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Muller D.,European Neuroscience Institute ENI G | Cherukuri P.,European Neuroscience Institute ENI G | Henningfeld K.,University of Gottingen | Henningfeld K.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | And 10 more authors.
Science | Year: 2014

Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass types ranging from "slow" to "fast," whose biophysical properties govern the timing, gradation, and amplitude of muscle force. Here we identify the noncanonical Notch ligand Delta-like homolog 1 (Dlk1) as a determinant of motor neuron functional diversification. Dlk1, expressed by ∼30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in the mouse and chick. Dlk1 suppresses Notch signaling and activates expression of the K+ channel subunit Kcng4 to modulate delayed-rectifier currents. Dlk1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Our findings provide insights into the development of motor neuron functional diversity and its contribution to the execution of movements.


Snaidero N.,Max Planck Institute for Experimental Medicine | Snaidero N.,University of Gottingen | Mobius W.,Max Planck Institute for Experimental Medicine | Mobius W.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | And 12 more authors.
Cell | Year: 2014

Central nervous system myelin is a multilayered membrane sheath generated by oligodendrocytes for rapid impulse propagation. However, the underlying mechanisms of myelin wrapping have remained unclear. Using an integrative approach of live imaging, electron microscopy, and genetics, we show that new myelin membranes are incorporated adjacent to the axon at the innermost tongue. Simultaneously, newly formed layers extend laterally, ultimately leading to the formation of a set of closely apposed paranodal loops. An elaborated system of cytoplasmic channels within the growing myelin sheath enables membrane trafficking to the leading edge. Most of these channels close with ongoing development but can be reopened in adults by experimentally raising phosphatidylinositol-(3,4,5)-triphosphate levels, which reinitiates myelin growth. Our model can explain assembly of myelin as a multilayered structure, abnormal myelin outfoldings in neurological disease, and plasticity of myelin biogenesis observed in adult life. PaperFlick © 2014 Elsevier Inc.


Ehrenreich H.,Max Planck Institute for Experimental Medicine | Ehrenreich H.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Nave K.-A.,Max Planck Institute for Experimental Medicine | Nave K.-A.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain
Genes | Year: 2014

Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these "umbrella diagnoses", genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. "Risk genotypes" of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease) phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS ("phenotype-based genetic association studies"). Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Willig K.I.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Willig K.I.,Max Planck Institute for Biophysical Chemistry | Barrantes F.J.,CONICET
Current Opinion in Chemical Biology | Year: 2014

Chemical synapses in brain are structural differentiations where excitatory or inhibitory signals are vectorially transmitted between two neurons. Excitatory synapses occur mostly on dendritic spines, submicron sized protrusions of the neuronal dendritic arborizations. Axons establish contacts with these tiny specializations purported to be the smallest functional processing units in the central nervous system. The minute size of synapses and their macromolecular constituents creates an inherent difficulty for imaging but makes them an ideal object for superresolution microscopy. Here we discuss some representative examples of nanoscopy studies, ranging from quantification of receptors and scaffolding proteins in postsynaptic densities and their dynamic behavior, to imaging of synaptic vesicle proteins and dendritic spines in living neurons or even live animals. © 2014 Elsevier Ltd.


Tuoc T.,Research Group of Molecular Developmental Neurobiology | Tuoc T.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Tuoc T.,UniversitAtsmedizin Gottingen | Boretius S.,Max Planck Institute for Biophysical Chemistry | And 11 more authors.
Developmental Cell | Year: 2013

Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 overexpression results in the opposite phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of the Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture. © 2013 Elsevier Inc.


Koch J.C.,University of Gottingen | Lingor P.,University of Gottingen | Lingor P.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain
Experimental Eye Research | Year: 2016

Different pathological conditions including glaucoma, optic neuritis, hereditary optic atrophy and traumatic injury lead to a degeneration of retinal ganglion cell axons in the optic nerve. Besides this clinical relevance, several experimental models employ the optic nerve as a model system to examine general mechanisms of axonal degeneration in the central nervous system.Several experimental studies have demonstrated that an activation of autophagy is a prominent feature of axonal degeneration in the optic nerve independent of the underlying pathological condition. However, the function of autophagy in axonal degeneration remains still unclear. Inhibition of autophagy was found to attenuate axonal degeneration within the first hours after optic nerve lesion. Other studies focusing on survival of retinal ganglion cells at later postlesional time points report contradicting results, where both inhibition and induction of autophagy were beneficial for survival, depending on the model system or examination time. Therefore, a more precise understanding of the role and the kinetics of autophagy in axonal degeneration is mandatory to develop new therapies for diseases of the optic nerve.Here, we review the literature on the pathophysiological role of autophagy in axonal degeneration in the optic nerve and discuss its implications for future therapeutic approaches in diseases of the eye and the central nervous system involving axonal degeneration. © 2015 Elsevier Ltd.


