NEUROSCIENCENEUROSCIENCE ATAT EPFLEPFL // BMIBMI

BRAIN MIND INSTITUTE BLUE BRAIN PROJECT The BMI aims to explore brain function at multiple levels: genomics, gene The Blue Brain Project began in July 2005 as a collaboration Director: Pierre J. Magistretti Director: Henry Markram expression, protein expression and handling, biochemical and metabolic between Professor Henry Markram from the Brain Mind Institute dynamics, signaling pathways, molecular biophysics of ion channels and at the Ecole Polytechnique Fédérale de Lausanne (EPFL) and receptors, synaptic transmission, plasticity and integration, neuronal and International Business Machines (IBM), aimed at modeling the glial composition of the brain and the micro-circuits that they form, whole neocortical column. The neocortical column represents the basic brain structural and functional circuitry, structure and functional dynamics of functional unit of the cerebral cortex in mammals that underlies sensory and motor systems, emergence of complex behavior, physical nearly all sensory and cognitive processing. These units are limits of perception, and the emergence of higher brain functions in repeated millions of times across the cortex, with the basic humans. The aim is also to study the dysfunctions of the brain focusing on structure remaining the same from the mouse to man. From its autism, schizophrenia and neurodegenerative disorders. In addition, an origins – IBM’s BlueGene/L supercomputer and 10 years of important dimension for the BMI is to merge areas of experimental work experimental data from Professor Markram’s laboratory and – with theory and modeling. The BMI has established links with Universities the project has grown to include an international multidisciplinary and Hospitals in the Lemanic area, particularly with psychiatry and team of experimentalists, modelers and computer scientists. . Internationally the BMI aspires to network with laboratories across the USA, Europe and Japan. The BMI is also engaged in research alliances with local and international industries.

1313 FACULTYFACULTY MEMBERSMEMBERS ANDAND THEIRTHEIR RESEARCHRESEARCH LABORATORIESLABORATORIES

Laboratory of Neurodegenerative Diseases (LEN) Laboratory of Psychophysics (LPSY) Laboratory of Neural Microcircuitry (LNMC) Head of lab : Patrick Aebischer Head of lab : Michael Herzog Head of lab : Henry Markram

Description of research activities Description of research activities Description of research activities The main focus of our laboratory is to develop gene therapy approaches for Main topics of our research are: feature integration, contextual modulation, The laboratory adopts a multidisciplinary approach to the structure and the treatment of neurodegenerative diseases such as Parkinson’s disease, time course of information processing, and perceptual learning. In clinical function of the neocortex that is made of a repeating stereotypical microcircuit Alzheimer’s disease and amyotrophic lateral sclerosis. Our laboratory is also studies, deficits of visual information processing are investigated in of neurons. The goal of the laboratory has been to derive the blue print for this implicated in the development of new animal models based on virus-mediated schizophrenic patients. microcircuit. To study the different types of single neurons we employ whole- overexpression or silencing of genes involved in neurodegenerative diseases. cell patch clamp studies in neocortical slices to obtain the electrophysiological For both gene therapy and development of models viral vectors such as Methods profile of neurons to aspirate cytoplasm for single cell multiplex RT-PCR lentivirus and adeno-associated virus are produced and used in our Psychophysics, TMS EEG, Eye Tracking, and Mathematical Modeling. studies and to load the neurons with dyes to allow subsequent 3D anatomical laboratory. For therapeutic purposes the technique of genetically engineered computer reconstruction of each neuron. This approach enables us to derive encapsulated cells allowing the localized secretion of various proteins as well the electrophysiological behaviour, the anatomical structure, as well as the as drug-testing are also widely implemented. The functional effects are genetic basis of the anatomy and physiology of each type of cell. The characterized through the use of a wide variety of techniques including laboratory has also developed a multidisciplinary approach to studying behavioural assessment, in vivo imaging techniques, morphological analysis diseases such as Autism. We have developed an insult-based animal model and biochemical measurements. Laboratory of Molecular