXC 257:  NeuroCure - Towards a Better Outcome of Neurological Disorders

• Subject Area: Neurosciences
• Term: from 2007 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 39052203

• Final Report Year: 2019

Final Report Abstract

Neurological and psychiatric disorders pose a massive burden to society, and our understanding of the underlying molecular and pathophysiological mechanisms is limited. At the same time, the translation, or transfer, of knowledge from basic research into clinical application has proven difficult. For this reason, NeuroCure has set out to narrow the current gap between basic and clinical neuroscience and thereby promote the development and application of new therapies and diagnostic tools. To achieve the critical mass for excellent research in the neurosciences, we appointed more than 25 outstanding scientists, including excellent female researchers and promising early career scientists. Their integration into the existing scientific environment was promoted by collaborative projects with a strong interdisciplinary and translational focus. In addition, visiting fellow programs enabled us to recruit many international experts, including Nobel Laureates, for research stays in Berlin. Excellent research is also driven by the development of new technologies. NeuroCure therefore established several technology platforms that provide state-of-the-art instruments and expertise, e. g. in the areas of imaging and automated behavioral analysis of animal models of various diseases. In addition, the NeuroCure Clinical Research Center, a fully equipped outpatient facility, provides full administrative and logistic support for high-quality clinical trials. Successful translation additionally requires a strong interdisciplinary mind-set. We therefore developed an international MSc/PhD program with a focus on interdisciplinary research and translation, combining comprehensive training with advice from experienced neuroscientists across disciplines. Moreover, in line with our commitment to advance equal opportunity within the Cluster and our partner institutions, NeuroCure promoted the recruitment of excellent female scientists to higher academic positions through diverse measures. Finally, in cooperation with the Charité and our partner institutions, we overcame institutional and administrative barriers and established the Einstein Center for Neurosciences Berlin. Through these extensive measures, NeuroCure has substantially strengthened collaborations between basic and clinical researchers. The success of the Cluster is documented by many high-impact publications and a significant increase in collaborative research grants in Berlin. In the future, we will continue to use this momentum to secure Berlin’s position at the forefront of translational neuroscience.

