Annual Report BMI 2015-16 by EPFL School of Life Sciences

BMI

Brain Mind Institute The mission of the Brain Mind Institute (BMI) is to understand the fundamental principles of brain function in health and disease, by using and developing unique experimental, theoretical, technological and computational approaches. The scientific challenge addressed by the BMI consists of connecting different levels of analysis of brain activity, such that cognitive functions can be understood as a manifestation of specific brain processes; specific brain processes as emerging from the collective activity of thousands of cells and synapses; synaptic and neuronal activity in turn as emerging properties of the biophysical and molecular mechanisms of cellular compartments. Research at the BMI focuses on four main areas: • Mechanisms of brain function and dysfunction, with a particular focus on neurodegeneration and stress-related psychopathologies. • Molecular and cellular mechanisms of synapse and microcircuit function up to the behavioral level and including metabolic aspects. • Sensory and body perception and cognition in humans. • Designing innovative interventions to restore sensorimotor functions after neural disorders.

Sandi Carmen - Director

In all areas, the BMI strives to integrate knowledge gained by multidisciplinary approaches and across different disciplines and research laboratories. An important second mission of the BMI is to bridge scientific approaches and questions with research carried out in the EPFL campus, as well as in related institutions and companies in the area, specifically with the fields of nano- and micro-technology, computer sciences, physics, neuroprosthetics, robotics, signal and medical imaging processing, genetics, metabolism, neuroeconomics, psychiatry and neurology. Major goals of the BMI are to bridge basic science approaches with clinical applications and to merge areas of experimental work with theory and modeling. Finally, the BMI is fully engaged in the teaching mission of the School of Life Sciences at the Bachelor and Master levels –with a full Neuroscience track at the Master level– and organizes the PhD program in Neurosciences. http://sv.epfl.ch/BMI

Aebischer Lab Patrick Aebischer - Full Professor - President of EPFL

Patrick Aebischer was trained as an MD (1980, Geneva University) and a Neuroscientist (1983, Fribourg University) in Switzerland. As Faculty member at Brown University (USA), he became Chairman of the Artificial Organs, Biomaterials and Cellular Technology program in 1991. He returned to Switzerland in 1992, as Professor and Director of the Surgical Research Division and Gene Therapy Center at CHUV. President of EPFL from 2000 until 2016, he is also the founder of three biotech companies.

len.epfl.ch

Introduction

Results Obtained

Although our understanding of the molecular mechanisms leading to neurodegenerative diseases has dramatically improved, very few treatments have shown disease-modifying effects. Several factors may explain this lack of efficacy. The brain is a poorly accessible organ, which limits the access to therapeutic drugs, and the pathogenic processes that affect neurons and other cell types in the CNS are notoriously complex. Treating neurodegeneration requires therapeutic approaches carefully adapted to various factors, including the molecular causes of the disease, the type of cells affected and the stage of the disease. In this context, our group explores the possibilities to devise novel treatments using viral vectors for gene therapy, as well as innovative systems for protein delivery to the CNS.

We have further developed an innovative gene therapy using RNA interference (RNAi) for the treatment of ALS caused by SOD1 mutations (Dirren et al, 2015). We have designed an AAV vector able to downregulate SOD1 in both motoneurons and astrocytes in the spinal cord. This vector has synergistic therapeutic effects that dramatically improve the motor function of treated mice. By analyzing the therapeutic effects of silencing mutated SOD1 in astrocytes, we found an effect on the ability of surviving motoneurons to reinnervate the neuromuscular junctions left unoccupied by degenerating neurons (see Figure). We are currently exploring the molecular cause of the aberrant crosstalk between neuron and glial cells in ALS.

We mainly use AAV vectors for the delivery of genes, artificial miRNAs and the CRISPR-Cas9 gene editing technology. In particular, we are developing gene therapy for motoneuron disorders, including amyotrophic lateral sclerosis (ALS). Our lab also exploits AAV-based techniques for modeling CNS diseases. We use this approach to explore the pathogenic effects of proteins such as α-synuclein and tau, which are centrally implicated in Parkinson’s and Alzheimer’s diseases. These models of neurodegeneration are used to identify pathogenic processes and test neuroprotective treatments.

Keywords Neurodegenerative diseases, gene therapy, animal models, Parkinson’s disease, Amyotrophic lateral sclerosis, Alzheimer’s disease, viral vectors, AAV, cell encapsulation, passive immunization.

Our lab has developed a mouse model of tauopathies based on the local injection of AAV vectors to overexpress human tau. This model is used to determine why tau can be toxic to neuronal cells, with a focus on the propensity of the tau protein to misfold. Conformational changes of the tau protein control binding to microtubules and subsequent pathological effects. The same approach is used to locally express the tau protein and quantify propagation along neuronal networks. In parallel, we are developing cellular implants continuously secreting recombinant antibodies for passive immunization against Alzheimer’s disease (Lathuiliere et al, 2016). In collaboration with the Holt lab at Harvard Medical School, we have finalized a proof-of-concept study to restore the function of the TMC protein using AAV vectors in a mouse model of inherited deafness (Askew et al, Science Translational Medicine 2015). This project is currently being pursued with the aim to inactivate the dominant effect of the Beethoven TMC1 mutation using the CRISPR-Cas9 gene editing technology.

BMI - Brain Mind Institute

Team Members Research and Teaching Associate

Bernard Schneider

Postdoctoral Fellows

Julianne Bobela-Aebischer Nathalie Bernard-Marissal Paola Solanes Pamela Valdès PhD Students

Wojciech Bobela Vanessa Laversenne Sameer Nazeeruddin Cylia Rochat Lu Zheng Lab Technicians

Aline Aebi Philippe Colin Fabienne Pidoux Vivianne Padrun Christel Sadeghi Visiting Students Gene therapy for mutated D -mediated delivery of artificial microR s for D silencing in astrocytes promotes the re-innervation of neuromuscular junctions following neurodegeneration. (a) ransduction of astrocytes in the mouse spinal cord. (b) Gene therapy prevents muscle atrophy.

Daniel Blessing (CHUV) Administrative Assistants

Marie Künzle

Selected Publications » Ryu, D., Mouchiroud, L., Andreux, P.A., Katsyuba, E., Moullan, N., Nicolet-Dit-Félix, A.A., Williams, E.G., Jha, P., Lo Sasso, G., Huzard, D., Aebischer, P., Sandi, C., Rinsch, C. and Auwerx J. (2016) Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 22(8): 879-888. » Lathuilière, A., Laversenne, V., Astolfo, A., Kopetzki, E., Jacobsen, H., Stampanoni, M., Bohrmann, B., Schneider, B.L. and Aebischer, P. (2016) A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies. Brain 139 :1587-1604. » Dirren, E., Aebischer, J., Rochat, C., Towne, C., Schneider, B.L., Aebischer, P. (2015) Silencing of SOD1 expression in motoneurons and/or astrocytes rescues neuromuscular function of G93ASOD1 mice. Ann Clin

Transl Neurol 2(2):1671-84. » Filézac de l’Etang, A., Maharjan, N., Cordeiro Braña, M., Ruegsegger, C., Roos, A., Schneider, B.L., Weis, J., Saxena, S. (2015) Marinesco-Sjögren syndrome protein SIL1 regulates motoneuron subtype-selective ER

stress in ALS. Nat Neurosci 8(2): 227-238. » Ciron, C., Knott, G., Kelly, D., Aebischer, P., and Schneider, B.L. (2015). PGC-1α activity in nigral dopaminergic neurons controls vulnerability to α-synuclein. Acta Neuropathol Comm 3:16. » Askew, C., Rochat, C., Pan, B., Asai, Y., Ahmed, H., Child, E., Schneider, B.L., Aebischer, P., and Holt J.R. (2015). Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med 7(295): 295ra108. » Chen, J.L., Margolis, D.J., Stankov, A., Sumanovski, L.T., Schneider, B.L. and Helmchen, F. (2015) Pathway-specific reorganization of projection neurons in somatosensory cortex during learning. Nat Neurosci 18(8): 1101-1108.

Blanke Lab Olaf Blanke - Full Professor - Director of the Center for Neuroprosthetics

Olaf Blanke is founding director of the Center for Neuroprosthetics and holds the Bertarelli Foundation Chair in Cognitive Neuroprosthetics at the Ecole Polytechnique Fédérale de Lausanne (EPFL). He directs the Laboratory of Cognitive Neuroscience at EPFL and is Professor of Neurology at the University Hospital of Geneva. Blanke’s neuroscience research is dedicated to the study of consciousness and how bodily processing encodes the self. This work includes pioneering technology research in virtual reality, augmented reality, and robotics that is dedicated to control and enable complex subjective experiences (i.e. experience engineering). In his medical projects in neurorehabilitation and neuroprosthetics Blanke develops devices and procedures for diagnostics and therapeutics with a focus in robotic psychiatry and cogniceuticals.

lnco.epfl.ch

Introduction

Results Obtained

The Blanke Lab (Bertarelli Chair in Cognitive Neuroprosthetics) has two missions – the neuroscientific study of consciousness and the development of cognitive neuroprostheses. In neuroscience we investigate the brain mechanisms of body perception, body awareness and how they form consciousness, combining psychophysical and cognitive paradigms, neuroimaging techniques (high resolution fMRI, intracranial and surface EEG, TMS). We have pioneered the use of engineering techniques such as robotics, haptics, and digital technologies (virtual and augmented reality) and their full integration with behavioral and neuroscience technologies (including MRI-compatible robotics), leading to the new research field of cognetics: the field of robotics and digital technologies dedicated to neuroscience research in cognition and consciousness studies.

This year saw the continuation of our efforts to understand the interplay between interoceptive and exteroceptive signals in shaping consciousness of self and environment. In two converging lines of research we showed that the subjective experience of our visual world is modulated by interoceptive signals of cardiac (Salomon et al., Journal of Neuroscience, 2016) and proprioceptive origins (Faivre et al., Journal of Neuroscience, 2017). In the same vein, we showed that the processing of cardiac signals is altered under states of illusory self-consciousness (Park et al., Journal of Neuroscience, 2016). These three studies indicate that bodily signals (including interoceptive signals) are a key determinant for perceptual and self-consciousness (Blanke et al., Neuron 2015). Another line of work documented how the integration of signals from vision, touch, and balance shape self-consciousness and in particular our first-person perspective (Pfeiffer et al., Neuroscience of Consciousness 2016), peripersonal space, and self-identification (Salomon et al., Cognition, under review). Translating these insights into cogniceutical technologies (Rognini and Blanke, Trends in Cognitive Sciences 2016) we developed novel immersive digital therapies and successfully treated patients suffering chronic regional pain syndrome (Solcà et al., submitted), neuropathic leg pain (Pozeg et al., in revision) and phantom limb syndrome (Rognini et al., submitted) and also investigated the neural underpinnings of painful body regions (Akselrod et al., in revision; Serino et al., in revision; Givraz et al., Neuroimage 2017).

