BMI Annual Report 2014 by EPFL School of Life Sciences

EPFL School of Life Sciences BMI - Brain Mind Institute Report 2014

EPFL School of Life Sciences - 2014 Annual Report

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.

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

BMI - Brain Mind Institute

• Designing innovative interventions to restore sensorimotor functions after neural disorders.

EPFL School of Life Sciences - 2014 Annual Report

Aebischer Lab Patrick Aebischer

Full Professor - President of EPFL

http://len.epfl.ch/

Introduction

Patrick Aebischer was trained as an MD (1980) and a Neuroscientist (1983) at the Universities of Geneva and Fribourg in Switzerland. Until 1992, he worked as Faculty member at Brown University in Providence (USA), where he became Chairman of the Section of Artificial Organs, Biomaterials and Cellular Technology in 1991. He returned to Switzerland in 1992, as Professor and Director of the Surgical Research Division and Gene Therapy Center at the Centre Hospitalier Universitaire Vaudois in Lausanne. Since 2000, Patrick Aebischer has been President of the EPFL. He is the founder of 3 biotech companies.

Understanding the cause of neurodegeneration and translating these findings into effective treatments is a daunting task. A number of findings suggest that protein misfolding during brain aging is a key mechanism in several neurodegenerative diseases, providing novel targets for therapeutic intervention. However, it remains uncertain how these pathologies could be cured or prevented. Our lab explores the causes and possible treatments for neurodegenerative diseases using state-of-the-art techniques to manipulate gene expression in the central nervous system (CNS). In particular, we develop viral vector technologies, mainly based on adeno-associated and lentiviral vectors, to target in the rodent CNS the cell types that contribute to pathogenic changes in amyotrophic lateral sclerosis and Parkinson’s disease. In parallel, we explore the possibility to use genetically modified cells to deliver therapeutic molecules in the brain, such as recombinant antibodies for passive immunization against misfolded protein species. Furthermore, our lab develops relevant animal and cellular models of neurodegenerative pathologies, including Alzheimer’s and Parkinson’s diseases, with the objective to test and validate therapies. In particular, we develop gene transfer technologies to replicate pathologies linked to the accumulation and misfolding of molecules such as Tau and alphasynuclein in the rodent brain. Our aim is to use these animal models to validate the efficacy of specific compounds and gene therapies, and explore the mechanisms that lead to neuronal dysfunction and death. In this context, one line of research is to understand how the protein pathology observed in several diseases propagates throughout the CNS, which may open new avenues for therapeutic intervention.

Keywords

Gene therapy, animal models of disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Alzheimer’s disease, viral vectors, adeno-associated virus, cell encapsulation, passive immunization.

Results Obtained in 2014

During the past two years, our lab has mainly focused its research on three research axes. In order to design a gene therapy approach against amyotrophic lateral sclerosis (ALS), we have explored the possibility to target motoneurons and astrocytes throughout the spinal cord using adeno-associated viral vectors (AAV). Specific combinations of AAV capsids and promoters have been found that allow for widespread gene delivery in the mutated SOD1 mouse model of ALS (Dirren et al., 2014). This technology has been used to express artificial microRNAs in order to reduce SOD1 levels. We have obtained significant improvements in the motor function of the treated mice, providing preclinical proof-of-principle evidence for the therapeutic efficacy of this approach (Dirren et al, 2015). We are currently addressing the possibility to evaluate gene therapy in SOD1 ALS patients. A second line of research has explored the delivery of anti-amyloid β antibodies using encapsulated cellular implants (see Figure). A novel encapsulation technology has been developed to support the long-term implantation of muscle cells genetically engineered to secrete recombinant antibodies in the subcutaneous tissue (Lathuilière et al, 2014). Peripheral delivery of anti-amyloid β antibodies prevents the deposition of amyloid plaques in the brain of a mouse model of Alzheimer’s disease. Finally, using an animal of Parkinson’s disease based on AAV-induced overexpression of human α-synuclein in nigral dopaminergic neurons (Gaugler et al, 2012), we have explored possible interaction of the pathology with genetic determinants of the aging process. We have found that the activity of the transcription factor FoxO3a has a strong effect on α-synuclein toxicity, and controls accumulation of the protein via changes in autophagic activity (Pino et al, 2014). This study adds to our work on the role of the FoxO3a/PGC-1α axis in the α-synuclein pathology, highlighting the critical importance of the transcriptional control of autophagic and mitochondrial activities in Parkinson’s disease.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Senior Scientist Bernard Schneider Postdoctoral Fellows Julianne Aebischer Nathalie Bernard-Marissal Maria Gabriela Mercado Guerra Pamela Valdès

PhD Students Wojciech Bobela Vanessa Laversenne Sameer Nazeeruddin Cylia Rochat Lu Zheng

Technicians Aline Aebi Philippe Colin Geneviève Dayer Fabienne Pidoux Vivianne Padrun Christel Sadeghi

Visiting Students Patrick Chirdon (Fullbright) Abhishek Verma (Fullbright) Giorgio Ulrich Duygu Deniz Bas Caitriona Mae Callan Hena Sara Ahmed Veselina Petrova Marco Edoardo Schukraft

Administrative Assistants Marie Künzle Ursula Zwahlen

BMI - Brain Mind Institute

(a) Implantation of genetically modiﬁed cells within a permeable device to produce antibodies targeting the amyloid pathology in the brain. Encapsulating device (b) and implanted cells (c). (d) The survival of cells genetically modiﬁed to express luciferase can be monitored by light emission.