Link to the final report

https://doi.org/10.2314/KXP:1698804903

Publications

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• Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors. Nat Neurosci, 2009. 12:1373-1380
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• Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell, 2009. 138:1222-1235
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• An embedded subnetwork of highly active neurons in the neocortex. Neuron, 2010. 68:1043-1050
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• Impact of spikelets on hippocampal CA1 pyramidal cell activity during spatial exploration. Science, 2010. 327:474-477
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• RIM-binding protein, a central part of the active zone, is essential for neurotransmitter release. Science, 2011. 334:1565-1569
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• Suppressing immunosuppression after stroke. N Engl J Med, 2011. 365:2134-2136
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• Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature, 2012. 486:256-260
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• Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly. Nat Neurosci, 2012. 15:1219-1226
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• Coupled control of desensitization and gating by the ligand binding domain of glutamate receptors. Neuron, 2012. 74:845-857
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• Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol, 2012. 233:102-111
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• Essential role of interleukin-6 in post-stroke angiogenesis. Brain, 2012. 135:1964-1980
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• Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning. EMBO J, 2012. 31:1217-1230
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• Segregation of axonal and somatic activity during fast network oscillations. Science, 2012. 336:1458-1461
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• The cellular basis of GABA(B)-mediated interhemispheric inhibition. Science, 2012. 335:989-993
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• The transcription factor c-Maf controls touch receptor development and function. Science, 2012. 335:1373-1376
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• Association between childhood trauma and low hair cortisol in depressed patients and healthy control subjects. Biol Psychiatry, 2013. 74:e15-17
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• Functional and structural brain changes in anti-N-methyl-D- aspartate receptor encephalitis. Ann Neurol, 2013. 74:284-296
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• Identifying the perfusion deficit in acute stroke with resting-state functional magnetic resonance imaging. Ann Neurol, 2013. 73:136-140
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• Immunoproteasomes are important for proteostasis in immune responses. Cell, 2013. 152:935-937
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• Restoring polyamines protects from age-induced memory impairment in an autophagydependent manner. Nat Neurosci, 2013. 16:1453-1460
  Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, Kramer JM, Liu KS, Schroeder S, Stunnenberg HG, Sinner F, Magnes C, Pieber TR, Dipt S, Fiala A, Schenck A, Schwaerzel M, Madeo F, Sigrist SJ
  (See online at https://doi.org/10.1038/nn.3512)
• Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature, 2013. 499:233-237
  Posor Y, Eichhorn-Gruenig M, Puchkov D, Schoneberg J, Ullrich A, Lampe A, Muller R, Zarbakhsh S, Gulluni F, Hirsch E, Krauss M, Schultz C, Schmoranzer J, Noe F, Haucke V
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• Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci, 2013. 36:587-597
  Mergenthaler P, Lindauer U, Dienel GA, Meisel A
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• Ultrafast endocytosis at mouse hippocampal synapses. Nature, 2013. 504:242
  Watanabe S, Rost BR, Camacho-Perez M, Davis MW, Sohl-Kielczynski B, Rosenmund C, Jorgensen EM
  (See online at https://doi.org/10.1038/nature12809)
• Clathrin regenerates synaptic vesicles from endosomes. Nature, 2014. 515:228-233
  Watanabe S, Trimbuch T, Camacho-Perez M, Rost BR, Brokowski B, Sohl-Kielczynski B, Felies A, Davis MW, Rosenmund C, Jorgensen EM
  (See online at https://doi.org/10.1038/nature13846)
• Cortical fosGFP expression reveals broad receptive field excitatory neurons targeted by POm. Neuron, 2014. 84:1065-1078
  Jouhanneau JS, Ferrarese L, Estebanez L, Audette NJ, Brecht M, Barth AL, Poulet JF
  (See online at https://doi.org/10.1016/j.neuron.2014.10.014)
• Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements. Brain, 2014. 137:3012-3024
  Barow E, Neumann WJ, Brucke C, Huebl J, Horn A, Brown P, Krauss JK, Schneider GH, Kuhn AA
  (See online at https://doi.org/10.1093/brain/awu258)
• Different patterns of local field potentials from limbic DBS targets in patients with major depressive and obsessive compulsive disorder. Mol Psychiatry, 2014. 19:1186-1192
  Neumann WJ, Huebl J, Brucke C, Gabriels L, Bajbouj M, Merkl A, Schneider GH, Nuttin B, Brown P, Kuhn AA
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• Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA, 2014. 311:1622-1631
  Ebinger M, Winter B, Wendt M, Weber JE, Waldschmidt C, Rozanski M, Kunz A, Koch P, Kellner PA, Gierhake D, Villringer K, Fiebach JB, Grittner U, Hartmann A, Mackert BM, Endres M, Audebert HJ; STEMO Consortium
  (See online at https://doi.org/10.1001/jama.2014.2850)
• Grid-layout and theta-modulation of layer 2 pyramidal neurons in medial entorhinal cortex. Science, 2014. 343:891-896
  Ray S, Naumann R, Burgalossi A, Tang Q, Schmidt H, Brecht M
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• Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science, 2014. 344:634-638
  Voss FK, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ
  (See online at https://doi.org/10.1126/science.1252826)
• MutationTaster2: mutation prediction for the deepsequencing age. Nat Methods, 2014. 11:361-362
  Schwarz JM, Cooper DN, Schuelke M, Seelow D
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• Photoinactivation of glutamate receptors by genetically encoded unnatural amino acids. J Neurosci, 2014. 34:980-991
  Klippenstein V, Ghisi V, Wietstruk M, Plested AJ
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• Regulation of the mammalian elongation cycle by subunit rolling: a eukaryotic-specific ribosome rearrangement. Cell, 2014. 158:121-131
  Budkevich TV, Giesebrecht J, Behrmann E, Loerke J, Ramrath DJ, Mielke T, Ismer J, Hildebrand PW, Tung CS, Nierhaus KH, Sanbonmatsu KY, Spahn CM
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• Beyond Molecular Codes: Simple Rules to Wire Complex Brains. Cell, 2015. 163:285-291
  Hassan BA, Hiesinger PR
  (See online at https://doi.org/10.1016/j.cell.2015.09.031)
• Functional Diversity of Subicular Principal Cells during Hippocampal Ripples. J Neurosci, 2015. 35:13608-13618
  Bohm C, Peng Y, Maier N, Winterer J, Poulet JF, Geiger JR, Schmitz D
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• Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci, 2015. 16:358-372
  Heppner FL, Ransohoff RM, Becher B
  (See online at https://doi.org/10.1038/nrn3880)
• Impact of peripheral myeloid cells on amyloid-beta pathology in Alzheimer’s disease-like mice. J Exp Med, 2015. 212:1811-1818
  Prokop S, Miller KR, Drost N, Handrick S, Mathur V, Luo J, Wegner A, Wyss-Coray T, Heppner FL
  (See online at https://doi.org/10.1084/jem.20150479)
• Optogenetic acidification of synaptic vesicles and lysosomes. Nat Neurosci, 2015. 18:1845-1852
  Rost BR, Schneider F, Grauel MK, Wozny C, Bentz C, Blessing A, Rosenmund T, Jentsch TJ, Schmitz D, Hegemann P, Rosenmund C
  (See online at https://doi.org/10.1038/nn.4161)
• Presynaptic spinophilin tunes neurexin signalling to control active zone architecture and function. Nat Commun, 2015. 6:8362
  Muhammad K, Reddy-Alla S, Driller JH, Schreiner D, Rey U, Bohme MA, Hollmann C, Ramesh N, Depner H, Lutzkendorf J, Matkovic T, Gotz T, Bergeron DD, Schmoranzer J, Goettfert F, Holt M, Wahl MC, Hell SW, Scheiffele P, Walter AM, Loll B, Sigrist SJ
  (See online at https://doi.org/10.1038/ncomms9362)
• Prevention of stroke-associated pneumonia: where next? Lancet, 2015. 386:1802-1804
  Meisel A, Smith CJ
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• Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments. EMBO J, 2015. 34:2334-2349
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• Robust research: Institutions must do their part for reproducibility. Nature, 2015. 525:25-27
  Begley CG, Buchan AM, Dirnagl U
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• Structural snapshots of actively translating human ribosomes. Cell, 2015. 161:845-857
  Behrmann E, Loerke J, Budkevich TV, Yamamoto K, Schmidt A, Penczek PA, Vos MR, Burger J, Mielke T, Scheerer P, Spahn CM
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• The Developmental Rules of Neural Superposition in Drosophila. Cell, 2015. 162:120-133
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• Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation. Acta Neuropathol, 2015. 130:799-814
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• Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling. Nat Neurosci, 2016. 19:1311-1320