In our clinical research projects we translate our cognetic insights to the development of new diagnostic and therapeutic approaches along two main lines of exploration: robotic psychiatry and cogniceuticals. In robotic psychiatry we are designing robotic devices, including wearable robotic solutions, to develop novel diagnostic and therapeutic solutions for two major neuropsychiatric diseases (schizophrenia and Parkinson’s disease), centering on hallucinations and psychosis. In cogniceuticals we develop novel immersive digital devices and therapies for chronic pain by integrating digital technologies (i.e. virtual reality) with brain stimulation and latest research from the cognitive neurosciences. Our devices induce technology-mediated pain relief in patients suffering from complex regional pain syndrome, phantom limb pain, and neuropathic leg pain in spinal cord injury.

Keywords Multisensory, sensorimotor, cognitive neuroscience, self, robotics, haptics, virtual-augmented reality, neurology, psychiatry.

Major efforts in 2016 have been devoted to the development of the emergent field of robotic psychiatry by (1) developing and testing our new robotic and haptic devices, by (2) applied neuroscience research, and by (3) investigating the diagnostic potential of our robotic devices in patients suffering from hallucinations and psychosis caused by schizophrenia and Parkinson’s disease. In 2016, we achieved full robotic integration for high-density EEG recordings (Bernasconi et al., in preparation) using a previously designed robotic device (Blanke et al., Current Biology 2014) and developed and tested a new MRI compatible robot for fMRI studies (Hara et al., Journal of Neuroscience Methods 2014; Blondiaux et al., in preparation) at our newly installed MR scanner at Campus Biotech Geneva.

BMI - Brain Mind Institute

Team Members

We have extended our clinical robotic psychiatry network to include hospitals in Geneva, Lausanne, and Sion and made major progress in the development of establishing diagnostic procedures and devices. Several major studies using these devices have been completed in 2016 and accomplished the robotically controlled induction of mild psychotic symptoms in healthy controls (Blondiaux et al., in preparation; Faivre et al., in preparation), informing the development of robotic-based diagnostic criteria in schizophrenia and Parkinson’s disease (Serino et al., in preparation; Salomon at al., in preparation).

Postdoctoral Fellows Fosco Bernasconi Elisa Canzoneri Nathan Faivre Michael Hill Hyeongdong Park Isabella Pasqualini Giulio Rognini Roberta Ronchi Roy Salomon Andrea Serino Jevita Potheegadoo Marianne Stephan Bassolino Michela Simon Gallo

Robot-controlled induction of an apparition. Participants performed stroking hand movements via a master robot in the front, while receiving an altered sensory feedback via a slave robot on their back. By manipulating through the robotic system the spatio-temporal congruency between movements and sensory feedback, we were able to systematically induce in the participants an illusory feeling of another person standing behind them, i.e., feeling of a presence. he sensory motor con ict and the induced experience activates a network of brain areas, including the sensorymotor cortices, the temporal parietal junction and the insular cortex, as shown by converging data from highdensity G (shown in the picture), f R and lesion analysis.

Selected Publications » Faivre , N., Doenz, J., Scandola, M., Dhanis, H., Bello Ruiz, J., Bernasconi, F., Salomon, R. and Blanke, O. (2017) Self-grounded vision: hand ownership modulates visual location through cortical beta and gamma oscillations. The Journal of Neuroscience 37: 11-22. » Grivaz, P., Blanke, O. and Serino, A. (2017) Common and distinct brain regions processing multisensory bodily signals for peripersonal space and body ownership. NeuroImage 147: 602-618. » Park, H.D., Bernasconi, F., Bello Ruiz, J., Pfeiffer, C., Salomon, R. and Blanke, O. (2016) Transient modulations of neural responses to heartbeats covary with bodily self-consciousness. The Journal of Neuroscience 36: 8453-8460. » Salomon, R., Ronchi, R., Doenz, J., Bello Ruiz, J., Herbelin, B., Martet, R., Schaller, K. and Blanke, O. (2016) The insula mediates access to awareness of visual stimuli presented synchronously to the heartbeat. The

Journal of Neuroscience 36: 5115-5127. » Rognini, G. and Blanke, O. (2016) Cognetics: Robotic interfaces for the conscious mind. Trends in Cognitive Science 20:162-164. » Canzoneri, E., Di Pellegrino, G., Herbelin, B., Blanke, O. and Serino, A. (2016) Conceptual processing is referenced to the experienced location of the self, not to the location of the physical body. Cognition 154: 182192. » Pfeiffer, C., Grivaz, P., Herbelin, B., Serino, A. and, Blanke, O. (2016) Visual gravity contributes to subjective first-person perspective, Neuroscience of Consciousness 1-12.

PhD Students Michel Akselrod Eva Blondiaux Lucie Brechet Petr Grivaz Silvia Marchesotti Polona Pozeg Marco Solcà Quentin Theillaud Matteo Franza Hyukjun Moon Myeong Song Giedre Stripeikyte Pavo Orepic Chang Wenwen Master’s Students Herberto Camacho Giuliana Sorrentino Matteo Vissani Mattia Pinardi Anush Swaminathan Christina Shea Kai Yue Wang Julia Brügger-Baumann Caroline Peters Technical staff Javier Bello Ruiz Robin Mange Medical Doctor Pierre Progin Marco Solcà Administrative Assistant Sonia Neffati-laifi

Courtine Lab Grégoire Courtine - Associate Professor - IRP Chair in Spinal Cord Repair

Grégoire Courtine was trained in Mathematics, Physics and Neurosciences. He obtained his PhD from the INSERM Motricity and Plasticity in France. After his postdoctoral training at UCLA, he established his own laboratory at Zurich (UZH) in 2008, before becoming Associate Professor at the EPFL in 2012. He founded a startup in 2015.

Introduction

Results Obtained

The World Health Organization (WHO) estimates that as many as 500’000 people suffer from a spinal cord injury each year, with dramatic consequences for the quality of life of affected individuals. Over the past 15 years, Prof Courtine and his team have developed a multifaceted intervention that reestablished voluntary control of paralyzed legs in rodent and primate models of spinal cord injury. This intervention acts over two time windows. Immediately, electrical and chemical stimulations of the lumbar spinal cord reawaken the neuronal networks below the injury that coordinate leg movements. In the long term, will-powered training regimens enabled by the electrochemical stimulation and robotic assistance promote neuroplasticity of residual connections. The goal of the laboratory is to refine this intervention with next-generation neurotechnologies, understand the underlying mechanisms, and translate these approaches into medical devices and therapeutic practices for accelerating and improving functional recovery after spinal cord injury in humans. To this aim, we are combining preclinical and clinical studies in mice, rats, non-human primates and human patients. We are also collaborating with our start-up to develop the neurotechnologies necessary to apply these concepts in paraplegic people.

Neuromodulation therapies (Neuron 2016; Nature Medicine 2016): We have identified the mechanisms underlying the facilitation of locomotion with electrical spinal cord stimulation. This conceptual framework guided the development of hardware and software to improve our neuromodulation therapies. We collaborated with Prof. Micera to develop a control platform through which neuromodulation parameters can be adjusted in real-time, based on movement feedback. Using this hardware and software, we designed control algorithms that achieve precise adjustment of leg movements in paralyzed rats.

Keywords Spinal cord injury, neurorehabilitation, neuroprosthetics, neural interface, locomotion.

courtine-lab.epfl.ch

Brain-spine interface to restore motor function (Nature, 2016): We have designed and implemented wireless control systems in monkeys that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the animals to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we tested the brain-spine interface after an experimental spinal cord injury. The brain-spine interface restored weight-bearing locomotion of a paralyzed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury. Clinical neurorobotic platform: With the CHUV and the SUVA, we established a new neurorobotic platform that brings together innovative monitoring and robotic technologies. A clinical trial has started in 2016 to evaluate the ability of spinal cord stimulation and robot-assisted gait training to improve motor function in people with incomplete spinal cord injury.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows Nicholas James Claudia Kathe Jean-Baptiste Mignardot Karen Minassian Tomislav Milekovic Ismael Seanez-Gonzalez Fabien Wagner PhD Students Mark Anderson Selin Anil Leonie Asboth Béatrice Barra Sabry Barlatey Kay-Alexander Bartholdi Marco Bonizzato Simon Borgognon Newton Cho Emanuele Formento Jérôme Gandar Nathan Greiner Camille Le Goff Galyna Pidpruzhnykova Shiqi Sun Sophie Wurth

onceptual and technological design of the brain spine interface. ( ) eural signal recorded from motor cortex (2) decoder running on the control computer identified motor states. ( ) hese motor states triggered electrical spinal cord stimulation protocols. ( ) he stimulator was connected to a spinal implant targeting specific dorsal roots of the lumbar spinal cord. opyright . Ruby

Technicians /Research Assistants Laetitia Baud Soline Odouard Elodie Rey Polina Shkorbatova Scientific Coordinator Quentin Barraud Administrative Assistant Pauline Hoffmann

Selected Publications » Capogrosso,& M., Milekovic,& T., Borton,& D. et al. (2016) A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539(7628): 284-288.

» Wenger,& N., Martin Moraud,& E., Gandar,& J. et al. (2016) Spatiotemporal neuromodulation therapies engaging muscle synergies to improve motor control after spinal cord injury. Nature Medicine. 22(2):138-145. » Martin Moraud,& E., Capogrosso,& M. et al. (2016) Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron 89(4):814-828.