Selected Publications » Dirren E., Towne C.L., Setola V., Redmond D.E. Jr, Schneider B.L., Aebischer P. 2014. Intracerebroventricular injection of adeno-associated virus 6 and 9 vectors for cell type-specific transgene expression in the spinal cord. Hum Gene Ther. 25(2):109-20. » Lathuilière A., Cosson S., Lutolf M.P., Schneider B.L., Aebischer P. 2014. A high-capacity cell macroencapsulation system supporting the long-term survival of genetically engineered allogeneic cells. Biomaterials. 35(2):779-91. » Lathuilière A., Bohrmann B., Kopetzki E., Schweitzer C., Jacobson H., Moniatte M., Aebischer P., Schneider B.L. 2014. Genetic engineering of cell lines using lentiviral vectors achieves high-level antibody secretion following encapsulated implantation. Biomaterials. 35(2): 792-802. » Kaplan A, Spiller KJ, Towne C, Kanning KC, Choe GT, Geber A, Akay T, Aebischer P, Henderson CE. 2014. Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron. 81(2):333-48. » Pino E., Amamoto R., Zheng L., Cacquevel M., Sarria J.C., Knott G.W., Schneider B.L. 2014. FOXO3 determines the accumulation of �-synuclein and controls the fate of dopaminergic neurons in the substantia nigra. Hum Mol Genet. 23(6):1435-52. » Valdés P., Mercado G., Vidal R.L., Molina C., Parsons G., Court F.A., Martinez A., Galleguillos D., Armentano D., Schneider B.L., Hetz C. 2014. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc Natl Acad Sci U S A. 111(18):6804-9. » Oueslati A., Schneider B.L., Aebischer P., Lashuel H.A. 2013. Phosphorylation by PLK2 enhances �-synuclein turnover and protects against its toxicity E. coli. Proc Natl Acad Sci U S A. 110(41): E3945-54. » Löw K., Aebischer P., Schneider B.L. 2013. Direct and retrograde transduction of nigral neurons with AAV6, 8 and 9, and intraneuronal persistence of viral particles, Hum Gene Ther. 24(6):613-29.

EPFL School of Life Sciences - 2014 Annual Report

Blanke Lab Olaf Blanke

Full Professor - Director of the Center for Neuroprosthetics

http://lnco.epfl.ch

Introduction

Olaf Blanke is the founding director of the Center for Neuroprosthetics and Bertarelli Foundation Chair in Cognitive Neuroprosthetics at the Ecole Polytechnique Fédérale de Lausanne (EPFL). He also directs the Laboratory of Cognitive Neuroscience at EPFL and is Professor of Neurology at the Department of Neurology at the University Hospital of Geneva. Blanke’s human neuroscience research is dedicated to the understanding of how the brain represents our body and the neuroscientific study of consciousness using human neuroimaging and cognitive psychology. In clinical neuroscience he pursues intracranial neurosurgical investigations as well as neuroprosthetics and neurorehabilitation in neurological, orthopaedic, and psychiatric patients. He pioneered cognitive neuroprosthetics by using engineering techniques such as robotics, haptics, virtual reality to develop novel treatments for cognition and consciousness disorders.

The Laboratory of Cognitive Neuroscience (Bertarelli Chair in Cognitive Neuroprosthetics) is part of the Brain Mind Institute and the Center for Neuroprosthetics. Research in the Blanke Lab targets the brain mechanisms of multisensory body perception and consciousness. Projects rely on the investigation of healthy subjects, neurological, psychiatric, and orthopedic patients by combining psychophysical and cognitive paradigms, neuroimaging techniques (high resolution fMRI, EEG, and intracranial human recordings) with several engineering-based approaches (robotics, brain-computer interfaces, virtual reality, augmented reality). Our work over the last 10 years has been fundamental to describe a neuroscientific theory of self-consciousness. For this we used technology to induce complex altered states in humans under controlled-conditions (virtual and augmented reality, robotics) and were able to describe the detailed mechanisms of bottom-up sensory signals and their integration in a brain network consisting of posterior parietal cortex, insula and frontal cortex. Finally, we are dedicated to applying our neuroscience and technology findings in the fields of neuroprosthetics, sensory substitution, and neurorehabilitation with our clinical partners at the Sion Rehabilitation Hospital, as well as the Geneva and Lausanne University Hospitals, where we continue to develop the fields of robotic psychiatry and cogniceuticals.

Keywords

Multisensory perception, bodily awareness, consciousness, neuroprosthetics, neurorehabilitation, intracranial human electrophysiology, neuroimaging, EEG, neuropsychology, cognitive neurology, epileptology, virtual reality, robotics, haptics.

Results Obtained in 2014

In robotic psychiatry, a major achievement was the design and application of a master-slave robotic system (Hara et al., Journal of Neuroscience Methods, 2014) that manipulates sensorimotor signals to induce altered bodily experience and psychosis-like states in healthy participants (Blanke et al., Current Biology 2014). We also studied the same mental states and the involved brain circuits in a large group of neurological patients (Blanke et al., Current Biology 2014). Most recently, we have started to investigate the involved brain circuits in healthy participants by using a new robotic system that is fully compatible with modern brain imaging (MRI). In cogniceuticals, we have launched a major effort in treating patients with chronic pain, of neurological and orthopedic origin. These studies on chronic pain are directly motivated by our neuroscience research on multisensory brain mechanisms (including interoceptive signals) of bodily experience and consciousness. In neuroscience we showed that bodily experience and consciousness arise from the integration of visual and tactile signals with interoceptive signals (Aspell et al., Psychological Science 2013) and that such integration occurs in bilateral insular and temporo-parietal cortex (Heydrich & Blanke, Brain 2013; Ionta et al., Social Cognitive and Affective Neuroscience 2014). We also showed that manipulating multisensory bodily inputs impact physiological states of the body, leading to a decrease in physical body temperature (Salomon et al., Frontiers in Neuroscience 2013) and to analgesia (Romano et al., Beh Brain Res 2014). To translate our cogniceutical approach to patients with chronic pain, we have setup a new integrated virtual reality platform with our clinical partners in the Rehabilitation clinics in Sion and Geneva (ongoing research). Finally, a new line of our research in neuroscience focuses on how these low-level multisensory mechanisms affect cognitive functions, such as social cognition (Teneggi et al., Current Biology, 2013), processing of bodily sounds (Van Elk et al., Biological Psychology, 2014a, 2014b) and visual consciousness (Faivre et al., Current Opinion in Neurology, 2015).

