Henry Markram

École Polytechnique Fédérale de Lausanne, Lausanne, Vaud, Switzerland

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Publications (181)1006.76 Total impact

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    ABSTRACT: Background: We present a physically-based computational model of the light sheet fluorescence microscope (LSFM). Based on Monte Carlo ray tracing and geometric optics, our method simulates the operational aspects and image formation process of the LSFM. This simulated, in silico LSFM creates synthetic images of digital fluorescent specimens that can resemble those generated by a real LSFM, as opposed to established visualization methods producing visually- plausible images. We also propose an accurate fluorescence rendering model which takes into account the intrinsic characteristics of fluorescent dyes to simulate the light interaction with fluorescent biological specimen. Results: We demonstrate first results of our visualization pipeline to a simplified brain tissue model reconstructed from the somatosensory cortex of a young rat. The modeling aspects of the LSFM units are qualitatively analysed, and the results of the fluorescence model were quantitatively validated against the fluorescence brightness equation and characteristic emission spectra of different fluorescent dyes. AMS subject classification: Modelling and simulation 
    BMC Bioinformatics 08/2015; 16 (Suppl 11)(S8). DOI:10.1186/1471-2105-16-S11-S8 · 2.67 Impact Factor
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    ABSTRACT: Background: We present a physically-based computational model of the light sheet fluorescence microscope (LSFM). Based on Monte Carlo ray tracing and geometric optics, our method simulates the operational aspects and image formation process of the LSFM. This simulated, in silico LSFM creates synthetic images of digital fluorescent specimens that can resemble those generated by a real LSFM, as opposed to established visualization methods producing visually-plausible images. We also propose an accurate fluorescence rendering model which takes into account the intrinsic characteristics of fluorescent dyes to simulate the light interaction with fluorescent biological specimen. Results: We demonstrate first results of our visualization pipeline to a simplified brain tissue model reconstructed from the somatosensory cortex of a young rat. The modelling aspects of the LSFM units are qualitatively analysed, and the results of the fluorescence model were quantitatively validated against the fluorescence brightness equation and characteristic emission spectra of different fluorescent dyes.
    BioVis 2015, Dublin, Ireland; 07/2015
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    Srikanth Ramaswamy · Henry Markram
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    ABSTRACT: The thick-tufted layer 5 (TTL5) pyramidal neuron is one of the most extensively studied neuron types in the mammalian neocortex and has become a benchmark for understanding information processing in excitatory neurons. By virtue of having the widest local axonal and dendritic arborization, the TTL5 neuron encompasses various local neocortical neurons and thereby defines the dimensions of neocortical microcircuitry. The TTL5 neuron integrates input across all neocortical layers and is the principal output pathway funneling information flow to subcortical structures. Several studies over the past decades have investigated the anatomy, physiology, synaptology, and pathophysiology of the TTL5 neuron. This review summarizes key discoveries and identifies potential avenues of research to facilitate an integrated and unifying understanding on the role of a central neuron in the neocortex.
    Frontiers in Cellular Neuroscience 06/2015; 9:233. DOI:10.3389/fncel.2015.00233 · 4.18 Impact Factor
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    ABSTRACT: Bursts of activity in networks of neurons are thought to convey salient information and drive synaptic plasticity. Here we report that network bursts also exert a profound effect on Spike-Timing-Dependent Plasticity (STDP). In acute slices of juvenile rat somatosensory cortex we paired a network burst, which alone induced long-term depression (LTD), with STDP-induced long-term potentiation and depression (LTP and LTD). We observed that STDP-induced LTP was either unaffected, blocked or flipped into LTD by the network burst, and that STDP-induced LTD was either saturated or flipped into LTP, depending on the relative timing of the network burst with respect to spike coincidences of the STDP event. We hypothesized that network bursts flip STDP-induced LTP to LTD by depleting resources needed for LTP and therefore developed a resource-dependent STDP learning rule. In a model neural network under the influence of the proposed resource-dependent STDP rule, we found that excitatory synaptic coupling was homeostatically regulated to produce power law distributed burst amplitudes reflecting self-organized criticality, a state that ensures optimal information coding.