  Bohme MA, Beis C, Reddy-Alla S, Reynolds E, Mampell MM, Grasskamp AT, Lutzkendorf J, Bergeron DD, Driller JH, Babikir H, Gottfert F, Robinson IM, O’Kane CJ, Hell SW, Wahl MC, Stelzl U, Loll B, Walter AM, Sigrist SJ
  (See online at https://doi.org/10.1038/nn.4364)
• Autophagosome Formation by Endophilin Keeps Synapses in Shape. Neuron, 2016. 92:675-677
  Kuijpers M, Haucke V
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• Brain networks modulated by subthalamic nucleus deep brain stimulation. Brain, 2016. 139:2503-2515
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• Disruption of Kcc2-dependent inhibition of olfactory bulb output neurons suggests its importance in odour discrimination. Nat Commun, 2016. 7:12043
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• High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol, 2016. 132:361-375
  Baufeld C, Osterloh A, Prokop S, Miller KR, Heppner FL
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• Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons. Elife, 2016. 5:e19374
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• Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures. Am J Hum Genet, 2016. 98:473-489
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• Neural correlates of ticklishness in the rat somatosensory cortex. Science, 2016. 354:757-760
  Ishiyama S, Brecht M
  (See online at https://doi.org/10.1126/science.aah5114)
• Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol, 2016. 131:365-378
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• RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. Proc Natl Acad Sci USA, 2016. 113:11615-11620
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• Scattering compensation by focus scanning holographic aberration probing (F-SHARP). Nature Photonics, 2016. 11:116-123
  Papadopoulos IN, Jouhanneau J-S, Poulet JFA, Judkewitz B
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• Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release. PLoS Biol, 2016. 14:e1002563
  Gupta VK, Pech U, Bhukel A, Fulterer A, Ender A, Mauermann SF, Andlauer TF, Antwi-Adjei E, Beuschel C, Thriene K, Maglione M, Quentin C, Bushow R, Schwarzel M, Mielke T, Madeo F, Dengjel J, Fiala A, Sigrist SJ
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• Structural Hippocampal Damage Following Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Biol Psychiatry, 2016. 79:727-734
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• Superactivation of AMPA receptors by auxiliary proteins. Nat Commun, 2016. 7:10178
  Carbone AL, Plested AJ
  (See online at https://doi.org/10.1038/ncomms10178)
• The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci, 2016. 19:20-27
  Hambardzumyan D, Gutmann DH, Kettenmann H
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• Where Have All the Rodents Gone? The Effects of Attrition in Experimental Research on Cancer and Stroke. PLoS Biol, 2016. 14:e1002331
  Holman C, Piper SK, Grittner U, Diamantaras AA, Kimmelman J, Siegerink B, Dirnagl U
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• Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology, 2017. 88:366-370
  Scheibe F, Pruss H, Mengel AM, Kohler S, Numann A, Kohnlein M, Ruprecht K, Alexander T, Hiepe F, Meisel A
  (See online at https://doi.org/10.1212/wnl.0000000000003536)
• Cognition-mediated evolution of low-quality floral nectars. Science, 2017. 355:75-78
  Nachev V, Stich KP, Winter C, Bond A, Kamil A, Winter Y
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• Control of AMPA receptor activity by the extracellular loops of auxiliary proteins. Elife, 2017. 6:e28680
  Riva I, Eibl C, Volkmer R, Carbone AL, Plested AJ
  (See online at https://doi.org/10.7554/eLife.28680)
• Cortical dendritic activity correlates with spindle-rich oscillations during sleep in rodents. Nat Commun, 2017. 8:684
  Seibt J, Richard CJ, Sigl-Glockner J, Takahashi N, Kaplan DI, Doron G, de Limoges D, Bocklisch C, Larkum ME
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• Dendritic calcium spikes are clearly detectable at the cortical surface. Nat Commun, 2017. 8:276
  Suzuki M, Larkum ME
  (See online at https://doi.org/10.1038/s41467-017-00282-4)
• Fructosedriven glycolysis supports anoxia resistance in the naked mole-rat. Science, 2017. 356:307-311
  Park TJ, Reznick J, Peterson BL, Blass G, Omerbasic D, Bennett NC, Kuich P, Zasada C, Browe BM, Hamann W, Applegate DT, Radke MH, Kosten T, Lutermann H, Gavaghan V, Eigenbrod O, Begay V, Amoroso VG, Govind V, Minshall RD, Smith ESJ, Larson J, Gotthardt M, Kempa S, Lewin GR
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• Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming. Nat Commun, 2017. 8:15293
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