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Akselrod Michel Brechet Lucie Gale Steven Grivaz Petr Kaliuzhna Mariia Marchesotti Silvia Pfeiffer Christian Pozeg Polona Rognini Giulio Solcà Marco

Master’s Students Blondiaux Eva Dönz Jonathan Muhech Amira Lukowska, Marta Vuillaume Laurène Visiting PhD Students Muret Dollyane Noël Jean-Paul

Laboratory Engineers Bello Ruiz Javier Mange Robin

Administrative Assistant Neffati-Laifi Sonia

Physician/MDs Pierre Prognin Solcà Marco

BMI - Brain Mind Institute

Postdoctoral Fellows Bernasconi Fosco Blefari Maria Laura Canzoneri Elisa Faivre Nathan Martuzzi Roberto Ronchi Roberta Salomon Roy Schurger Aaron Serino Andrea Kanayama Noriaki

Robot-controlled feeling of a presence. Participants performed hand movements in the front, while receiving altered sensory feedback on their back. If the spatio-temporal congruency between movements and feedback was manipulated by the robot, participants illusorily felt as another person was standing behind them.

Selected Publications » Blanke, O., Pozeg, P., Hara, M., Heydrich, L., Serino, A., Yamamoto, A., Higuchi, T., Salomon, R., Seeck, M., Landis, T., Arzy, S., Herbelin, B., Bleuler, H., Rognini, G. (2014). Neurological- and robot-controlled induction of an apartition. Cell Current Biology 24(22):2681-6. » Hara, M., Salomon, R., van der Zwaag, W., Kober, T., Rognini, G., Nabae, H., Yamamoto, A., Blanke, O., Higuchi, T. (2014). A novel manipulation method of human body ownership using an fMRI-compatible master-slave system. J Neuroscience Methods. 235:25-34. » Romano, D., Pfeiffer, C., Maravita, A., Blanke, O. (2014). Illusory self-identification with an avatar reduces arousal responses to painful stimuli. Behavioral Brain Research 261:275-81. » Heydrich, L., Blanke, O. (2013). Distinct illusory own-body perceptions caused by damage to posterior insula and extrastriate cortex. Brain 136: 790-803. » Aspell, J.E., Heydrich, L., Blanke, O. (2013). Turning body and self inside out: Visualized heartbeats alter bodily self-consciousness and tactile perception. Psychological Science 24: 2445-2453. » Teneggi, C., Canzoneri, E., di Pellegrino, G., Serino, A. (2013). Social modulation of peripersonal space boundaries. Cell Current Biology 23(5):406-11. » Ionta, S., Martuzzi, R., Salomon, R., Blanke, O. (2013). The brain network reflecting bodily self-consciousness: a functional connectivity study. Social Cognitive Affective Neuroscience. 9(12):1904-13.

EPFL School of Life Sciences - 2014 Annual Report

Courtine Lab Grégoire Courtine

Associate Professor - IRP Chair in Spinal Cord Repair

http://courtine-lab.epfl.ch/

Introduction

Grégoire Courtine was trained in Mathematics, Physics, and Neurosciences in France and Italy. After a Postdoc in Los Angeles (UCLA), he established his laboratory at the University of Zurich. In 2012, he was appointed the International Paraplegic Foundation Chair in Spinal Cord Repair at the Center for Neuroprosthetics at EPFL. His research program aims to develop neuroprosthetic treatments to improve recovery after spinal cord injury—an endeavor that has been reported in high-profile publications, and has extensively been covered in the media. His start-up, G-Therapeutics SA, aims to translate these medical and technological breakthroughs into treatments.

The World Health Organization (WHO) estimates that as many as 500’000 people suffer from a spinal cord injury each year. Over the past decade, we implemented an unconventional research program with the aim to develop radically new treatment paradigms to improve functional recovery after spinal cord injury. We have progressively conceived a treatment that integrates a serotonergic replacement therapy (Nature Neuroscience, 2009), electrical spinal cord stimulation (Science Translational Medicine, 2014; Science, 2015), next-generation weight-supporting robotic systems (Nature Medicine, 2012) and novel will-powered training regimes (Science, 2012). We have shown that this combinatorial treatment restored and refined locomotion after severe spinal cord injury in rodent models. Recovery occurs through the extensive and ubiquitous remodeling of residual neuronal connections in the brain and spinal cord. The goal of the laboratory is to translate this treatment into a medical practice for improving functional recovery after spinal cord injury in humans. To this aim, we have structured a translational, neuroprosthetic program that combines work in mice, rats, non-human primates, and humans. Specifically, our objective is to (i) identify the mechanisms underlying the immediate and long-term effects of our treatment in genetically modified mice using virus-mediated experimental manipulations, calcium imaging and optogenetics; (ii) refine all our methods and procedures in rat models of spinal cord injury; (iii) optimize and validate our new neurotechnologies and therapeutic concepts in non-human primate models; and (iv) deploy clinical studies that progressively integrate the different components of our interventions.

Keywords

Spinal cord injury, neural repair, neurorehabilitation, neuroprosthetics, brain-machine interface, robotics, neuronal recordings, optogenetics, EMG, kinematics, locomotion, neuromorphology, mice, rats, monkeys, humans.

Results Obtained in 2014

Mechanisms of recovery after spinal cord injury (Cell 2014): We had previously demonstrated that recovery after spinal cord injury relies on novel detour connections that bypass the injury. However, the circuit-level mechanism behind this process was not elucidated. We found that muscle spindles and associated circuits promote the establishment of these detour connections. These findings may contribute to improving our treatment strategies. Neuromodulation therapies (Science Translational Medicine, 2014; Science 2015): We have identified the mechanisms underlying the facilitation of locomotion with electrical spinal cord stimulation. This conceptual framework guided the development of innovative hardware and software to improve our neuromodulation therapies. We designed the first entirely stretchable, multimodal implants that exhibit unprecedented bio-integration in the central nervous system. This implant, developed in collaboration with Prof. Lacour, can deliver both electrical and chemical stimulations over the brain and spinal cord. In parallel, 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 animal models of neurological disorders. Wireless neurosensor (Neuron, 2014): Neuroscience research has been constrained by cables required to connect brain sensors to computers. In collaboration with Brown University, we developed and validated a wireless brain-sensing system that allows recordings of high-fidelity neural data during unconstrained behavior in primates. Gait rehabilitation platform: In collaboration with the CHUV, the SUVA and the Canton of Valais, we established a new Gait Platform that brings together innovative monitoring and rehabilitation technology. We will exploit this Gait Platform to evaluate the ability of our electrical stimulation protocols and robot-assisted training procedures to improve motor function after spinal cord injury.