    Frontiers in Cellular Neuroscience 06/2015; 9. DOI:10.3389/fncel.2015.00220 · 4.18 Impact Factor
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    ABSTRACT: Understanding the effects of environmental stimulation in autism can improve therapeutic interventions against debilitating sensory overload, social withdrawal, fear and anxiety. Here, we evaluate the role of environmental predictability on behavior and protein expression, and inter-individual differences, in the valproic acid (VPA) model of autism. Male rats embryonically exposed (E11.5) either to VPA, a known autism risk factor in humans, or to saline, were housed from weaning into adulthood in a standard laboratory environment, an unpredictably enriched environment, or a predictably enriched environment. Animals were tested for sociability, nociception, stereotypy, fear conditioning and anxiety, and for tissue content of glutamate signaling proteins in the primary somatosensory cortex, hippocampus and amygdala, and of corticosterone in plasma, amygdala and hippocampus. Standard group analyses on separate measures were complemented with a composite emotionality score, using Cronbach's Alpha analysis, and with multivariate profiling of individual animals, using Hierarchical Cluster Analysis. We found that predictable environmental enrichment prevented the development of hyper-emotionality in the VPA-exposed group, while unpredictable enrichment did not. Individual variation in the severity of the autistic-like symptoms (fear, anxiety, social withdrawal and sensory abnormalities) correlated with neurochemical profiles, and predicted their responsiveness to predictability in the environment. In controls, the association between socio-affective behaviors, neurochemical profiles and environmental predictability was negligible. This study suggests that rearing in a predictable environment prevents the development of hyper-emotional features in animals exposed to an autism risk factor, and demonstrates that unpredictable environments can lead to negative outcomes, even in the presence of environmental enrichment.
    Frontiers in Neuroscience 06/2015; 9:127. DOI:10.3389/fnins.2015.00127 · 3.70 Impact Factor
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    ABSTRACT: Despite decades of extracellular action potential (EAP) recordings monitoring brain activity, the biophysical origin and inherent variability of these signals remains enigmatic. We performed whole-cell patch recordings of excitatory and inhibitory neurons in rat somatosensory cortex slice while positioning a silicon probe in their vicinity to concurrently record intra- and extracellular voltages for spike frequencies under 20 Hz. We characterize biophysical events and properties (intracellular spiking, extracellular resistivity, temporal jitter, etc.) related to EAP-recordings at the single-neuron level in a layer-specific manner. EAP-amplitude was found to decay as the inverse of distance between the soma and the recording electrode with similar (but not identical) resistivity across layers. Furthermore, we assessed a number of EAP-features and their variability with spike activity: amplitude (but not temporal) features varied substantially (approx. 30-50% compared to mean) and non-monotonically as a function of spike frequency and spike order. Such EAP-variation only partly reflects intracellular somatic spike variability and points to the plethora of processes contributing to the EAP. Also, we show that the shape of the EAP-waveform is qualitative similar to the negative of the temporal derivative to the intracellular somatic voltage - as expected from theory. Finally, we tested to what extent EAPs can impact the lowpass filtered part of extracellular recordings, the local field potential (LFP), typically associated with synaptic activity. We found that spiking of excitatory neurons can significantly impact the LFP at frequencies as low as 20 Hz. Our results question the common assertion that LFPs act as proxy for synaptic activity. Copyright © 2014, Journal of Neurophysiology.
    Journal of Neurophysiology 05/2015; 114(1):jn.00628.2014. DOI:10.1152/jn.00628.2014 · 3.04 Impact Factor
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    Richard Frackowiak · Henry Markram
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    ABSTRACT: Cerebral cartography can be understood in a limited, static, neuroanatomical sense. Temporal information from electrical recordings contributes information on regional interactions adding a functional dimension. Selective tagging and imaging of molecules adds biochemical contributions. Cartographic detail can also be correlated with normal or abnormal psychological or behavioural data. Modern cerebral cartography is assimilating all these elements. Cartographers continue to collect ever more precise data in the hope that general principles of organization will emerge. However, even detailed cartographic data cannot generate knowledge without a multi-scale framework making it possible to relate individual observations and discoveries. We propose that, in the next quarter century, advances in cartography will result in progressively more accurate drafts of a data-led, multi-scale model of human brain structure and function. These blueprints will result from analysis of large volumes of neuroscientific and clinical data, by a process of reconstruction, modelling and simulation. This strategy will capitalize on remarkable recent developments in informatics and computer science and on the existence of much existing, addressable data and prior, though fragmented, knowledge. The models will instantiate principles that govern how the brain is organized at different levels and how different spatio-temporal scales relate to each other in an organ-centred context.