Neurobiology & Functional Neuroproteomics of Autism (the Valproic acid animal model) and study the gene expression (LMNN) changes, protein expression, synaptic malfunctioning, circuit malfunctioning, Methods Head of lab : Hilal A. Lashuel whole brain malfunctioning and behavioural alterations. Molecular and cellular biology, viral vector design and production, macroencapsulation technique, immunohistology on cells and tissue sections, Description of research activities Methods stereotaxic brain and spinal cord injections, behavioural assessment of both Research efforts in our laboratory focus on understanding the role of protein DNA microarrays and qPCR, Western Blotting, immunohistochemical staining, mice and rats,imaging techniques, statistical analyses aggregation, more specifically amyloid fibril formation in the pathogenesis of single neuron patch-clamp, multi-neuron recording, multi-electrical array neurodegenerative diseases including Alzheimer's disease Parkinson's disease stimulation, multi-unit recording in vivo, test battery for behavioural profiling of and Huntington disease. In particular we are working on defining the rats and mice. biochemical mechanism of amyloid fibril formation of two amyloidogenic proteins α-synuclein and amyloid-beta (Aβ) and how they contribute to each of About the Blue Brain Project Laboratory of Cognitive (LNCO) their respective diseases, Parkinson's and Alzheimer's diseases. Using By the end of 2007 a simulation-based research process has been developed Head of lab : Olaf Blanke multifaceted approaches that employ tools from chemistry biophysics structural to generate a cellular-level model of a 2-week-old rat somatosensory biology and molecular and cell biology our group is working to elucidate the neocortex based on extensive experimental data. The 10,000 Description of research activities structural basis of amyloid toxicity in neurodegenerative diseases. A detailed threedimensional model neurons were placed in the neocortical volume (550 We focus our investigations on the functional and neural mechanisms of body understanding of the mechanism of amyloid fibril formation and its relation to μm in diameter by 1,200 μm high) and arranged in 6 layers according to their perception corporeal awareness and self . Projects rely on the disease pathology should contribute to our understanding of the mechanism of morphological and electrical properties. The cells have model ion channels, investigation of healthy subjects as well as neurological patients (who suffer pathogenesis and the identification of therapeutic targets for treating and/or determined by gene expression data, distributed along their membrane from selective neurocognitive deficits and illusions) by combining preventing these devastating diseases. surfaces to reproduce the experimentally observed diversity of electrical firing psychophysical and cognitive paradigms with state of the art properties seen in cortical pyramidal cells and interneurons. Potential synaptic techniques such as intracranial EEG surface EEG fMRI and . Methods locations between cells are identified through a touch detection process that Our interdisciplinary expertise - bridging cognitive neurology experimental chemistry, biophysics, structural biology, proteomics, molecular and cell biology. searches for axons and dendrites in proximity to each other. Functional epileptology intracranial electrophysiology experimental psychology and synapses are placed according to experimental observations of the probability neuroimaging - has recently been extended to engineering-based approaches of synaptic interactions between different cell types. The entire circuit, once to cognition building a virtual reality (VR) neuroimaging platform with a constructed, is run through a barrage of tests to calibrate the network circuitry portable 256 channel EEG system (VR-EEG). This VR-EEG platform allows according to experimental data. This includes systematic checks of the ion us to carry out cognitive experiments in highly realistic ecologically valid channels, electrical behavior of neurons, composition of the column, patterns environments that close the perception-action loop while the participants’ Laboratory of Functional Neurogenomics (LNGF) of connectivity and behavior of monosynaptic and polysynaptic pathways. The brain activity (and soon also of brain damaged neurological patients) is Head of lab : Ruth Luthi-Carter model network is then run through a series of test protocols evaluating its continually monitored. Next to studying the neural mechanisms of bodily self capacity for replicating network level phenomena. consciousness