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Anderson Mark Asboth Leonie Bartholdi Kay Beauparlant Janine Friedli Wittler Lucia Gander Jérôme Pidpruzhnykova Galyna Vollenweider Isabel Wenger Nikolaus Le Goff Camille Anil Selin

Technicians /Research Assistants Baud Laetitia Duis Simone Kreider Julie

Scientiﬁc Coordinator Van den Brand Rubia

Administrative Assistant Nguyen Kim-Yen

BMI - Brain Mind Institute

Postdoctoral Fellows Barraud Quentin Borton David Laurens Jean Martinez Gonzalez Cristina Mignardot Jean-Baptiste Milekovic Tomislav Musienko Pavel Pavlova Natalia Von Zitzewitz Joachim Wagner Fabien

A completely paralyzed rat can be made to walk over obstacles and upstairs by electrically stimulating the severed part of the spinal cord. EPFL scientists discovered how to control in real-time how the rat moves forward and how high it lifts its limbs.

Selected Publications » » » » » » » » » »

Courtine G, Bloch J. (2015) Defining ecological strategies in neuroprosthetics. Neuron. 2015 April. Minev I.R., et al. (2015) Electronic dura mater for long-term multimodal neural interfaces, Science 347, 6218, 159-163. Vollenweider I et al. (2014) Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury, Cell, 159(7):1626-39. Yin M et al. (2014) Wireless Neurosensor for Full-Spectrum Electrophysiology Recordings during Free Behavior. Neuron. 2014 Dec 17;84(6):1170-82. Wenger N et al. (2014) Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury. Science Translational Medicine. 2014 Sep 24;6(255):255ra133. Borton D et al. Personalized neuroprosthetics Science Translational Medicine. 2013 Nov 6;5(210):210rv2. Capogrosso M et al. (2013) A computational model for epidural electrical stimulation of spinal sensorimotor circuits. Journal of Neuroscience 33: 19326-40. Beauparlant J et al. (2013) Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury. Brain. 2013 Nov;136(Pt 11):3347-61. Van den Brand R et al. (2012) Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 336(6085): 1182-1185. Dominici N et al. (2012) Novel robotic interface to evaluate, enable, and train locomotion and balance after neuromotor disorders. Nature Medicine. (18) 1142–1147.

EPFL School of Life Sciences - 2014 Annual Report

Fraering Lab Patrick C. Fraering

Tenure-track Assistant Professor

http://fraering-lab.epfl.ch/

Introduction

Patrick Fraering studied biology at the University Louis Pasteur of Strasbourg, where he earned a master’s degree in biochemistry (1995) and pre-doctoral research degree in molecular and cellular biology at the CNRS (1996). In 2001, he received his PhD at the University of Fribourg. In 2002, he joined the lab of Prof. D. Selkoe at Harvard Medical School where he studied the molecular basis of Alzheimer’s disease. In 2007, he has been appointed assistant professor at the EPFL’s School of Life Sciences.

Our main interest is the understanding of the molecular and biological mechanisms implicated in the pathological process that leads to Alzheimer’s disease, the most frequent age related neurological disorder. More specifically, we focus our research on γ-secretase, an intramembranecleaving protease that is directly implicated in the generation of the amyloid-beta peptides (Aβ), the accumulation of which causes AD. Toward advancing the biochemistry and neurobiological functions of γ-secretase, with attendant therapeutic applications, our long-term goals are: • To get new insight into the structure and function of the γ-secretase protease complex, including a better understanding of its regulatory mechanisms, • To understand how mutations in Presenilin and APP causing early onset familial Alzheimer’s disease affect the biochemical properties of γ-secretase and the processing of APP, • To shed new light on the neurobiological functions of γ-secretase, and understand how, through the cleavage of Neurexins and Neuroligins, it regulates the activity and the plasticity of neuronal synapses, • To identify endogenous γ-secretase modulators of APP processing and Aβ production, and • To elucidate the precise mode of action, at the molecular level, of chemical γ-secretase modulators (GSMs) currently tested in clinical trials. Our vision is to provide new molecular targets and strategies for rational drug design to safely treat or prevent Alzheimer’s disease.

Keywords

Molecular and cellular biology of Alzheimer’s disease, γ-secretase, amyloid-beta peptides (Aβ), intramembrane-cleaving proteases, synaptic activity and plasticity, therapeutic targets, translational research.

Results Obtained in 2014

The adipocyte differentiation protein APMAP is an endogenous modulator of γ-secretase and Aβ production. The deposition of amyloid-beta (Aβ) aggregates in the brain is a major pathological hallmark of Alzheimer’s disease (AD) and the endogenous modulation of γ-secretase may be implicated in the sporadic, age-dependent form of this disorder. In this study, we report the identification of the adipocyte differentiation protein APMAP as a novel endogenous modulator of Aβ generation. We found that APMAP interacts physically with γ-secretase and its substrate APP. In cells, the partial depletion of APMAP drastically increased the levels of APP-CTFs, with the consequence being increased secretion of Aβ. In wild-type and APPPS1 transgenic mice, partial adeno-associated virus-mediated APMAP knockdown in the hippocampus increased Aβ production by ~20% and ~55%, respectively. Together, our data demonstrate that APMAP is a negative regulator of Aβ production through its interaction with γ-secretase and APP. Early-onset Alzheimer’s disease mutations in APP, but not γ-secretase modulators, affect epsilon-cleavage-dependent AICD production. Pathological amino acid substitutions in the amyloid precursor protein (APP) and chemical γ-secretase modulators (GSMs) affect the processing of APP by the γ-secretase complex, and the production of Aβ42, the accumulation of which is considered causative of Alzheimer’s disease (AD). We demonstrate in this study that mutations in the transmembrane domain of APP causing aggressive early-onset familial AD (FAD) affect both γ- and ε-cleavage sites, by raising the Aβ42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). Our findings suggest that it is the combination of higher Aβ42 to Aβ40 ratio and the loss of AICD50-99 that explains the extreme aggressiveness of APP mutations with regard to the onset of the disease. We further show that GSMs, which shift Aβ42 production towards the shorter Aβ38, unequivocally spare the ε-site and APP- and Notch-ICDs production and conserve their Aβ42-lowering and Aβ38-raising properties on all tested FAD substrates. GSMs can thus be used for the treatment of patients with both sporadic and genetic forms of AD.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Jean-René Al Attia Eugenio Barone Erika Borcel