DiGiovanna,& J., Dominici,& N. et al. (2016) Engagement of the rat hindlimb motor cortex across natural locomotor behaviors. J Neurosci 36(40):10440-10455 von Zitzewitz,& J., Asboth,& L. et al. (2016) A neurorobotic platform for locomotor prosthetic development in rats and mice. J Neural Eng 13(2): 026007. Wurth, S. et al. (2017) Long-term usability and bio-integration of polyimide-based intra-neural stimulating electrodes. Biomaterials 122 :114-129. Friedli&,L., Rosenzweig,& E.S. et al. (2015) Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Science Translational Medicine 7: 302ra134 & Equal contribution » » » »

Gerstner Lab Wulfram Gerstner - Full Professor - Director of the Teaching Section

Wulfram Gerstner is Director of the Laboratory of Computational Neuroscience LCN at the EPFL. After studies of Physics in Tübingen and at the Ludwig-Maximilians-University Munich (Master 1989), Wulfram Gerstner spent a year as a visiting researcher in Berkeley. He received his PhD in theoretical physics from the Technical University Munich in 1993 with a thesis on associative memory and dynamics in networks of spiking neurons. After short postdoctoral stays at Brandeis University and the Technical University of Munich, he joined the EPFL in 1996 as assistant professor. Promoted to Associate Professor with tenure in February 2001, he is since August 2006 a full professor with double appointment in the School of Computer and Communication Sciences and the School of Life Sciences.

lcnl.epfl.ch

Introduction

Results Obtained

At the LCN, we use neural modeling in order to understand the role of dynamics for computation in brain-like structures. Dynamics and temporal aspects play a role on all levels of information processing in the brain. On the neuronal level, we study aspects of temporal coding by “spikes”, i.e., the short electrical pulses (action potentials) that neurons use for signal transmission. On the behavioral level we focus on the dynamics of spatial navigation in a known or unknown environment. On all levels, temporal aspects of learning play a role, e.g. spike-time dependent learning or reinforcement learning.

The major efforts of the lab (partly financed by the Swiss National Science Foundation and the Human Brain Project) were focused on algorithms of synaptic plasticity that would be biologically plausible, yet compact enough for large simulations, and - most importantly - of functional significance. We have found general rules relating Hebbian synaptic plasticity to receptive field development (Brito and Gerstner). Moreover, we summarized conceptual ideas on the need of novel synaptic learning paradigms in several reviews. In a different line of research, we worked on simplified neuron models (Mensi et al.).

Models of spiking neurons In contrast to most artificial neural networks, real neurons communicate with short pulses. How could the brain use pulse coding for information processing? What are the dynamical properties of networks of spiking neurons? What is a good description of spiking neurons. We have developed the Spike Response Model as a generalized framework to describe neuronal firing behavior. One of the advantages of this framework is that we can use systematic fitting procedure exploiting the theory of Generalized Linear Models, so as to rapidly extract parameters directly from experimental data.

Keywords Computational neuroscience, spiking neuron models, plasticity, learning

Spike-timing dependent learning rules Experimental data show that the change of a synaptic weight from a neuron i to a neuron j depends on the relative timing of the pulses of neurons i and j, as well as on the postsynaptic membrane potential. What are relevant time scales of induction and consolidation? What would be a compact computational model of the main effects? What are the computational consequences of such asymmetric learning rules? We have developed an orchestrated plasticity model that covers effects observed in various labs across various time scales. The model combines Hebbian with homeostatic effects via homosynaptic and heterosynaptic plasticity as well as aspects of neuromodulation and consolidation while remaining computationally tractable.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Johanni Brea Gilra Aditya Tilo Schwalger Ho Ling LI PhD Students

Florian Colombo Dane Corneil Mohammadjavad Faraji Chiara Gastaldi Olivia Gozel Bernd Illing Marco Lehmann Vasiliki Liakoni Samuel Muscinelli Alex Seeholzer Hesam Setareh Master students model of learning novel hand movements generated by spike patterns.

Parima Ahmadipouranari Administrative Assistant

Rosa Turielle

Selected Publications » Brea, J., Gaal, A.T., Urbanczik, R. and Senn, W. (2016) Prospective coding by spiking neurons. PLoS Computational Biology 12: e1005003.

» Brea, J.M. and Gerstner, W. (2016) Does computational neuroscience need new synaptic learning paradigms? Current Opinion in Behavioral Sciences 11:61-66. » Mensi, S., Hagens, O., Gerstner, W. and Pozzorini, C. (2016) Enhanced sensitivity to rapid input fluctuations by nonlinear threshold dynamics in neocortical pyramidal neurons. PLoS Computational Biology 12: e1004761. » Fremaux, N. and Gerstner, W. (2016) Neuromodulated-spike-timing-dependent plasticity, and theory of three-factor learning rules. Frontiers in Neural Circuits 9: 85. » Brito, C.S.N. and Gerstner, W. (2016) Nonlinear Hebbian learning as a unifying principle in receptive field formation. PLoS Comput Biol 12: e1005070

Gräff Lab Johannes Gräff - Tenure-track Assistant Professor

Intrigued by how genes can influence behavior – and vice versa – Johannes Gräff conducted his PhD in the lab of Isabelle Mansuy at the ETH Zürich to specialize in neuroepigenetic processes that regulate learning and memory. Then as a postdoc at MIT with Li-Huei Tsai, he showed that epigenetic mechanisms are causally involved in neurodegeneration-associated memory loss, as well as with updating traumatic memories from the distant past. Since 2013, Dr. Gräff has been a tenure-track assistant professor at the Brain Mind Institute of the Faculty of Life Sciences, and the Nestle Chair for Neurosciences at EPFL.

graefflab.epfl.ch

Introduction

Results Obtained

Our lab is interested in three main questions. How and where are long-term memories stored in the brain? Why are memories lost during neurodegeneration such as in Alzheimer’s Disease? How can traumatic memories from the past be overcome? To answer these questions, our lab focuses on the emerging field of neuroepigenetics. “Epi-genetic” mechanisms, i.e. modifications to the chromatin that regulate gene expression without changing the DNA sequence itself, have not only been shown to react to fluctuating environmental contingencies, but also to encode the cell fate of neurons and other cell types during development. With this Janus-faced property of being at once dynamic and stable, we believe that epigenetic mechanisms harbor the potential to better explain the molecular processes that govern learning, memory and memory loss. In extension, because epigenetic mechanisms are also amenable to pharmacological intervention, they might constitute a novel angle on how to counteract memory loss and resilient traumatic memories.

Two more postdocs were hired, one of whom (BS) holds an EMBO long-term fellowship (LTF) and another one ( JSM) secured a SYNAPSIS postdoctoral fellowship. JG obtained an Alzheimer’s Association New Investigator Research Grant, became an MQ and NARSAD fellow, and was awarded an ERC Starting Grant. Several projects show promising results while others are still in the ramping-up phase.

Keywords Epigenetics, Long-term memories, Memory loss, Alzheimer’s Disease, PTSD (post-traumatic stress disorder)

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Jose Sanchez-Mut Bianca Silva Zimbul Albo PhD Students

Ossama Khalaf Allison Burns Lucie Dixsaut Technician

Liliane Glauser Administrative Assistant

Soledad Andany

mmunohistochemical labeling of the mouse brain showing a cell that was activated when the animal remembered a traumatic event (green) and that was re-activated when the same animal successfully extinguished the traumatic memory (red).

Selected Publications » Silva B.A., Gross, C.T. and Gräff, J. (2016) The neural circuits of innate fear: detection, integration, action, and memorization. Learning and Memory 23: 544-555.

» Anda F.C., Madabhushi, R., Rei, D., Meng, J., Gräff. J., Durak, O., Meletis, K., Richter, M., Schwanke, B., Mungenast, A., and Tsai, L.H. (2016) Cortical neurons gradually attain a post-mitotic state. Cell Research 26: 1033-1047. » » » »

Poirazi, P., Belin, D., Gräff, J., Hanganu-Opatz, I. and Lopez-Bendito, G. (2016) Balancing family with a successful career in neuroscience. European Journal of Neuroscience 44: 1797-1803. Khalaf. O. and Gräff, J. (2016) Structural, synaptic, and epigenetic dynamics of enduring memories. Neural Plasticity 2016:3425908. Sanchez-Mut, J.V. and Gräff, J. (2015) Epigenetic alterations in Alzheimer’s disease. Frontiers in Behavioral Neuroscience 9: 347 Rei, D., Mason, X., Seo, J., Gräff, J., Rudenko, A., Wang, J., Rueda, R., Siegert S., Cho, S., Canter, R.G., Mungenast, A.E., Deisseroth, K. and Tsai, L.H. (2015) Basolateral amygdala bidirectionally modulates stressinduced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway. PNAS 112: 7291-7296.

Herzog Lab Michael Herzog - Full Professor - Director of the Doctoral Program in Neuroscience (EDNE)

Introduction

Results Obtained

In humans, vision is the most important sense. Surprisingly, the neural and computational mechanisms of even the simplest forms of visual processing, such as spotting a pen on a cluttered desk, are largely unknown. Our research aims to understand how and why humans can cope with visual tasks so remarkably well. In addition, we investigate vision in healthy aging and have established an endophenotype of schizophrenia based on visual masking.

To cope with the complexity of vision, most models in neuroscience and computer vision are of hierarchical and feedforward nature. Low-level vision, such as edge and motion detection, is explained by basic low-level neural circuits, whose outputs serve as building blocks for more complex circuits computing higher level features such as shape and entire objects. There is an isomorphism between states of the outer world, neural circuits, and perception, inspired by the positivistic philosophy of the mind. In a variety of publications, we have shown that although such an approach is conceptually and mathematically appealing, it fails to explain many phenomena including crowding, visual masking, and non-retinotopic processing. We have proposed instead that models of visual processing need to take into account a ‘‘flexible” grouping stage, which operates on all levels of visual processing. Grouping can depend on small spatial changes, ‘‘invisible” to low-level processes, which lead to strong changes of perception. Because of the complex grouping process, there cannot be an isomorphism between external world states, basic stereotyped circuits, and perception. Subjective terms such as grouping can, at least at the moment, not be eliminated.