    Philosophical Transactions of The Royal Society B Biological Sciences 05/2015; 370(1668). DOI:10.1098/rstb.2014.0171 · 6.31 Impact Factor
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    ABSTRACT: We present a physically-based computational model of the light sheet fluorescence microscope (LSFM). Based on Monte Carlo ray tracing and geometric optics, our method simulates the operational aspects and image formation process of the LSFM. An extension for previous fluorescence models is developed to account for the intrinsic characteristics of fluorescent dyes in order to accurately simulate light interaction with fluorescent-tagged biological specimen. This extension was quantitatively validated against the fluorescence brightness equation and experimental spectra of different dyes. We demonstrate first results of our rendering pipeline to a simplified brain tissue model reconstructed from the somatosensory cortex of a young rat.
    Eurographics 2015 - Posters, Zürich, Switzerland; 05/2015
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    ABSTRACT: The spatial arrangement of Ca2+ channels and vesicles remains unknown for most CNS synapses, despite of the crucial importance of this geometrical parameter for the Ca2+ control of transmitter release. At a large model synapse, the calyx of Held, transmitter release is controlled by several Ca2+ channels in a "domain overlap" mode, at least in young animals. To study the geometrical constraints of Ca2+ channel placement in domain overlap control of release, we used stochastic MCell modelling, at active zones for which the position of docked vesicles was derived from electron microscopy (EM). We found that random placement of Ca2+ channels was unable to produce high slope values between release and presynaptic Ca2+ entry, a hallmark of domain overlap, and yielded excessively large release probabilities. The simple assumption that Ca2+ channels can be located anywhere at active zones, except below a critical distance of ~ 30 nm away from docked vesicles ("exclusion zone"), rescued high slope values and low release probabilities. Alternatively, high slope values can also be obtained by placing all Ca2+ channels into a single supercluster, which however results in significantly higher heterogeneity of release probabilities. We also show experimentally that high slope values, and the sensitivity to the slow Ca2+ chelator EGTA-AM, are maintained with developmental maturation of the calyx synapse. Taken together, domain overlap control of release represents a highly organized active zone architecture in which Ca2+ channels must obey a certain distance to docked vesicles. Furthermore, domain overlap can be employed by near-mature, fast-releasing synapses.
    PLoS Computational Biology 05/2015; 11(5):e1004253. DOI:10.1371/journal.pcbi.1004253 · 4.83 Impact Factor
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    ABSTRACT: Extensive mapping of neuronal connections in the central nervous system requires high-throughput um-scale imaging of large volumes. In recent years, different approaches have been developed to overcome the limitations due to tissue light scattering. These methods are generally developed to improve the performance of a specific imaging modality, thus limiting comprehensive neuroanatomical exploration by multimodal optical techniques. Here, we introduce a versatile brain clearing agent (2,2'-thiodiethanol; TDE) suitable for various applications and imaging techniques. TDE is cost-efficient, water-soluble and low-viscous and, more importantly, it preserves fluorescence, is compatible with immunostaining and does not cause deformations at sub-cellular level. We demonstrate the effectiveness of this method in different applications: in fixed samples by imaging a whole mouse hippocampus with serial two-photon tomography; in combination with CLARITY by reconstructing an entire mouse brain with light sheet microscopy and in translational research by imaging immunostained human dysplastic brain tissue.
    Scientific Reports 04/2015; 5. DOI:10.1038/srep09808 · 5.58 Impact Factor
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    ABSTRACT: Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention.