PhD Students Mitko Dimitrov Sébastien Mosser Magda Palczynska

Master’s Students/Internships Juliette Ezpeleta Jeremy Fraering Claudia Freymond Hermeto Gerber Andres Lopez Alexandre Matz Risa Suzuki Giorgio Ulrich

Administrative Assistants Monica Navarro Francine Sallin

BMI - Brain Mind Institute

The adipocyte differentiation protein APMAP (green), by colocalizing in primary cortical neurons with the γ-secretase complex (red), regulates the production of the amyloid-beta peptides implicated in Alzheimer’s disease.

Selected Publications » S. Mosser, J.R. Alattia, M. Dimitrov, A. Matz, J. Pascual, B. Schneider, and P.C. Fraering* (2014). The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain. Hum. Mol. Genet. 2015 Jan 15;24(2):371-82. » A. Matz, B. Halamoda-Kenzaoui, R. Hamelin, S. Mosser, J.R. Alattia, M. Dimitrov, M. Moniatte, and P.C. Fraering* (2014). Identification of new Presenilin-1 phosphosites: implications in the activity of γ secretase and Aβ production. J Neurochem. 2014 Dec 2. doi: 10.1111/jnc.12996. » E. Barone, S. Mosser, and P.C. Fraering* (2014). Cofilin-1 activity is modulated by age, Alzheimer’s disease pathology and γ-secretase. BBA Molecular Basis of Disease, 2014 Oct 11. pii: S0925-4439(14)00310-X. doi: 10.1016/j.bbadis.2014.10.004. » M. Dimitrov, J.R. Alattia, T. Lemmin, L. Rajwinder, A. Fligier, J. Houacine, I. Hussain, F. Radtke, M. Dal Peraro, D. Beher, and P.C. Fraering* (2013). Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nature Commun., 2013 Aug 2;4:2246 » J.R. Alattia, M. Matasci, M. Dimitrov, L. Aeschbach, D.L. Hacker, F.M. Wurm, and P.C. Fraering* (2013). Highly efficient production of the Alzheimer’s γ-secretase integral membrane protease complex by a multi-gene stable integration approach. Biotechnol Bioeng. 2013 Jul;110(7):1995-2005. » I. Hussain, J. Fabrègue, L. Anderes, S. Ousson, F. Borlat, V. Eligert, S. Berger, M. Dimitrov, J.R. Alattia, P.C. Fraering, and D. Beher. (2013). The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-β generation. J Biol Chem. 2013 Jan 25;288(4):2521-31.

EPFL School of Life Sciences - 2014 Annual Report

Gerstner Lab Wulfram Gerstner

Full Professor - Director of the Teaching Section

http://lcn1.epfl.ch/

Introduction

At the Laboratory of Computational Neuroscience, we use neural modeling in order to understand the role of dynamics for computation in brainlike structures. Dynamics and temporal aspects play a role on all levels of information processing in the brain. Wulfram Gerstner is Director of the Laboratory of Computational Neuroscience LCN at the EPFL. He studied physics at the universities of Tubingen and Munich and received a PhD from the Technical University of Munich. His research in computational neuroscience concentrates on models of spiking neurons and spike-timing dependent plasticity, on the problem of neuronal coding in single neurons and populations, as well as on the role of spatial representation for navigation of rat-like autonomous agents. He currently has a joint appointment at the School of Life Sciences and the School of Computer and Communications Sciences at the EPFL. He teaches courses for Physicists, Computer Scientists, Mathematicians, and Life Scientists.

We have three different lines of work: Neurons, Learning rules, and functional networks. On the neuronal level, we study aspects of temporal coding by `spikesâ&#x20AC;&#x2122;, i.e., the short electrical pulses (action potentials) that neurons use for signal transmission. The lab is well known for its work on the adaptive exponential integrate-and-fire neuron as well as for generalized integrate-andfire models that can be fitted to experimental data during somatic current injections. In particular, the time course of the subthreshold membrane potential and spike times are predicted by the model for arbitrary timedependent currents. On the level of synaptic learning rules, the lab has a long tradition in modeling synaptic plasticity, in particular spike-timing dependent plasticity. We have described synaptic plasticity as a function of postsynaptic voltage in combination with spike-timing, and have also developed models of synaptic consolidation across multiple time scales. We are also interested in developing a framework of learning under neuromodulatory control. On the behavioral level, we focus on the dynamics of visual processing or memory retrieval in large model networks. Via modeling we aim to link the dynamics of synaptic plasticity to learning of new behaviors. We put particular emphasis on the potential role of Spike Timing Dependent Plasticity (STDP) under the influence of neuromodulators. This concept can be applied to reward-based learning of novel motor task; long-term storage and consolidation of memory, or learning by surprise.

Keywords

Computational neuroscience, models of spiking neurons, models of synaptic plasticity and STDP, models of learning.

Results Obtained in 2014

Models of brain dynamics: Experimentalists have recently shown that during an arm movement, neurons in the motor cortex show characteristic activity patterns. In a paper in Neuron (Hennequin et al. 2014), we have now shown that many of these features can be explained by a model of interacting neurons where the activity of excitatory neurons is stabilized through smartly tuned inhibition. Most of the work reported in the paper was performed as part of the PhD thesis of Guillaume Hennequin here at EPFL, undertaken in the frame of the PhD Program in Neuroscience. Temporal Coding in single neurons: Neurons have to transmit information about time-dependent stimuli they receive, but they should not spend too much energy and therefore minimize the number of output spikes. In a paper in Nature Neuroscience (Pozzorini et al., 2013), we demonstrate that neurons achieve close-tooptimal information transmission by using adaptation on many different time scales ranging from tens of milliseconds to tens of seconds. These results have been possible thanks to a novel mathematical method of extracting parameters of neuron models directly from experimental data of neurons during patch-clamp recordings while stimulated with a timedependent input. Synaptic Plasticity and Learning: Hebbian learning is a candidate rule for synaptic plasticity, and can be formulated as models of rate-based or spike-timing dependent plasticity. Whatever the exact formulation, Hebbian learning needs to be complemented by a weight control mechanism to avoid instabilities. Previously, theoreticians often applied ad-hoc rescaling of synaptic weights with the argument that homeostasis would be the analogous biological mechanism. In a paper in PLOS Computational Biology (Zenke et al. 2013), we now show that plasticity with homeostasis needs an ultra-fast rate detector and control loop. Indeed, the control loop has to be as fast as plasticity itself. The conclusion is that the biologically found homeostatic mechanisms are excluded as candidates for weight normalization.