Keywords Michael Herzog studied Mathematics, Biology, and Philosophy. In 1996, he earned a PhD in biology under the supervision of Prof.Fahle (Tübingen) and Prof. Poggio (MIT). Then, he joined Prof. Koch’s lab at Caltech as a post-doctoral fellow. From 1999-2004, Dr. Herzog was a senior researcher at the University of Bremen and then he held a professorship for neurobiopsychology at the University of Osnabrück for one year. Since 2004, Dr. Herzog has been a professor of psychophysics at the Brain Mind Institute at the EPFL where he has established his laboratory.

lpsy.epfl.ch

Spatio-temporal vision, perceptual & reinforcement learning, ageing & schizophrenia.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Vitaly Chicherov Aaron Clarke Mattew Pachai Einat Rashal Albulena Shaqiri PhD Students

Amr Abdul-Jawwad Alban Bornet Adrien Doerig Leïla Drissi Daoudi Ophélie Favrod Lukasz Grzeczkowski Maya Jastrzebowska Marc Lauffs Janir Ramos Da Cruz Evelina Thunell He Xu Engineer

Marc Repnow isual processing and Global Gestalt. ernier acuity is determined by the configuration of the entire stimulus of the entire visual field. (a) bservers discriminated the vernier offset direction (left vs. right). (b) hresholds increased when the vernier was embedded in a s uare. (c-e) hresholds gradually decreased when the number of anking s uares increased. From anassi, ayim, erzog, 20 .

Invited Professor

Gregory Francis

Administrative Assistant

Delphine Audergon Laure Dayer

Selected Publications » Herzog, M.H., Kammer, T. and Scharnowski, F. (2016) Time slices: What Is the duration of a percept? PLoS Biology,14(4): e1002433.

» Pachai, M., Doerig, A. and Herzog, M.H. (2016) How best to unify crowding? Current Biology 26: R352–R353. » Herzog, M. H., Thunell, E. and Ögmen H. (2016) Putting low-level vision into global context: why vision cannot be reduced to basic circuits. Vision Research 126: 9-18.

» Lauffs, M.M., Shaqiri, A., Brand, A., Roinishvili, M., Chkonia, E., Ögmen, H., and Herzog, M. H. (2016) Local versus global and retinotopic versus non-retinotopic motion processing in schizophrenia patients. Psychiatry Research 246: 461–465. » Herzog, M.H. and Manassi, M. (2015) Uncorking the bottleneck of crowding: a fresh look at object recognition. Current Opinion in Behavioral Sciences 1:86–93. » Herzog, M.H., Sayim, B., Chicherov, V. and Manassi, M. (2015) Crowding, grouping, and object recognition: A matter of appearance. Journal of Vision 15 (6): 5. » Grzeczkowski, L., Tartaglia, E., Mast, F.W. and Herzog, M.H. (2015) Linking perceptual learning with identical stimuli to imagery perceptual learning. Journal of Vision 15(10): 13

Hess Bellwald Lab Kathryn Hess Bellwald - Associate Professor

PhD in mathematics from MIT in 1989 at the age of 21. Postdocs in Stockholm, Nice, and Toronto, and at the EPFL. Adjunct professor of mathematics at the EPFL in 1999 and associate professor of mathematics and life sciences in 2015.

hessbellwald-lab.epfl.ch

Introduction

Results Obtained

The lab focuses on algebraic topology and its applications, primarily in the life sciences (in particular neuroscience and cancer biology), but also in materials science. We apply methods from Topological Data Analysis (TDA), a new branch of mathematics developed for the study of big data. TDA has evolved rapidly and has already been shown to detect significant structure in data that is invisible to standard methods. The toolbox of TDA consists of sophisticated statistical methods based on algebraic topology, the best known of which is probably the Mapper technique, which is particularly good at detecting meaningful clustering in point cloud data sets.

1) We established a link between neural network structure and its emergent function, taking the direction of synaptic transmission into account, through topological analysis of the underlying directed graph. Analysis of the digital reconstruction of the neural microcircuit published by the Blue Brain Project revealed a remarkably intricate topology of synaptic connectivity, containing an abundance of cliques of neurons bound into cavities that guide the emergence of correlated activity, indicating that the brain processes stimuli by forming increasingly complex functional cliques and cavities.

We also develop and apply innovative topological approaches to network theory. We construct and study simplicial complexes, known as clique complexes, arising from the graphs underlying brain networks, as we have shown that certain topological invariants of these complexes encode important network information. Among such invariants are the Euler characteristic and the Betti numbers of the clique complex, as well as more subtle, topological analogues of known graph-theoretic measures. Homotopy theory and category theory are areas of expertise of lab members in pure mathematics.

Keywords Computational topology, topological data analysis, network theory, homotopy theory.

2) We developed a tool for the classification of branching structures, which are usually described qualitatively based on visual inspection and quantitatively by morphometric parameters. Neither description provides a solid foundation for categorization. We introduced a stable, generic descriptor for any branching morphology, which is computed in linear computational time by tracking the topological evolution of the tree using spheres of varying diameters, centered at the root of the morphology. We thereby established a mathematically rigorous benchmark that can be used to test different classification schemes of random and neuronal trees. 3) We developed a tool for the classification of nanoporous crystalline materials, the performance of which in applications can vary by orders of magnitude depending only on the pore structure. Our method topologically quantifies similarity of pore structures, enabling us to identify materials with similar pore geometries and to screen for materials that are similar to known top-performing structures. In the case of methane storage, we showed that materials separate into topologically distinct classes requiring different optimization strategies.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Magdalena Kedziorek Martina Scolamiero Gard Spreemann Katharine Turner Jean Verrette PhD Students

Martina Rovelli Kay Werndli Dimitri Zaganidis Scientific collaborator

Jérôme Scherer

Administrative Assistant

Maroussia Schafffner-Portillo

( ) xamples of the most common simplex types in the microcircuit, by dimension. (B) chematic description of the most common simplex types. ( ) Result of binning simplices according to their multiplicity in the network. n magenta the most common type.

Selected Publications » Brisken, C., Hess, K. and Jeitziner, R. (2015) Progesterone and overlooked endocrine pathways in breast cancer pathogenesis. Endocrinology 156: 3442-3450. » » » » » »

Chacholski, W., Dror Farjoun, E., Flores, R. and Scherer, J. (2015) Cellular properties of nilpotent spaces. Geometry and Topology 19 (5): 2741–2766. Dror Farjoun, E. and Scherer, J. (2015) Conditionally flat functors on spaces and groups. Collectanea Mathematica 66 (1): 149–160. Chorny, B. and Scherer, J. (2015) Goodwillie calculus and Whitehead products. Forum Mathematicum 27 (1): 119–130. Hess, K. (2016) The Hochschild complex of a twisting cochain. J. Algebra 451: 302-356. Hess, K. and Shipley, B. (2016) Waldhausen K-theory of spaces via comodules. Advances in Mathematics 290: 1079-1137. Chacholski, W., Scherer, J. and Werndli, K. (2016) Homotopy excisision and cellularity. Annales Institut Fourier 66: 2641-2665

Lashuel Lab Hilal A. Lashuel - Associate Professor

B.Sc. degree in chemistry (City University of New York), PhD in bioorganic chemistry (Texas A&M University). 2000-2004: Research fellow and instructor of neurology at Harvard Medical School. 2004: Assistant Professor BMI-EPFL. 2012-2013: Visiting Associate Professor, Stanford University. 2014-2015: Executive Director Qatar Biomedical Research Institute

lashuel-lab.epfl.ch

Introduction

Results Obtained

Research in the Lashuel laboratory focuses on applying integrated chemical, biophysical, and molecular/cellular biology approaches to elucidate the molecular and structural basis of protein misfolding and aggregation and the mechanisms by which these processes contribute to the pathogenesis of neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD).

The role of post-translational modifications (PTMSs) in the pathogenesis of Parkinson’s disease (PD) and Huntington’s disease (HD): We reported, for the first time, a semisynthetic strategy for generating site-specifically nitrated proteins opens up new possibilities for investigating the role of nitration in regulating protein structure and function in health and disease (Burai et al). We completed successfully the synthesis of all known α-syn (28 proteins) and exon-1 of the Huntingtin protein (Httex1, >40 proteins) PTMs, and assessed the role of each of PTM and cross-talk between different PTMs in regulating the structure and aggregation of these proteins in vitro. Our studies demonstrated that the function of these proteins are under complex regulatory mechanisms involving cross-talk among different PTMs (Dikiy et al and Burai et al). The generation of these unique libraries of modified proteins have paved the way for new projects focusing on elucidating the role of these PTMs in regulating the spreading of pathology and the discovery of novel biomarkers, antibodies and imaging agents and assays to facilitate early detection and monitoring of disease progression and response to therapies in Parkinson’s disease and Huntington’s disease (in collaboration with industry, UCB, IRBM & Biolegend. Novel Model of Parkinson’s disease: We developed a new neuronal model that recapitulates many of the key features of Lewy body pathology in PD (Fares et al). We showed that the failure to reproduce human α-Syn (hα-Syn) fibrillization into LBs in mice could be attributed to interactions between hα-Syn and its endogenously expressed mouse α-Syn homologue. This model enable real-time assessment of inclusion formation and thus provides unique opportunities to elucidate molecular and cellular determinants that influence the mechanisms of α-Syn fibrillization in living neurons, and to identify pathways, antibodies and drugs that modulate this process and protect against neurodegeneration in PD. Mechanisms of amyloid toxicity: We demonstrated that fibril growth and seeding capacity play key roles in amyloid-beta (Eleuteri et al) and α-synuclein(Mahul-Mellier et al) mediated toxicity and showed that drugs we developed to inhibit fibril growth and seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD. Furthermore, we demonstrated that photomodulation suppresses protects against neuronal loss in a genetic Model of Parkinson’s Disease.

Current research efforts cover the following topics: 1. Elucidating the sequence, molecular and cellular determinants underlying protein aggregation, propagation and toxicity; 2. Developing novel chemical approaches and tools to investigate the role of post-translational modifications in regulating the function/dysfunction of proteins implicated in the pathogenesis of AD, PD and HD; 3. Identification of biomarkers and imaging agents for early detection and monitoring of disease progression and response to therapies; 4. Developing novel cellular to test and validate therapeutic targets, and assess disease modifying strategies based on modulating protein modification, aggregation, pathology spreading and clearance. Research in the Lashuel laboratory is funded by several funding agencies (Swiss National Science Foundation, Horizon 2020) and foundations (CHDI and Michael J Fox) and through strategic partnerships with pharmaceutical and biotech companies (AC Immune and UCB and Biolegend).