Koch J.C.,University of Gottingen | Tonges L.,University of Gottingen | Barski E.,University of Gottingen | Michel U.,University of Gottingen | And 4 more authors.
Cell Death and Disease | Year: 2014

The Rho/ROCK/LIMK pathway is central for the mediation of repulsive environmental signals in the central nervous system. Several studies using pharmacological Rho-associated protein kinase (ROCK) inhibitors have shown positive effects on neurite regeneration and suggest additional pro-survival effects in neurons. However, as none of these drugs is completely target specific, it remains unclear how these effects are mediated and whether ROCK is really the most relevant target of the pathway. To answer these questions, we generated adeno-associated viral vectors to specifically downregulate ROCK2 and LIM domain kinase (LIMK)-1 in rat retinal ganglion cells (RGCs) in vitro and in vivo. We show here that specific knockdown of ROCK2 and LIMK1 equally enhanced neurite outgrowth of RGCs on inhibitory substrates and both induced substantial neuronal regeneration over distances of more than 5mm after rat optic nerve crush (ONC) in vivo. However, only knockdown of ROCK2 but not LIMK1 increased survival of RGCs after optic nerve axotomy. Moreover, knockdown of ROCK2 attenuated axonal degeneration of the proximal axon after ONC assessed by in vivo live imaging. Mechanistically, we demonstrate here that knockdown of ROCK2 resulted in decreased intraneuronal activity of calpain and caspase 3, whereas levels of pAkt and collapsin response mediator protein 2 and autophagic flux were increased. Taken together, our data characterize ROCK2 as a specific therapeutic target in neurodegenerative diseases and demonstrate new downstream effects of ROCK2 including axonal degeneration, apoptosis and autophagy. © 2014 Macmillan Publishers Limited.


Wilts B.D.,University of Gottingen | Schaap I.A.T.,University of Gottingen | Schaap I.A.T.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Schmidt C.F.,University of Gottingen
Biophysical Journal | Year: 2015

Cowpea chlorotic mottle virus (CCMV) forms highly elastic icosahedral protein capsids that undergo a characteristic swelling transition when the pH is raised from 5 to 7. Here, we performed nano-indentation experiments using an atomic force microscope to track capsid swelling and measure the shells' Young's modulus at the same time. When we chelated Ca2+ ions and raised the pH, we observed a gradual swelling of the RNA-filled capsids accompanied by a softening of the shell. Control experiments with empty wild-type virus and a salt-stable mutant revealed that the softening was not strictly coupled to the swelling of the protein shells. Our data suggest that a pH increase and Ca2+ chelation lead primarily to a loosening of contacts within the protein shell, resulting in a softening of the capsid. This appears to render the shell metastable and make swelling possible when repulsive forces among the capsid proteins become large enough, which is known to be followed by capsid disassembly at even higher pH. Thus, softening and swelling are likely to play a role during inoculation. © 2015 Biophysical Society.


Cabral-Calderin Y.,University of Gottingen | Cabral-Calderin Y.,Leibniz Institute for Primate Research | Schmidt-Samoa C.,University of Gottingen | Wilke M.,University of Gottingen | And 2 more authors.
Journal of Cognitive Neuroscience | Year: 2015

When our brain is confronted with ambiguous visual stimuli, perception spontaneously alternates between different possible interpretations although the physical stimulus remains the same. Both alpha (8–12 Hz) and gamma (>30 Hz) oscillations have been reported to correlate with such spontaneous perceptual reversals. However, whether these oscillations play a causal role in triggering perceptual switches remains unknown. To address this question, we applied transcranial alternating current stimulation (tACS) over the posterior cortex of healthy human participants to boost alpha and gamma oscillations. At the same time, participants were reporting their percepts of an ambiguous structure-from-motion stimulus. We found that tACS in the gamma band (60 Hz) increased the number of spontaneous perceptual reversals, whereas no significant effect was found for tACS in alpha (10 Hz) and higher gamma (80 Hz) frequencies. Our results suggest a mechanistic role of gamma but not alpha oscillations in the resolution of perceptual ambiguity. © 2015 Massachusetts Institute of Technology.


Balasubramanian G.,Max Planck Institute for Biophysical Chemistry | Balasubramanian G.,Center for Nanoscale Microscopy and Molecular Physiology of the Brain | Lazariev A.,Max Planck Institute for Biophysical Chemistry | Arumugam S.R.,Max Planck Institute for Biophysical Chemistry | Duan D.-W.,Max Planck Institute for Biophysical Chemistry
Current Opinion in Chemical Biology | Year: 2014

Nitrogen-Vacancy (NV) color center in diamond is a flourishing research area that, in recent years, has displayed remarkable progress. The system offers great potential for realizing futuristic applications in nanoscience, benefiting a range of fields from bioimaging to quantum-sensing. The ability to image single NV color centers in a nanodiamond and manipulate NV electron spin optically under ambient condition is the main driving force behind developments in nanoscale sensing and novel imaging techniques. In this article we discuss current status on the applications of fluorescent nanodiamonds (FND) for optical super resolution nanoscopy, magneto-optical (spin-assisted) sub-wavelength localization and imaging. We present emerging applications such as single molecule spin imaging, nanoscale imaging of biomagnetic fields, sensing molecular fluctuations and temperatures in live cellular environments. We summarize other current advances and future prospects of NV diamond for imaging and sensing pertaining to bio-medical applications. © 2014 Elsevier Ltd.

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