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Dane Corneil Mohammadjavad Faraji Felipe Gerhard Olivia Gozel Marco Lehmann Laureline Logiaco Skander Mensi

PhD Students con’t Samuel Muscinelli Christian Pozzorini Alex Seeholzer Hesam Setareh Carlos Stein Friedemann Zenke Lorric Ziegler

Master’s Students Parima Ahmadipour Alexander Aivazidis Florian Colombo Vasiliki Liakoni Claire Meissner Ivan Slijepčević Tomas van Pottelbergh

Administrative Assistant Chantal Mellier

BMI - Brain Mind Institute

Postdoctoral Fellows Moritz Deger David Kastner Kerstin Preuschoff Tilo Schwalger

What is a good neuron model? If the same stimulus is injected in both the model and a real neuron, the model should be able to predict the spike times as well as the subthreshold voltage of the real neuron.

Selected Publications » » » » » » »

Gerstner W., Kistler W. M., Naud R. and Paninski L. Neuronal Dynamics: From Single Neurons to Networks and Models of Cognition. Cambridge University Press, 978-1-107-06083-8, 2014. Book. Deger M., Schwalger T., Naud R. and Gerstner W (2014). Fluctuations and information filtering in coupled populations of spiking neurons with adaptation, Physical Review E, vol. 90, num. 6, p. 062704. Zenke F. and Gerstner W. (2014). Limits to high-speed simulations of spiking neural networks using general-purpose computers, Frontiers in Neuroinformatics, vol. 8, num. 76. Hennequin G., Vogels T. and Gerstner W. (2014). Optimal Control of Transient Dynamics Balanced Networks Supports Generation of Complex Movements, Neuron, vol. 82, p. 1394–1406 Zenke F., Hennequin G. and Gerstner W. (2013). Synaptic Plasticity, in Neural Networks Needs Homeostasis with a Fast Rate Detector, Plos Computational Biology, vol. 9, num. 11. Pozzorini C. A., Naud R., Mensi S. and Gerstner W. (2013). Temporal whitening by power-law adaptation in neocortical neurons, Nature Neuroscience, vol. 16, num. 7, p. 942-U216. Rüter J., Sprekeler H., Gerstner W. and Herzog M. H. (2013). The Silent Period of Evidence Integration in Fast Decision Making, PLoS ONE, vol. 8, num. 1, p. e46525.

EPFL School of Life Sciences - 2014 Annual Report

Gräff Lab Johannes Gräff

Tenure-track Assistant Professor

http://graefflab.epfl.ch

Introduction

Our lab is interested in three main questions. How and where are longterm 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? 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.

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, have not only been shown to react to fluctuating environmental contingencies, but also to encode the fate of neurons and other cell types during development. With this Janus-faced property of being at once dynamic and stable, we hypothesize that epigenetic mechanisms might underlie the processes that converge newly learned information into a persisting memory. In particular, we focus on the following research topics: We speculate that epigenetic modifications might provide molecular memory marks on the chromatin to facilitate both the processing and storage of memories. We are deciphering how this molecular mnemonic can best be installed and subsequently read. We could show that malfunctioning epigenetic mechanisms contribute to the neurodegeneration-associated cognitive decline. Using a combination of genetic and environmental tools in mice, we are now addressing what triggers such malfunctioning, and how can we counteract it? Just as epigenetic mechanisms contribute to cognitive decline, they also contribute to engrave memories from the past. Using an animal model of PTSD in combination with cognitive behavioral therapy-like approaches, pharmacological interventions and molecular biology, we are aiming at elucidating the molecular basis for resilient traumatic memories and new approaches to overcome them.

Keywords

Neuroepigenetics, long-term memories, neurodegeneration, Alzheimer’s disease, traumatic memories, memory loss, memory trace.

Results Obtained in 2014

The lab opened in the fall of 2013 and we have since installed all necessary equipment and techniques so that we hope that the years to come will yield valuable results. In our current project, we propose to identify the neuronal subpopulations and the molecular mechanisms underlying remote fear memory extinction. To this end, we will use an innovative combination of transgenic mouse models with direct in situ manipulations of neuronal subpopulations and cell type-specific transcriptomic and epigenetic analyses. Specifically, we will address the following groundbreaking questions: What are the neuronal subpopulations that are causally implicated in the successful extinction of remote fear memories? The answer to this question will allow to determine whether the original traumatic memory trace has been permanently modified, or whether a new memory trace of safety has been superimposed over the original one – an important unanswered question in the field of memory research. What are the epigenetic mechanisms that underlie successful memory extinction? Answering this question reaches beyond the state-of-the-art in the field of neuroepigenetics, as it pledges to analyze memory-related epigenetic modifications in a cell population-specific manner, a hitherto unachievable level of specificity. Is there a common molecular denominator that defines successfully extinguished memories? By defining a molecular signature of the neuronal subpopulations that subserve successful memory extinction, this approach will provide an easy-to-use and reliable tool for the future efficacy comparison of intervention strategies against traumatic memories, which is a significant improvement over currently employed methods with that purpose. This proposed tool will further help to better understand remote memory extinction, which is not only worth achieving in the context of traumatic memories, but also for other dysfunctions such as addictive behaviors, where associative memories form a physiologically harmful fundament.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Jose Sanchez-Mut

PhD Students Ossama Khalaf Leonhard von Meyenn

Technician Liliane Glauser

Administrative Assistant Soledad Andany

BMI - Brain Mind Institute

Immunohistochemical labeling of the mouse hippocampus showing cells that are activated when recalling traumatic memories (green) and those activated after successful memory extinction (red).