Keywords Protein aggregation, post-translational modifications, biomarkers neurodegeneration, Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Anne-Laure Mahul-Mellier Bruno Fauvet Bohumil Maco Elena Tobolkina Jean-Christoph Copin Joan Romani Aumedes John Warner Juan Reyes Layane Hanna-el-Daher Mahmood Haj-Yahya Niran Maharjan Ritwik Burai Sean Deguire PhD Students

Anass Chiki Mohamed Bilal Fares Nadine Ait-Bouziad Sophie Vieweg Technicians schematic depiction illustrating the experimental approaches used in our group to elucidate the molecular mechanisms of protein aggregation, toxicity and pathology spreading and to identify and develop novel biomarkers and therapeutic strategies for early detection and treatment of neurodegenerative diseases.

Driss Boudeffa Nathalie Jordan Céline Vocat Administrative Assistant

Marie Rodriguez

Selected Publications » Fares, M.B., Maco, B., Oueslati, A., Rockenstein, E., Ninkina, N., Buchman, V., Masliah, E. and Lashuel, H.A. * (2016) . Induction of de novo α-Synuclein fibrillization in a novel neuronal model for Parkinson’s disease. Proc. Natl. Acad. Sci. U S A. 16;113(7):E912-21. » Vieweg S, Ansaloni A, Wang Z, and Lashuel HA*. “An Intein-based Strategy for the Production of Tag-free Huntingtin Exon 1 Proteins Enables New Insights into the Polyglutamine Dependence of Httex1 Aggregation and Fibril Formation”, J. Biol. Chem, 2016 291(23):12074-86. » Dikiy I, Fauvet B, Jovičić A, Mahul-Mellier A, Desorby C, El-Turk F, Gitler AD, Lashuel HA*, Eliezer D*. Semisynthetic and in vitro phosphorylation of alpha-synuclein at Y39 promotes functional partly-helical membrane-bound states resembling those induced by PD mutations. ACS Chem Biol. 2016 Jul 11. [Epub ahead of print] » Mahul-Mellier, A., Vercruysse, F., Maco, B., Ait-Bouziad, N., De Roo, M., Muller, D. and Lashuel, H.A.* (2015) “Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death, Cell

Death and Differentiation, 2015, 22(12):2107-22. » Burai, R., Ait-Bouziad, N., Chiki, A. and Lashuel, H.A.* (2015) “Elucidating the Role of Site-Specific Nitration of α-Synuclein in the Pathogenesis of Parkinson’s Disease via Protein Semisynthesis and Mutagenesis.” J Am Chem Soc. 2015 Apr 22;137(15):5041-52. » Eleuteri, S., Di Giovanni, S., Rockenstein, E., Mante, M., Adame, A., Trejo, M., Wrasidlo, W., Wu, F., Fraering, P.C., Masliah, E.and Lashuel, H.A*. (2015). Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer’s disease. Neurobiology of Disease. 2015 Feb; 74:144-57. » Oueslati, A., Lovisa, B., Perrin, J., Wagnières, G., van den Bergh, H., Tardy, Y. and Lashuel, H.A.* (2015). Photobiomodulation Suppresses Alpha-Synuclein-Induced Toxicity in an AAV-Based Rat Genetic Model of Parkinson’s Disease. PLoS One. 10(10):e0140880.

Magistretti Lab Pierre Magistretti - Full Professor

Pierre Magistretti is a professor at the Brain Mind Institute at EPFL and at the Center for Psychiatric Neuroscience of the University of Lausanne/CHUV and an internationally recognized leader in the field of brain energy metabolism and glia biology. His group has discovered some of the mechanisms that underlie the coupling between neuronal activity and energy consumption by the brain. Professor Magistretti received the Theodore-Ott Prize (1997), was the international Chair (20072008) at the Collège de France, Paris, was President of FENS (2002 – 2004) and IBRO Secretary General (2009-2012). Since October 2010, Dr. Magistretti is the director of NCCR SYNAPSY - “The synaptic bases of mental diseases”.

lndc.epfl.ch

Introduction

Results Obtained

Research in the LNDC is centered on the study of the cellular and molecular mechanisms of brain energy metabolism. The key question addressed is how the energy is delivered to neurons in register with synaptic activity (see Figure). We have identified a set of mechanisms demonstrating the role of astrocytes in coupling synaptic signals mediated by glutamate to the entry of glucose into the brain parenchyma and the provision of energy substrates to restore the energy budget of neurons. We have also shown that energy can be delivered to neurons in register to neuronal activity from glycogen selectively stored in astrocytes. Another dimension of the metabolic coupling between astrocytes and neurons that our group has unveiled is related to synaptic plasticity and the processes of learning and memory. We have shown that lactate transfer from astrocytes to neurons is required for these processes. We have also demonstrated the existence of “metabolic plasticity” through which transcriptionally‐regulated adaptations of certain genes of brain energy metabolism occur in relation to synaptic plasticity as observed during learning and addiction. The laboratory is also interested in microscopy imaging techniques, such as digital holographic microscopy (DHM), that allow the visualization of dynamic cellular processes, including those involved in plasticity and neurodegeneration.

The main focus of our work during the last two years was to understand the role of signaling mediated by lactate produced by astrocytes on neuronal function. In addition to its role as an energy substrate for neurons, we have discovered that lactate plays a role in learning and memory. We have previously shown that lactate is necessary for the establishment of long term memory as well as for the maintenance of long-term potentiation in vivo in rat and has a stimulatory effect on the expression of neuronal plasticity-related genes (e.g. Arc, Zif 268, BDNF) (Suzuki et al, 2011; Yang et al, 2014). In line with this, we recently demonstrated that astrocytic glycogen-derived lactate also plays an important role in appetitive learning i.e. disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine (Bourry-Jamot et al, 2015). Furthermore, we found that a set of genes involved in neuro-metabolic coupling between astrocytes and neurons, such as the lactate transporter MCT1, is induced by learning in an inhibitory avoidance task (Tadi et al, 2015). Interestingly, using a gene-to-behavior approach we were able to demonstrate that inhibitory avoidance learning was impaired in MCT1-deficient mice, further demonstrating the importance of lactate transfer in memory processes (Tadi et al, 2015). These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived lactate in long-term memory as well as the action of L-lactate as a signaling molecule for neuronal plasticity (see Figure). Finally, we provided an in depth characterization of the neuroprotective properties of lactate using DHM, a real-time imaging technique able to detect early signs of cell death in culture. Indeed, lactate was shown to efficiently protect neurons from an excitotoxic insult through a mechanism involving an autocrine/paracrine ATP signalling on purinergic receptors (see Figure; Jourdain et al, 2016).

Keywords Neuroenergetics, neuron-glia interaction, learning & memory, neuroprotection.

BMI - Brain Mind Institute

Team Members Senior Scientist

Gabriele Grenningloh Scientists

Igor Allaman Sophie Burlet Pascal Jourdain Sylvain Lengacher (CTI) Jean-Marie Petit Postdoctoral Fellows

Charles Finsterwald (CTI) Swananda Marathe Manuel Zenger PhD Students

Benjamin Boury-Jamot Scientific Assistants

Sara De Jesus Dias Melanie Wirth euron-glia metabolic coupling Role of glia-derived lactate (produced in a neuronal activity-dependent manner via glycolysis and glycogenolysis) in neuronal plasticity and neuroprotection.

Technicians

Cendrine Barrière Elena Gasparotto Trainee

Raquel Sandoval Ortega Administrative Assistant

Selected Publications

Monica Navarro Suarez

» Magistretti, P.J. and Allaman, I. (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86(4):883-901. » Boury-Jamot, B., Carrard, A., Martin, J.L., Halfon, O., Magistretti, P.J.* and Boutrel, B*. (2015) Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol Psychiatry 21: 1070-1076. *Co-last authors » Jolivet, R., Coggan, J.S., Allaman, I. and Magistretti, P.J. (2015) Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble. PLoS Comput Biol.11(2):e1004036. » Tadi, M., Allaman, I., Lengacher, S., Grenningloh, G. and Magistretti, P.J. (2015) Learning-induced gene expression in the hippocampus reveals a role of neuron -astrocyte metabolic coupling in long term memory.

PLoS One 10(10):e0141568. » Carrard, A., Elsayed, M., Margineanu, M., Boury-Jamot, B., Fragnière, L., Meylan, E.M., Petit, J.M., Fiumelli, H., Magistretti, P.J.*and Martin, J.L.* (2016) Peripheral administration of lactate produces antidepressantlike effects. Mol Psychiatry doi: 10.1038/mp.2016.237. *Co-last authors » Calì, C., Baghabra, J., Boges, D.J., Holst, G.R., Kreshuk, A., Hamprecht, F.A., Srinivasan, M., Lehväslaiho, H. and Magistretti, P.J. (2016) Three-dimensional immersive virtual reality for studying cellular compartments in 3D models from EM preparations of neural tissues. J Comp Neurol 524(1):23-38. » Mächler, P., Wyss, M.T., Elsayed, M., Stobart, J., Gutierrez, R., von Faber-Castell, A., Kaelin, V., Zuend, M., San Martín, A., Romero-Gómez, I., Baeza-Lehnert, F., Lengacher, S., Schneider, B.L., Aebischer, P., Magistretti, P.J., Barros, L.F. and Weber, B. (2016) In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab 23(1):94-102.

Group Digital Holographic* Microscopy*

Pierre Marquet Pascal Jourdain

Professor Emeritus*

Christian Depeursinge PhD Students*

Keven Bourgeaux Kaspar Rothenfusser Manuel Zenger

Markram Lab Henry Markram - Full Professor - Director of the Blue Brain Project

Henry Markram is the Principal Investigator of the LNMC and Director of the Blue Brain Project. He began his research career in South Africa in the 1980s, moved to Israel and then to the EPFL, where he founded the BMI in 2002. He has focused on neural microcircuitry pioneering the multi-neuron patch-clamp approach. His discoveries include Spike Timing Dependent Plasticity, Redistribution of Synaptic Efficacy, and Long-Term Microcircuit Plasticity. He has also been active in autism research and co-developed the Intense World Theory of Autism.

markram-lab.epfl.ch

Introduction

Results Obtained

The Laboratory of Neural Microcircuitry (LNMC) is dedicated to understanding the structure, function and plasticity of neural microcircuitry in the neocortex. To achieve this goal, the LNMC systematically characterizes the electrophysiological, structural and molecular properties of individual neurons, local rules of connectivity, the synaptic properties of interconnected neurons and the role of neuromodulation in microcircuit dynamics. Since the functional properties of the microcircuit are ultimately defined by the dynamic repertoire of its constituent neurons and synapses, the LNMC invests considerable effort in unravelling the molecular underpinnings of these dynamic properties. This work includes the development of high throughput protocols to characterize ion channels and to derive single cell transcriptome data specific neuron types. The experimental data generated by LNMC is used by the Blue Brain Project to build realistic in silico reconstructions and simulations of neocortical microcircuitry. The LNMC has also used its expertise to characterize neurocircuitry in a rat models of autism, using the results to develop a novel theory of autism (the “Intense World Theory”) and to demonstrate the beneficial effects of rearing in a predictable, enriched environment.