experimentally we expect this novel technological amalgam to Description of research activities also become a key research technique in the larger field of the cognitive A primary focus of our group is to understand the molecular bases for the loss as well as the adjacent fields of virtual reality and presence of neuronal function in neurodegenerative diseases. Our studies are centered Laboratory of Sensory Processing (LSENS) research. around disease-related perturbations of neurotransmitter signaling and Head of lab : Carl Petersen transcription. One major emphasis of our current studies is the pathogenesis Methods of Huntington's disease and other polyglutamine disorders. These diseases Experimental psychology, virtual reality, multichannel surface EEG, Description of research activities result from dominantly inherited trinucleotide expansion mutations. Despite We investigate synaptic mechanisms of sensory perception and associative intracranial EEG, electrical cortical stimulation, fMRI, neuropsychology, lesion the known origin of these disorders the disease course is currently intractable. mapping (brain damage). learning. Experiments in mice investigate cortical processing of sensory input, Thus, a more detailed understanding of the disease process is urgently focusing on the signalling pathway from the mystacial whiskers to the warranted. In parallel with our efforts to better understand and treat somatosensory barrel cortex. The goal is to understand coding, development neurodegenerative illnesses, we consider what the perturbations observed in and plasticity of perceptions at the level of individual neurons and their disease can reveal about the brain’s normal function. We are currently synaptic interactions within a well-defined signalling pathway. examining the contributions of particular individual and functionally related sets of molecules to neurotransmitter signaling and neuronal survival. Laboratory of Molecular & Cellular Niology of Alzheimer’s Disease Methods We have developed and applied methods for studying brain function in awake (UPFRA) Methods Head of lab : Patrick Fraering behaving mice: Whole-cell recordings; Voltage-sensitive dye imaging; Methologically we have special expertise in gene expression profiling Calcium-sensitive dye imaging; Two photon microscopy; Behavioural training; techniques including microarray analysis laser-capture microdissection and Lentiviral manipulations; Anatomical reconstructions Description of research activities small scale real-time QPCR techniques. We also produce neural cell subtype Due to the increasing mean life expectancy there is considerable interest in cultures (neurons astrocytes oligodendrocytes and microglia) and have the understanding of the molecular and biochemical mechanisms of age facilities and expertise to produce and utilize lentiviral gene transfer vectors. related diseases. By far the most frequent age related neurological disorder is Additional competencies include promoter analysis methodologies and a good Alzheimer’s disease (AD). Toward advancing the biochemistry of γ-secretase working knowledge of animal models of Huntington’s and other polyglutamine Laboratory of Behavioral Genetics (LGC) (which is directly implicated in the production of the amyloidogenic A peptides) diseases. with attendant therapeutic implications, our goals are to understand the Head of lab : Carmen Sandi structure, function and mechanism of the protease complex and how disease- causing presenilin mutations alter its activity, thus leading to Description of research activities and Alzheimer’s disease. Such understanding may The lab focuses on the interactions between stress and cognitive function, with a focus on learning and memory processes and on psychiatric disorders. ultimately suggest therapeutic strategies for skewing the specificity of the γ- secretase complex in the opposite direction, away from production of the Projects in the lab can be classified in three main research lines: (i) Laboratory of Neuroenergetics and Cellular Dynamics (LNDC) understanding the contribution of stress to cognitive function; (ii) elucidating deleterious Aβ42. Head of lab : Pierre J. Magistretti the mechanisms involved in the negative impact of chronic stress on brain function and cognition; and (iii) searching for novel cognitive enhancers. Methods Description of research activities We are focusing on understanding the molecular mechanisms that lead to In our research projects we study the role of synaptic proteins in the Our laboratory has two main lines of research: the principal one is to try to facilitating effects of stress in