Selected Publications » Tsai, L.-H., and J. Gräff, 2014 “On the resilience of remote traumatic memories against exposure-therapy-mediated attenuation”. EMBO Reports, 15, 853-861. » Gräff J.*, Joseph N.F.*, Horn M.E., Meng J., Samiei A., Meng J., Seo J., Rei D., Bero A.W., Phan T.X., Wagner F., Holson E., Xu J., Sun J., Neve R.L., Mach R.H., Haggarty S.J., and L.-H. Tsai, 2014 “Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories”. » Gräff J., Kahn M., Samiei A., Gao J., Ota K.T., Rei D., and L.-H. Tsai, 2013 “A Dietary Regimen of Caloric Restriction or Pharmacological Activation of SIRT1 to Delay the Onset of Neurodegeneration”. Journal of Neuroscience, 33, 8951-60. » Gräff J., and L.-H.Tsai, 2013 “Histone acetylation: Molecular mnemonics on the chromatin”. Nature Reviews Neuroscience, 14, 97-111. » Gräff J., and L.-H.Tsai, 2013 “The potential of HDAC inhibitors as cognitive enhancers”. Annual Reviews of Pharmacology and Toxicology, 53, 311-330.

EPFL School of Life Sciences - 2014 Annual Report

Herzog Lab Michael Herzog

Associate Professor - Director of the Doctoral Program in Neuroscience (EDNE)

http://lpsy.epfl.ch/

Introduction

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.

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. For this reason, robots are still “object blind”. 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.

Keywords

Spatio-temporal vision (crowding, non-retinotopic processing, visual masking), perceptual and reinforcement learning, ageing & schizophrenia research.

Results Obtained in 2014

Crowding & Masking. In crowding, the perception of a target strongly deteriorates when flanked by neighboring elements. Crowding is usually explained by pooling models, which are well in the spirit of the hierarchical, feedforward model of object recognition. Neurons in higher visual areas, with larger receptive fields, pool information from lower level neurons. Because of pooling, features of the target and flanking elements are jumbled and so feature identification is lost at the earliest stages of processing. A prediction of these models is that crowding increases when flankers are added. We showed that, to the contrary, adding flankers can improve performance (Manassi et al., 2013) and that neural processing occurs in later, rather than early, visual areas (Chicherov, et al., 2014). Perceptual learning & individual differences. Perceptual learning is learning to perceive. Features that we have not learned to detect, will be blind to us. For example, only wine experts can differentiate between different types of grapes, an ability that usually needs years of training. One prediction of perceptual learning is that we all should see the world differently depending on what we have learned during our life time. However, we found no correlation in the performance of basic visual stimuli. The same person can be good in Gabor detection and inferior with Vernier acuity (Cappe et al., 2014). Decision Making. It is usually assumed that stimulus evidence drives a drift process towards one of two decision variables. We found that there is a silent evidence integration stage, which was overlooked previously. In collaboration with Wulfram Gerstner, we characterized these processes mathematically (Rüter et al., 2013).

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Céline Cappe Aaron Clarke Daniela Herzig Aire Raidvee Albulena Shaqiri

PhD Students Vitaly Chicherov Ophélie Favrod Lukasz Grzeczkowski Marc Lauffs Mauro Manassi Izabela Szumska Evelina Thunell

Master’s Student Adrien Doerig

Invited Professor Gregory Francis

Administrative Assistant Laure Dayer

Engineer Marc Repnow

BMI - Brain Mind Institute

In crowding, flankers deteriorate performance. Usually, target-flanker interactions are thought to occur early on. Using EEG and inverse solution techniques, we found that crowding is best reflected by processes in higher cortical areas including the lateral occipital cortex (with parietal and temporal overlap) and a smaller area on the medial surface (precuneus). From Chicherov et al., 2014.

Selected Publications » Bakanidze G., Roinishvili M., Chkonia E., Kitzrow W., Richter S., Neumann K., Herzog M.H., Brand A., Puls I. (2013). Association of the nicotinic receptor α7 subunit gene (CHRNA7) with schizophrenia and visual backward masking. Front. Psychiatry, 4:133. doi: 10.3389/fpsyt.2013.00133. » Cappe, C., Clarke, A., Mohr, C., Herzog M. H. (2014). Is there a common factor for vision? Journal of Vision. 14(8): 1—11. » Chicherov, V., Plomp, G., Herzog, M.H., (2014). Neural correlates of visual crowding. NeuroImage, 93, 23–31. » Manassi M., Sayim B., Herzog M.H. (2013). When crowding of crowding leads to uncrowding. Journal of Vision, 13(13):10. doi: 10.1167/13.13.10. » Rüter J., Sprekeler H., Gerstner W., Herzog M.H. (2013). The silent period of evidence integration in fast decision making. PLOS ONE, 8(1):e46525

EPFL School of Life Sciences - 2014 Annual Report

Lashuel Lab Hilal A. Lashuel

Associate Professor

http://lashuel-lab.epfl.ch

Introduction

Hilal A. Lashuel received his B.Sc. degree in chemistry from the City University of New York in 1994 and his PhD in bioorganic chemistry from Texas A&M University in 2000. In 2001, he moved to Harvard Medical School and the Brigham and Women’s Hospital as a research fellow in the Center for Neurologic Diseases where he was later promoted to an instructor in neurology. In 2005, Dr. Lashuel joined the Brain Mind Institute as a tenure track assistant professor and was promoted in 2011 to an associate professor. Currently, Dr. Lashuel is on sabbatical leave from EPFL, and serves as the executive director of the Qatar Biomedical Research Institute (QBRI) in Doha, Qatar.

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). Current research efforts cover the following topics: • Elucidating the sequence, molecular and cellular determinants underlying protein aggregation, propagation and toxicity; • developing innovative chemical approaches and novel tools to monitor and control protein folding, self-assembly and post-translation in vitro and in vivo with spatial and temporal resolution; • developing novel cellular and animal models of neurodegenerative diseases to validate novel therapeutic targets, and assess disease modifying strategies based on modulating protein aggregation and clearance.