During 2015 and 2016, the LNMC developed important new methods for neuroscience research, continued its longstanding work in fundamental neuroscience, and applied its expertise in applied research on autism. On the methods front, J-P Ghobril participated in the development of a new, highly versatile method to make mouse brains transparent for microscopy, and used the method to acquire whole brain single-cell resolution scans of fluorescently labelled cells, achieving major reductions in scanning time. O. Hagens worked with Christof Koch and others to develop a fast novel method to build accurate neuron models, using data from simple stimulation protocols. Both these results will contribute to brain modelling in the Blue Brain Project. Meanwhile, LNMC continued its long-standing program of basic neuroscience research, producing important new findings on the modulation of plasticity by network state. Interestingly, the same stimuli that produce longterm potentiation when the network is relatively inactive, lead to long-term depression when the network is highly active. Other fundamental research showed that intracellular spiking has a significant effect on extracellular action potentials (EAP) – casting doubt on the common belief that local field potentials are a direct proxy for synaptic activity. Finally, the lab concluded a major project on the etiology of autism, based on the “Intense World Theory of Autism”. The project, based on a rat model of autism, showed that exposure to a predictable, enriched environment in early infancy can produce improved cognitive and behavioural outcomes. This novel finding suggests the possibility of applications in the treatment of human infants at high risk for autism.

Keywords Neurons, synaptic plasticity, neural microcircuits, neuronal coding, patch clamp, signal integration, electrophysiology, single cell gene expression, ion channels, neuron morphology, modeling, autism.

BMI - Brain Mind Institute

Team Members Postdoctoral Fellows

Monica Favre Sara Gonzalez Andino Olivier Hagens Emmanuelle Logette Michela Marani Kamila Markram Rodrigo Perin Maurizio Pezzoli Jesper Ryge PhD Students

Jean-Pierre Ghobril Ayah Khubieh Yi Jane Wuzhou Yang Technical Staff

Mirjia Herzog Deborah La Mendola Julie Meystre Trainees

onfocal block imaging of triple immunohistochemical labeling. D P labels all cells (blue). eu labels all neurons (Green), G B labels all G B ergic cells including glia (amber).

Victoria Aroworade Pierrik Chapuis Beat Geissmann Jean-Marc Comby Syed Easin Uddin Quentin Herzig Dejan Jovandic Auriane Maiza Sarah Mondoloni Nell Christophe Ramadani Faton Beatriz Rebollo Gonzalez Flavio Traversa Tahni-Ann Wilson David Wuthier Lionel Ponsonnet Cristina Radaelli Visiting Professor

Selected Publications

Giorgio Innocenti

» FMensi, S., Hagens, O., Gerstner, W. and Pozzorini, C. (2016) Enhanced sensitivity to rapid input fluctuations by nonlinear threshold dynamics in neocortical pyramidal neurons. PLoS Computational Biology 12: e1004761. » Raimondo, J.V., Tomes, H., Irkle, A., Kay, L., Kellaway, L. et al. (2016) Tight coupling of astrocyte pH dynamics to epileptiform activity revealed by genetically encoded pH sensors. Journal of Neuroscience 36: 7002-7013. » Favre, M.R., La Mendola, D., Meystre, J., Christodoulou, D., Cochrane M.J. et al. (2015) Predictable enriched environment prevents development of hyper-emotionality in the VPA rat model of autism. Frontiers in Neuroscience 9:127. » Delattre, V., Keller, D., Perich, M., Markram, H. and Muller, E.B. (2015) Network-timing-dependent plasticity. Frontiers in Cellular Neuroscience 9:220. » Anastassiou, C., Perin, R.d.C. , Buzsaki, G., Markram, H. and Koch, C. (2015) Cell-type- and activity-dependent extracellular correlates of intracellular spiking. J. Neurophys. 114 (1): 608-623. » Pozzorini, C. A., Mensi, S., Hagens, O., Naud, R., Koch, C. et al. (2015) Automated high-throughput characterization of single neurons by means of simplified spiking models. PLoS Comp. Biol. 11 (4): e1004275. » Costantini, I., Ghobril, J.-P., Di Giovanna, A.P., Mascaro, A.L.A., Silvestri, L. et al. (2015) A versatile clearing agent for multi-modal brain imaging. Scientific Reports 5 (9808): 1-9

Consultant

Anthony Njoku

External Employee

Michele Giugliano Students

Laura Mekarni Caroline Violot Katya Guez Stagiaire

Axel Billaud

Administrative Assistant

Petersen Lab Carl Petersen - Full Professor

Carl Petersen studied physics as a bachelor student in Oxford (1989-1992). During his PhD supervised by Prof. Sir Michael Berridge in Cambridge (19921996) he investigated cellular and molecular mechanisms of calcium signalling. As a postdoc he joined the laboratory of Prof. Roger Nicoll at the University of California San Francisco (1996-1998) to investigate synaptic transmission and plasticity in the hippocampus. Moving to the Max Planck Institute for Medical Research in Heidelberg in the laboratory of Prof. Bert Sakmann (19992003), he began working on primary somatosensory cortex. Dr. Petersen opened his Laboratory of Sensory Processing in the Brain Mind Institute in the School of Life Sciences in the EPFL in 2003 as an Assistant Professor. In 2010 he was promoted to Associate Professor and again in 2014 to Full Professor.

lsens.epfl.ch

Introduction

Results Obtained

Neural circuits and synaptic mechanisms underlying sensory perception and associative learning

Research in the Laboratory of Sensory Processing contributed to two important areas of neuroscience in 2015-16:

Research in the Laboratory of Sensory Processing aims to define the neuronal circuits and synaptic mechanisms underlying sensory perception and associative learning in mice. To understand sensory processing at the level of individual neurons and their synaptic interactions within complex networks, we use electrophysiological and optical methods combined with molecular and genetic interventions both in vitro and in vivo. We want to know how specific neuronal networks contribute to the processing of sensory information in a learning- and context-dependent manner ultimately leading to behavioural decisions.

We are currently working on several complementary areas of research: 1.

2. 3.

Measurement and perturbation of neuronal activity correlated with quantified behavior in mice, focusing on the analysis of sensory percepts informed by the C2 whisker and reported through the execution of learned motor output. Basic operating principles and wiring diagrams of neocortical microcircuits, focusing on the mouse C2 barrel column. Genetic analysis of the determinants of sensory perception and associative learning, through combination of viral manipulations and gene-targeted mice.

Keywords Sensory perception, Motor control, Sensorimotor integration, Learning, Neocortex, Neuronal circuits, Synaptic transmission, Whole-cell membrane potential recording, Optogenetics, Two-photon microscopy.

Goal-directed sensorimotor transformation drives important aspects of mammalian behavior. The striatum is thought to play a key role in reward-based learning and action selection, receiving glutamatergic sensorimotor signals and dopaminergic reward signals. In the study of Sippy et al. (2015), we obtained whole-cell membrane potential recordings from the dorsolateral striatum of mice trained to lick a reward spout after a whisker deflection. Striatal projection neurons showed strong task-related modulation, with more depolarization and action potential firing on hit trials compared to misses. Direct pathway striatonigral neurons exhibited a prominent early sensory response. Optogenetic stimulation of direct pathway striatonigral neurons readily substituted for whisker stimulation evoking a licking response. Our data are consistent with direct pathway striatonigral neurons contributing to a â&#x20AC;&#x153;goâ&#x20AC;? signal for goal-directed sensorimotor transformation leading to action initiation. Little is known about the properties of synaptic connectivity and synaptic transmission in vivo. In the study of Pala and Petersen (2015), we combined single-cell optogenetics with whole-cell recordings to investigate glutamatergic synaptic transmission in vivo from single identified excitatory neurons onto two genetically-defined subtypes of inhibitory GABAergic neurons in layer 2/3 mouse barrel cortex. We found that parvalbumin-expressing (PV) GABAergic neurons received unitary glutamatergic synaptic input with higher probability than somatostatin-expressing (Sst) GABAergic neurons. Unitary excitatory postsynaptic potentials onto PV neurons were also faster and more reliable than inputs onto Sst neurons. Excitatory synapses targeting Sst neurons displayed strong short-term facilitation, while those targeting PV neurons showed little short-term dynamics.

BMI - Brain Mind Institute

Team Members Post doctoral

Sylvain Crochet Sami El-Boustani Vahid Esmaeili Célia Gasselin Xander Houbaert Taro Kiritani Johannes Mayrhofer Tanya Sippy Keita Tamura PhD Students

Matthieu Auffret Pierre Le Merre Semihcan Sermet Angeliki Vavladeli Georgios Foustoukos Technicians

natomical reconstruction of connected pairs of 2 xc→P (left) and xc→ st (right) neurons. xample whole-cell recording of u P Ps elicited in the P (red) and st (brown) neuron by a 50 z train of five -ms light pulses. ingle trial u P Ps are shown above and average u P Ps below (Pala and Petersen, 20 5)

Eloïse Charrière Katia Galan Administrative Assistant

Severine Sudre

Selected Publications » Sreenivasan, V., Esmaeili, V., Kiritani, T., Galan, K., Crochet, S. and Petersen, C.C.H. (2016) Movement initiation signals in mouse whisker motor cortex. Neuron 92: 1368-1382. » Sachidhanandam, S., Sermet, B.S. and Petersen, C.C.H. (2016) Parvalbumin-expressing GABAergic neurons in mouse barrel cortex contribute to gating a goal-directed sensorimotor transformation. Cell Reports 15: 700-706. » Yamashita, T. and Petersen, C.C.H. (2016) Target-specific membrane potential dynamics of neocortical projection neurons during goal-directed behavior. eLife 5: e15798.