    Scientific Reports 01/2015; 5:7919. DOI:10.1038/srep07919 · 5.58 Impact Factor
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    ABSTRACT: Active ingredients of spices (AIS) modulate neural response in the peripheral nervous system, mainly through interaction with TRP channel/receptors. The present study explores how different AIS modulate neural response in layer 5 pyramidal neurons of S1 neocortex. The AIS tested are agonists of TRPV1/3, TRPM8 or TRPA1. Our results demonstrate that capsaicin, eugenol, menthol, icilin and cinnamaldehyde, but not AITC dampen the generation of APs in a voltage- and time-dependent manner. This effect was further tested for the TRPM8 ligands in the presence of a TRPM8 blocker (BCTC) and on TRPM8 KO mice. The observable effect was still present. Finally, the influence of the selected AIS was tested on in vitro gabazine-induced seizures. Results coincide with the above observations: except for cinnamaldehyde, the same AIS were able to reduce the number, duration of the AP bursts and increase the concentration of gabazine needed to elicit them. In conclusion, our data suggests that some of these AIS can modulate glutamatergic neurons in the brain through a TRP-independent pathway, regardless of whether the neurons are stimulated intracellularly or by hyperactive microcircuitry.
    Scientific Reports 10/2014; 4:6825. DOI:10.1038/srep06825 · 5.58 Impact Factor
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    Javier DeFelipe · Eduardo Garrido · Henry Markram
    Trends in Neurosciences 10/2014; 37(10):525-527. DOI:10.1016/j.tins.2014.08.002 · 12.90 Impact Factor
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    ABSTRACT: Scientists in many disciplines use spatial mesh models to study physical phenomena. Simulating natural phenomena by changing meshes over time helps to better understand the phenomena. The higher the precision of the mesh models, the more insight do the scientists gain and they thus continuously increase the detail of the meshes and build them as detailed as their instruments and the simulation hardware allow. In the process, the data volume also increases, slowing down the execution of spatial range queries needed to monitor the simulation considerably. Indexing speeds up range query execution, but the overhead to maintain the indexes is considerable because almost the entire mesh changes unpredictably at every simulation step. Using a simple linear scan, on the other hand, requires accessing the entire mesh and the performance deteriorates as the size of the dataset grows. In this paper we propose OCTOPUS, a strategy for executing range queries on mesh datasets that change unpredictably during simulations. In OCTOPUS we use the key insight that the mesh surface along with the mesh connectivity is sufficient to retrieve accurate query results efficiently. With this novel query execution strategy, OCTOPUS minimizes index maintenance cost and reduces query execution time considerably. Our experiments show that OCTOPUS achieves a speedup between 7.3 and 9.2× compared to the state of the art and that it scales better with increasing mesh dataset size and detail.
    2014 IEEE 30th International Conference on Data Engineering (ICDE); 03/2014
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    V Delattre · D La Mendola · J Meystre · H Markram · K Markram
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    ABSTRACT: Neuroligins (Nlgns) are postsynaptic cell adhesion molecules that form transynaptic complexes with presynaptic neurexins and regulate synapse maturation and plasticity. We studied the impact of the loss of Nlgn4 on the excitatory and inhibitory circuits in somatosensory cortical slices of juvenile mice by electrically stimulating these circuits using a multi-electrode array and recording the synaptic input to single neurons using the patch-clamp technique. We detected a decreased network response to stimulation in both excitatory and inhibitory circuits of Nlgn4 knock-out animals as compared to wild-type controls, and a decreased excitation-inhibition ratio. These data indicate that Nlgn4 is involved in the regulation of excitatory and inhibitory circuits and contributes to a balanced circuit response to stimulation.
    Scientific Reports 10/2013; 3:2897. DOI:10.1038/srep02897 · 5.58 Impact Factor
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    ABSTRACT: Despite cash-strapped times for research, several ambitious collaborative neuroscience projects have attracted large amounts of funding and media attention. In Europe, the Human Brain Project aims to develop a large-scale computer simulation of the brain, whereas in the United States, the Brain Activity Map is working towards establishing a functional connectome of the entire brain, and the Allen Institute for Brain Science has embarked upon a 10-year project to understand the mouse visual cortex (the MindScope project). US President Barack Obama's announcement of the BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies Initiative) in April 2013 highlights the political commitment to neuroscience and is expected to further foster interdisciplinary collaborations, accelerate the development of new technologies and thus fuel much needed medical advances. In this Viewpoint article, five prominent neuroscientists explain the aims of the projects and how they are addressing some of the questions (and criticisms) that have arisen.