learning, perform gene expression studies to Alzheimer’s disease with the aim of identifying new therapeutic targets to understand the cellular and molecular mechanisms of neurometabolic safely treat the disease by using both genomic and proteomic approaches. investigate the impact of stress on the establishment of social memories and coupling, namely the processes by which appropriate energy substrates are are interested in the role of NCAM in memory formation. delivered to neurons where and when they are active. Our studies ongoing now for two decades have identified the interactions between neurons and Methods glial cells (astrocytes) as the basis of neurometabolic coupling. We are also Batteries of behavioral tasks for rodents (rats and mice); microsurgery and interested in understanding the bases of neurometabolic coupling in other psychopharmacology; laser capture microdissection; protein biochemistry Laboratory of Computational Neuroscience (LCN) aspects of brain function and dysfunction, such as learning and memory, the assays; immunohistochemistry; RT-PCR; in situ hybridization; 2-DGlucose Head of lab : Wulfram Gerstner sleep-wake cycle, as well as neurodegeneration. We are currently studying uptake imaging. transcriptionally-regulated adaptations in the level of expression of certain Description of research activities genes of brain energy metabolism in relation to neuronal plasticity as The activities in our laboratory focus on questions centered around temporal observed during learning, the sleep-wake cycle and certain pathological aspects of information processing in the brain: Models of spiking neurons, conditions such as neuroinflammation and neurodegeneration. spike-timing dependent learning rules, spatial representation and models of The second line of research is represented by a neurophotonics project, Laboratory of Synaptic Mechanisms (LSYM) the hippocampus. which is implemented through a joint effort with the Advanced Photonics Head of lab : Ralf Schneggenburger Laboratory at the STI Faculty, to develop a new type of microscope using Methods different optical modalities. Description of research activities Reduction of complex biological phenomena to simple models, mathematical Our main interest lies in understanding the cellular and molecular analysis of the models, simulation of model for simple and more complex Methods mechanisms that regulate Ca2+ signalling and Ca2+ dependent vesicle fusion paradigms. Primary cultures of neurons and astrocytes; a large spectrum of in the nerve terminal, and the factors that regulate the probability of neurochemical assays; modulation of gene expression in vitro and in vivo by transmitter release. We use a mammalian CNS synapse with a giant siRNAs and viral vectors; in situ hybridization; immunohistochemistry; ex vivo presynaptic terminal, the calyx of Held, as a model for CNS glutamatergic 2DG autoradiography; laser capture microdissection; DNA microarrays; qRT- synapses. The unusually large size of the calyx of Held allows us to make PCR; intracellular and patch-clamp recordings in primary cultures; direct whole-cell patch-clamp recordings from this nerve terminal, a technique fluorescence microscopy; digital holographic microscopy; behavioural testing that we have combined with presynaptic Ca2+ imaging and Ca2+ uncaging. In Laboratory of Social (GRHAD) (spatial memory); EEG recordings of sleep-wake cycle; microsurgery and icv another line of research, we study mechanisms that guarantee the Head of lab : Nouchine Hadjikhani administration of pharmacological agents. maintenance of nerve terminal function. It is likely that nerve terminals contain a specific protein re-folding apparatus, like heat-shock cognate proteins that Description of research activities are directed to the nerve terminal via cystein-string-protein (CSP), to The theme of our research is the neuroanatomical bases of emotional, social guarantee the continuous functioning of SNAREs and other presynaptic and cognitive difficulties in autism. We are in particular interested in trying to proteins during repeated rounds of exo- and endocytosis. find biomarkers of autism and in exploring whether cognitive behavioral training may induce brain plasticity together with improvement in Methods symptomatology. Brain slice preparation, patch-clamp electrophysiology, Ca2+ imaging, Ca2+ uncaging, kinetic modelling, in-vivo virus-mediated gene overexpression, Methods gene expression analysis (single-cell qPCR), shRNA-mediated gene Functional and anatomical brain imaging including diffusion tensor imaging. silencing, immunocytochemistry, tracer labelling. Neuropsychological testing.