» Urbain, N., Salin, P.A., Libourel, P.A., Comte, J.C., Gentet, L.J. and Petersen, C.C.H. (2015) Whisking-related changes in neuronal firing and membrane potential dynamics in the somatosensory thalamus of awake mice. Cell Reports 13: 647-656. » Sippy, T., Lapray, D., Crochet, S. and Petersen, C.C.H. (2015) Cell-type-specific sensorimotor processing in striatal projection neurons during goal-directed behavior. Neuron 88: 298-305. » Korogod, N., Petersen, C.C.H. and Knott, G.W. (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion and cryo fixation. eLife 4: e05793. » Pala, A. and Petersen, C.C.H. (2015) In vivo measurement of cell-type-specific synaptic connectivity and synaptic transmission in layer 2/3 mouse barrel cortex. Neuron 85: 68-75

Sandi Lab Carmen Sandi - Full Professor - Director of Brain Mind Institute

Introduction

Results Obtained

The Laboratory of Behavioral Genetics investigates the impact and mechanisms whereby stress and personality affect brain function and behavior, with a focus on the social domain and, particularly, on aggression and social hierarchies.

Social competition is a fundamental mechanism of evolution and the organization of individuals within dominance hierarchies an integral aspect of social groups. Little is known about the factors that affect individuals’ competitive success. Our laboratory has identified, both in humans and rodents, a key role for trait anxiety in the outcome of social competition between two conspecific individuals:

Specifically, we investigate: • Carmen Sandi was trained in Psychology and carried out her Ph.D. studies in Behavioral Neuroscience at the Cajal Institute, Madrid, in Spain. Following postdoctoral appointments at the University of Bordeaux and the Open University, UK, she was recruited by UNED in Madrid, where she headed the Stress and Memory Lab. After a sabbatical year in the University of Bern, she joined the EPFL in 2003. Her goal is to understand how stress affects brain function and behaviour and to reveal key neurobiological mechanisms that underlie individual differences in behaviour and cognition.

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The neurobiological mechanisms involved in the formation of social hierarchies, and their modulation by stress and anxiety. Our current work focuses in the mesolimbic system and the role of mitochondrial function in motivation and social competition. The mechanisms whereby early life stress enhances risk to develop psychopathology, with a main focus on the emergence of pathological aggression. We investigate the role of glucocorticoids in determining different neurodevelopmental trajectories following exposure to early life adversity. The mechanisms linking altered neuroplasticity during development and pathological aggression. We focus on genes involved in the polysialylation of the neural cell adhesion molecule NCAM and investigate alterations in gene expression and brain connectivity linked to dysfunctional behaviors.

Experimental approaches in the lab include a combination of behavioral, neurobiological, neuroimaging, neurochemical, pharmacological, metabolic, genetic and optogenetic methods. Although traditionally, the core of our work is carried out in rodents, we are currently translating our findings to humans using behavioral economics, experimental psychology (eye-tracking, computerbased tests), virtual reality, and neuroimaging and physiological approaches.

Keywords Stress, glucocorticoids, aggression, social hierarchy, psychopathology, anxiety, personality, neural cell adhesion molecules, mitochondrial function, psychopharmacology, optogenetics, neuroeconomics, neuroimaging.

lgc.epfl.ch

Using behavioral economic approaches, we found that under stressful conditions, competitive self-confidence is regulated in opposite directions depending on trait anxiety: low-anxiety individuals become overconfident, and high-anxiety individuals become underconfident, and cortisol responses were related to these effects. We have reproduced this competitive disadvantage of high-anxiety individuals in a rat model of social competition and investigated underlying mechanisms. Our results have identified a crucial role for mitochondrial function in the nucleus accumbens for social hierarchy establishment and its involvement in the low social competitiveness associated with high anxiety. Specifically, highanxious animals exhibit reduced mitochondrial complex I and II proteins and respiratory capacity as well as decreased ATP and increased ROS production in the nucleus accumbens. Moreover, in a dyadic contest between anxietymatched animals, microinfusion of specific mitochondrial complex I or II inhibitors into the nucleus accumbens reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in high-anxious individuals. Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.

BMI - Brain Mind Institute

Team Members Post Doctoral

Simone Astori Elias Gebara João Pedro de Matos Rodrigues Borja Rodriguez Herreros Thomas Larrieu Laia Morató Fornaguera Stephan Streuber Meltem Weger Ioannis Zalachoras PhD Students

Damien Huzard Leyla Loued-Khenissi Silvia Monari Aurélie Papilloud Alina Strasser Lab Techinicians

Jocelyn Grosse Marie-Isabelle Guillot de Suduiraut Olivia Zanoletti he establishment of a social hierarchy during a first encounter in rats is modulated by trait anxiety.

Trainee Biology Laboratory Assistants

Tanja Goodwin

Administrative Assistant

Barbara Goumaz

Selected Publications » Tzanoulinou, S., García-Mompó, C., Riccio, O., Grosse, J., Zanoletti, O., Dedousis, P., Nacher, J. and Sandi, C. (2016) Neuroligin-2 expression in the prefrontal cortex is involved in attention deficits induced by peripubertal stress. Neuropsychopharmacology 41: 751-761. » Bendahan, S., Goette, L., Thoresen, J., Loued-Khenissi, L., Hollis, F. and Sandi C. (2016) Acute stress alters individual risk taking in a time-dependent manner and leads to anti-social risk. Eur. J. Neurosci. doi:

10.1111/ejn.13395. » Hollis, F., van der Kooij, M. A., Zanoletti, O., Lozano, L., Cantó, C. and Sandi, C. (2015) Mitochondrial function in the brain links anxiety with social subordination. Proc. Natl. Acad. Sci. U S A. 112: 15486-15491. » Sandi, C. and Haller, J. (2015) Stress and the social brain: behavioral effects and neurobiological mechanisms. Nat. Rev. Neurosci. 16:290-304. » Tzanoulinou, S., García-Mompó, C., Riccio O., Grosse, J., Zanoletti O., Panagiotis, D., Nacher, J. and Sandi, C. (2016) Neuroligin-2 expression in the prefrontal cortex is involved in attention deficits induced by peripubertal stress. Neuropsychopharmacology 41:751-761. » Goette, L., Bendahan, S., Thoresen, J., Hollis, F., and Sandi, C. (2015) Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress. Psychoneuroendocrinology 54: 115-123. » van der Kooij, M.A. and Sandi, C. (2015) The genetics of social hierarchies. Curr. Opin. Behav. Sci. 2: 52-57

Schneggenburger Lab Ralf Schneggenburger - Full Professor

Ralf Schneggenburger obtained a PhD in Natural Sciences at the University of Göttingen in 1993, and was a post-doctoral fellow at the University of Saarland (1994) and at the Ecole Normale Supérieure (1994 - 1996). During further postdoctoral work and as a Research Group Leader at the Max-Planck Institute for biophysical Chemistry (Göttingen, 1996- 2005), he developed a research program in transmitter release mechanisms and presynaptic plasticity. In 2005, he was appointed as a Professor at EPFL and has since then been leading the Laboratory for Synaptic Mechanisms at the Brain Mind Institute.

lsym.epfl.ch

Introduction

Results Obtained

Nerve cells are embedded in complex neuronal circuits, and communicate with each other via the process of chemical synaptic transmission. The Schneggenburger lab investigates three research areas related to synaptic function in the brain:

Basic function of synapses. Together with the labs of Felix Schürmann and Henry Markram, we explored how Ca2+ channels influence the probability of vesicle fusion at the presynaptic active zone, using detailed computational modelling. The number, and distance of Ca2+ channels to docked vesicles is one important determinant of vesicle fusion probability at the synapse. However, the co-localization of vesicles and Ca2+ channels on the tens of nanometer range is difficult to study in the electron microscope. We now showed by computational modellingthat in synapses in which release is controlled by several Ca2+ channels (“domain overlap”), the channels must obey a certain minimal distance to docked vesicles to avoid saturation of the Ca2+ sensor for vesicle fusion (see Figure). The results suggest that in synapses with domain overlap release control, an ordered, but not random, arrangement of Ca2+ channels and vesicles exists (Keller et al. 2015, PLoS Comp. Biology).

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Basic function of synapses with a focus on transmitter release control.

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Molecular mechanisms of synapse development, focusing on mechanisms that determine the specific form and function of synapses.

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Synaptic plasticity, and neuronal circuits which underlie simple forms of learning in animals.

We investigate these questions in the mouse model of mammalian brain function, because of the availability of advanced genetic tools to identify and target specific neuronal populations in this mammalian species. We are especially interested in neuronal circuits which process sensory information, and focus on the auditory system, the sense of hearing. First, the auditory system has several highly specialized types of synapses, which serve as models to study the molecular mechanisms driving synapse specialization. Second, auditory stimuli, which can be easily applied in the lab environment, can elicit learning in rodents like fear conditioning, or can influence the synaptic wiring of cortical auditory circuits during critical periods of development. We are beginning to investigate the role of long-term synaptic plasticity at excitatory and inhibitory synapses in these processes.

Mechanisms of synapse development. The Ca2+ sensor proteins for vesicle fusion are encoded by Synaptotagmins (Syts), and there is a quite large number of Syt isoform genes in the mammalian genome (17). We could show that at a giant excitatory synapse in the auditory system, the calyx of Held, the Syt isoform is exchanged during brain development from Syt1 to Syt2, at a developmental period when the large calyx nerve terminal begins to grow (Kochubey et al. 2016). The results show that the hindbrain-specific Syt2 isoform is only started to be expressed, and functionally relevant, a few days after birth. The results also show that a major presynaptic protein can be exchanged during brain development. This process must involve gene expression changes in the nucleus of the presynaptic neuron, and axonal transport of the new Syt isoform to nerve terminals.

Keywords Synaptic transmission, neurotransmitter, glutamate, GABA, synaptic plasticity, synapse development, neuronal circuits, critical period plasticity.

BMI - Brain Mind Institute

Team Members Post Doctoral

Emmanuelle Berret Brice Bouhours Christopher Clark Michael Kintscher Olexiy Kochubey Evan Vickers PhD Students

Aiste Baleisyte Enida Gjoni Elin Kronander Shriya Palchaudhuri Wei Tang Techinicians

Tess Baticle Jessica Dupasquier Heather Murray Administrative Assistant

Delphine Audergon Francine Sallin he exclusion zone model of a2 channel localization at the presynaptic active zone of synapses. he minimal distance of Ca2 channels (red dots) to docked vesicles is indicated by the blue dashed line. aken, with permission, from eller et al. 20 5 Plos omputational Biology (5).