    Nature Reviews Neuroscience 08/2013; 14(9):659-64. DOI:10.1038/nrn3578 · 31.38 Impact Factor
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    ABSTRACT: Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.
    Frontiers in Behavioral Neuroscience 07/2013; 7:88. DOI:10.3389/fnbeh.2013.00088 · 4.16 Impact Factor
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    ABSTRACT: Brain activity generates extracellular voltage fluctuations recorded as local field potentials (LFPs). It is known that the relevant microvariables, the ionic currents across membranes, jointly generate the macrovariables, the extracellular voltage, but neither the detailed biophysical knowledge nor the required computational power have been available to model these processes. We simulated the LFP in a model of the rodent neocortical column composed of >12,000 reconstructed, multicompartmental, and spiking cortical layer 4 and 5 pyramidal neurons and basket cells, including five million dendritic and somatic compartments with voltage- and ion-dependent currents, realistic connectivity, and probabilistic AMPA, NMDA, and GABA synapses. We found that, depending on a number of factors, the LFP reflects local and cross-layer processing. Active currents dominate the generation of LFPs, not synaptic ones. Spike-related currents impact the LFP not only at higher frequencies but below 50 Hz. This work calls for re-evaluating the genesis of LFPs.
    Neuron 07/2013; 79(2):375-90. DOI:10.1016/j.neuron.2013.05.023 · 15.98 Impact Factor
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    ABSTRACT: [This corrects the article on p. e1002133 in vol. 7.].
    PLoS Computational Biology 06/2013; 9(6). DOI:10.1371/annotation/c002fbe1-712c-4608-9747-f1185f0b7cf4 · 4.83 Impact Factor
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    ABSTRACT: Modifications of synaptic efficacies are considered essential for learning and memory. However, it is not known how the underlying functional components of synaptic transmission change over long time scales. To address this question, we studied cortical synapses from young Wistar rats before and after 12 h intervals of spontaneous or glutamate-induced spiking activity. We found that, under these conditions, synaptic efficacies can increase or decrease by up to 10-fold. Statistical analyses reveal that these changes reflect modifications in the number of presynaptic release sites, together with postsynaptic changes that maintain the quantal size per release site. The quantitative relation between the presynaptic and postsynaptic transmission components was not affected when synaptic plasticity was enhanced or reduced using a broad range of pharmacological agents. These findings suggest that ongoing synaptic plasticity results in matched presynaptic and postsynaptic modifications, in which elementary modules that span the synaptic cleft are added or removed as a function of experience.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2013; 33(15):6257-66. DOI:10.1523/JNEUROSCI.3740-12.2013 · 6.75 Impact Factor

Publication Stats

16k Citations
1,006.76 Total Impact Points

Institutions

  • 2002–2015
    • École Polytechnique Fédérale de Lausanne
      • • Institute of Brain Mind
      • • Neural Microcircuitry Laboratory
      • • Blue Brain Project (BBP)
      Lausanne, Vaud, Switzerland
    • Graz University of Technology
      • Institute for Theoretical Computer Science
      Graz, Styria, Austria
  • 2002–2012
    • Hebrew University of Jerusalem
      • Department of Neurobiology
      Yerushalayim, Jerusalem District, Israel
  • 2011
    • California Institute of Technology
      • Division of Biology
      Pasadena, CA, United States
  • 2009
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 2004
    • Universität Bremen
      Bremen, Bremen, Germany
  • 1989–2003
    • Weizmann Institute of Science
      • Department of Neurobiology
      Tel Aviv, Tel Aviv, Israel
  • 1997
    • Brown University
      Providence, Rhode Island, United States
  • 1996
    • Max Planck Institute for Medical Research
      • Department of Molecular Neurobiology
      Heidelburg, Baden-Württemberg, Germany