Selected Publications » Kochubey, O., Babai, N. and Schneggenburger R. (2016) A Synaptotagmin isoform switch during the development of an identified CNS synapse. Neuron 90: 984-999.

» Keller, D., Babai, N., Han, Y., Kochubey, O., Markram, H., Schürmann, F. and Schneggenburger R. (2015) An exclusion zone for Ca2+ channels around docked vesicles explains release control by multiple channels at a CNS synapse. PLoS Comp. Biol. 11(5): e1004253. » Han, Y., Babai, N., Kaeser, P., Südhof, T.C. and Schneggenburger, R. (2015) RIM1 and RIM2 redundantly determine Ca2+ channel density and readily-releasable pool size at a large hindbrain synapse. J. Neurophysiology 113: 255-263. » Schneggenburger, R. and Rosenmund, C. (2015) Molecular mechanisms governing the Ca2+ regulation of evoked and spontaneous transmitter release. Nature Neuroscience 18: 935–941 (review)

Hill Lab Sean Hill - Adjunct Professor

Sean Hill is co-Director of the Blue Brain Project and Director of Neuroinformatics in the European Union funded Human Brain Project (HBP). Dr. Hill has also served as Executive Director and Scientific Director of the International Neuroinformatics Coordinating Facility (INCF) at the Karolinska Institutet in Stockholm, Sweden. After completing his Ph.D. in computational neuroscience at the UniversitĂŠ de Lausanne, Switzerland, Dr. Hill held postdoctoral positions at The Neurosciences Institute in La Jolla, California and the University of Wisconsin, Madison, then joined the IBM T.J. Watson Research Center and served as the Project Manager for Computational Neuroscience in the Blue Brain Project until his appointment at the EPFL

hill-lab.epfl.ch

Introduction

Keywords

The Laboratory for the Neural Basis of Brain States (LNBBS) is directed by Prof. Sean Hill and based at the Campus Biotech in Geneva, Switzerland. The laboratory focuses on understanding cortical and thalamocortical structure and function and the relationship to states of the brain including wakefulness, sleep and anesthesia. The group employs biophysically-detailed computational models and large-scale simulations to investigate the cellular and synaptic mechanisms underlying brain states in health and disease.

Large-scale simulation, neuroinformatics, microcircuitry, neocortex, thalamus, connectome, sleep, wakefulness, integrated information, brain atlases, TMS, EEG.

LNBBS is part of Blue Brain, a Swiss national brain initiative that applies advanced neuroinformatics, data analytics, high-performance computing infrastructure and simulation-based approaches to the challenge of understanding the structure and function of the mammalian brain in health and disease. Professor Hill also heads the Neuroinformatics division at Blue Brain. The Neuroinformatics division developed Blue Brain Nexus, the informatics infrastucture to organize, search, access and analyze heterogeneous neuroscience data including multi-scale brain atlases, machine learning, machine vision, data and text mining, data analysis and data-driven ontologies.

Results Obtained The lab has contributed to the release of the Blue Brain digital reconstruction of a neocortical microcircuitry and the major publication in Cell. In 2015, the lab also produced several publications regarding natural language parsing and text mining for neuroinformatics. In particular, the lab demonstrated the application of text mining techniques to find statements from the neuroscience literature on the whole mouse brain connectome. In 2016, the lab led the delivery of the first release of the Neuroinformatics Platform in the Human Brain Project (nip.humanbrainproject.eu), including data federation, semantic provenance graphs, atlas viewers and the KnowledgeSpace (knowledge-space.org).

BMI - Brain Mind Institute

Team Members Post Doctoral

Christian O’Reilly Bas-Jan Zandt PhD Students

Elisabetta Iavarone Administrative Assistant

Dace Stiebrina

xample of a P cell morphology ( ) and patch-clamping recording in slice for tonic (B) and burst (D) firing. orresponding single-cell simulated tonic ( ) and burst ( ) firing. Reconstructed circuit (F).

Selected Publications » Hill, S. L. (2016) How do we know what we know? Discovering neuroscience data sets through minimal metadata. Nature Reviews Neuroscience 17: 735–736.

» DeFelipe, J., Douglas, R. J., Hill, S. L., Lein, S., Martin, K. A., et al. (2016) Comments and general discussion on “The anatomical problem posed by brain complexity and size: a potential solution”. Frontiers in Neuroanatomy 10: 60. » » » » »

Leitner, F., Bielza, C., Hill, S. L., and Larrañaga, P. (2016) Data publications correlate with citation impact. Frontiers in Neuroscience.10:419. Vogelstein, J. T., Amunts, K., Andreou, A., Angelaki, D. and Ascoli, G., et al. (2016) Grand Challenges for Global Brain Sciences. Global Brain Workshop 2016. Johns Hopkins University, Baltimore, MD USA. Markram, H., et al. (2015) Reconstruction and simulation of neocortical microcircuitry. Cell 163(2): 456-492. Richardet, R., Chappelier, J.C., Telefont, M. and Hill, S. (2015) Large-scale extraction of brain connectivity from the neuroscientific literature. Bioinformatics 31(10):1640-1647. Peng, H., Hawrylycz, M., Roskams, J., Hill, S., Spruston, N., Meijering, E., & Ascoli, G. A. (2015) BigNeuron: large-scale 3D neuron reconstruction from optical microscopy images. Neuron 87(2): 252-256.

Schürmann Lab schuermann-lab.epfl.ch

Felix Schürmann - Adjunct Professor

Felix Schürmann is co-director of the Blue Brain Project and is closely involved in high performance computing research in the European Human Brain Project. Prof. Schürmann studied physics at the University of Heidelberg, Germany, supported by the German National Academic Foundation. Later, as a Fulbright Scholar, he obtained his Master’s degree (M.S.) in Physics from the State University of New York, Buffalo, USA, under the supervision of Richard Gonsalves. During these studies, he became curious about the role of different computing substrates and dedicated his masters thesis to the simulation of quantum computing. He won his Ph.D. at the University of Heidelberg, Germany, under the supervision of Karlheinz Meier. For his thesis he co-designed an efficient implementation of a neural network in hardware.

Introduction

Results Obtained

Modern in silico neuroscience leverages the computational capabilities of some of the largest computers available to science. However, it also has its own special computational characteristics and requirements and will remain a computational grand challenge for many years to come. Against this background, the Schürmann group focuses on the interface between in silico neuroscience and computer architectures. Key areas of research include techniques enabling faster and more detailed simulations of brain tissue, novel techniques for model building and visualization, and new ideas for brain-inspired computing substrates.

In 2015 and 2016, the Laboratory for Neurosimulation Technology collaborated closely with the Blue Brain Project’s HPC and visualization teams, following several different lines of research: 1.

Keywords Neurosimulation technology, In silico neuroscience, simulation, scientific computing

Understanding the computational characteristics of neurosimulations: the group developed a framework allowing quantitative analysis of a selected set of brain models. The metrics, which are based on information from the model and the underlying algorithm, reveal intrinsic differences among models. Combined with detailed analyses of the underlying algorithms they make it possible to predict how specific hardware characteristics will affect simulation performance. Lately, this analysis has also been extended to deep learning models. Accelerating neurosimulations: on the example of the open source NEURON simulator we investigate how these types of simulations can profit from next generation asynchronous execution models (ParalleX, HPX) to achieve better strong scaling and have implemented a first working version. For that, the group is engaged in a collaboration with Prof. Thomas Sterling from Indiana University. Leveraging novel architectures: We have started to explore novel nonvolatile memory technologies in supercomputers, as a way of addressing the heavy memory requirements of detailed brain simulations as well as other data-intensive parts of brain simulation workflows such as analysis. Part of this research is performed on the existing Blue Brain BlueGene/Q supercomputer that features integrated Flash memory (Blue Gene Active Storage). Part is performed at other compute centers such as the Argonne Leadership Computing Facility.

BMI - Brain Mind Institute

Team Members Post Doctoral

Judit Planas

PhD Students

Francesco Cremonesi Bruno Magalhães Administrative Assistant

Dace Stiebrina

isualization of the computational characteristics of different published brain models. he vertical shading denotes properties that can be associated to the single node performance, whereas the crosshatch shading denotes properties associated to network communication of the underlying computing architecture.

Selected Publications » Masoli, S., Rizza, M.F., Sgritta, M., van Geit, W., Schürmann, F. and D’Angelo, E. (2017) Single neuron optimization as a basis for accurate biophysical modelling: the case of cerebellar granule cells. Front. Cell.

Neurosci. 11: 71. » Lytton, W.W., Seidenstein, A.H., Dura-Bernal, S., McDougal, R.A., Schürmann, F. and Hines, M.L. (2016) Simulation neurotechnologies for advancing brain research: Parallelizing large networks in neuron. Neural Comput. 28(10):2063-2090. » Van Geit, W., Gevaert, M., Chindemi, G., Rössert, C., Courcol, J., Muller, E.B., Schürmann, F., Segev, I. and Markram, H. (2016) BluePyOpt: Leveraging open source software and cloud infrastructure to optimise model parameters in neuroscience. Front. Neuroinform. 10:17.

» Kumbhar, P., Hines, M.L., Ovcharenko, A., Mallon, D.A., King, J., Sainz, F., Schürmann, F. and Delalondre, F. (2016) Leveraging a cluster-booster architecture for brain-scale simulations. International Supercomputing Conference, Frankfurt, Germany. » Magalhaes, B., Tauheed, F., Heinis, T., Ailamaki, A. and Schürmann, F. (2016) An efficient parallel load-balancing framework for orthogonal decomposition of geometrical data. ISC High Performance, Frankfurt, Germany. » Eilemann, S., Delalondre, F., Bernard, J., Planas, J., Schürmann, F. et al. (2016) Key/value-enabled flash memory for complex scientific workflows with on-line analysis and visualization. Parallel and Distributed Processing Symposium, IEEE International (pp. 608-617). » Markram, H. et al., Schürmann, F. (2015) Reconstruction and simulation of neocortical microcircuitry. Cell 163: 456-492.

Editor: Laurence Mauro Many thanks to Friedrich Beermann, Lucia Baldi, Dietrich Reinhard, Sacha Sidjanski, Harald Hirling and Roland Chabloz at the Repro for their help and support!

12th edition 2015/2016 Produced and edited by the EPFL School of Life Sciences Printed at the EPFL “Atelier de Reprographie”

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