Keywords

Chemical biology, protein folding, protein aggregation, post-translational modifications, protein synthesis, amyloid, phosphorylation, neurodegeneration, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease.

Results Obtained in 2014

Developing chemical and semisynthetic approaches to enable site-specific introduction of single and multiple post-translational modifications into α-syn. α-synuclein (α-syn) is subjected to several post-translational modifications (PTMs), including acetylation, nitration, phosphorylation and ubiquitylation. Towards understanding the mechanisms by which these modifications regulate α-syn function, aggregation, cellular properties and toxicity, our group has developed a combination of total chemical and semisynthetic strategies that enable for the first time the site-specific introduction of simple (phosphorylation and acetylation) and complex (mono-, di- and tetra-ubiquitin chains) PTMs into α-syn and the generation of these proteins in sufficient (mgs) quantities. In addition, our group has played important roles in identifying novel enzymes that regulate α-syn phosphorylation, including c-Abl and PLK2, thus providing important tools for assessing the roles of these modifications in cellular and animal models of Parkinson’s disease (PD). In fact, we found that whereas phosphorylation at S129 by PLK2 targets α-syn for degradation and attenuates toxicity,Y39 phosphorylation by c-Abl decreases α-syn degradation. These findings highlight the potential role of PTMs in regulating α-syn clearance, and suggest that these enzymes may constitute viable therapeutic targets for the treatment of PD. Elucidating the effect of post-translational modifications and polyQ-length on the structure, aggregation, localization and toxicity of Huntingtin. Increasing evidence suggests that the expanded polyQ (> 37Q) within the first exon of Huntingtin (Httex1) plays a central role in the pathogenesis of Huntington’s disease (HD). PTMs within the N-terminal residues of the Htt protein have been also shown to play critical roles in modulating the structure, aggregation, subcellular localization and toxicity of N-terminal fragments and full-length Htt protein. Our laboratory has developed and optimized for the first time several efficient strategies that enable the production of all known PTM Httex1 species site-specifically (semi-synthetic), or unmodified proteins with unexpanded and expanded polyQ-lengths. We are now working on determining the structure, conformation, aggregation properties, toxicity and subcellular localization of these proteins to better understand how Httex1 contributes to the molecular pathogenesis of HD.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Ritwik Burai Jean-Christoph Copin Sean Deguire Bruno Fauvet Mahmood Haj-Yahya Bohumil Maco Anne-Laure Mahul-Mellier Juan Reyes John Warner

PhD Students Nadine Ait-Bouziad Mohamed Bilal Fares Sophie Vieweg

Technical Staff Anass Chiki Nathalie Jordan Céline Vocat

Administrative Assistant Dorothée Demeester

BMI - Brain Mind Institute

Chemical protein synthesis for elucidating the role of α-synuclein post-translational modiﬁcations (nitration, ubiquitination and phosphorylation) in regulating α-synuclein function (neurotransmission) and its role in Lewy body formation and the pathogenesis of Parkinson’s disease.

Selected Publications » Ansaloni, A., Wang, ZM., Jeong, JS., Ruggeri, FS., Dietler, G., Lashuel, HA. (2014). One-pot semisynthesis of exon 1 of the Huntingtin protein: new tools for elucidating the role of posttranslational modifications in the pathogenesis of Huntington’s disease. Angew Chem Int Ed Engl. 53(7):1928-33. » Mahul-Mellier, AL., Fauvet, B., Gysbers, A., Dikiy, I., Oueslati, A., Georgeon, S., Lamontanara, AJ., Bisquertt, A., Eliezer, D., Masliah, E., Halliday, G., Hantschel, O., Lashuel, HA. (2013). c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum Mol Genet. 23(11):2858-79. » Fauvet, B., Butterfield, SM., Fuks, J., Brik, A., Lashuel HA. (2013). One-pot total chemical synthesis of human α-synuclein. Chem Commun. 49(81):9254-6. » Oueslati, A., Schneider, BL., Aebischer, P., Lashuel, HA. (2013). Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo. Proc Natl Acad Sci. 110(41):E3945-54. » Schmid, AW., Fauvet, B., Moniatte, M., Lashuel, HA. Alpha-synuclein post-translational modifications as potential biomarkers for Parkinson disease and other synucleinopathies. Mol Cell Proteomics. 12(12):3543-58. » Haj-Yahya, M., Fauvet, B., Herman-Bachinsky, Y., Hejjaoui, M., Bavikar, S.N., Karthikeyan, S.V., Ciechanover, A., Lashuel, H.A., and Brik, A. (2013). Synthetic polyubiquitinated alpha-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology. Proc Natl Acad Sci U S A 110, 17726-17731.

EPFL School of Life Sciences - 2014 Annual Report

Magistretti Lab Pierre Magistretti

Full Professor

http://lndc.epfl.ch/

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”.

Introduction

Results Obtained in 2014

The laboratory is also interested in imaging microscopic techniques that allow the visualization of dynamic cellular processes, including those involved in plasticity and neurodegeneration. We collaborate with the Advanced Photonics Laboratory at the STI Faculty, in the application of digital holographic microscopy (DHM) combined with fluorescence microscopy and other coherent imaging approaches.

We next explored the role of lactate in another form of synaptic plasticity, namely addiction. Disruption of astrocyte-derived lactate release in the basolateral amygdala of rats not only transiently impaired the acquisition of a cocaine-induced conditioned place preference, but also persistently disrupted an established conditioning. These findings reveal a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce drug seeking.

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. 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. These results are relevant to functional brain imaging as they have provided understanding of the signals detected by these imaging techniques activation of specific neuronal pathways. Another dimension 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, the sleep-wake cycle and addiction.

Keywords

Neuroenergetics, neuro-glia interaction, brain metabolism, neuronal and glial plasticity, high-resolution optical imaging, digital holographic microscopy, cell dynamics, neurodegeneration, sleep, psychiatric disorders.

The main focus of our work during the last two years has been to better 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. In collaboration with the group of Christina Alberini at NYU, we found that astrocyte-derived lactate was necessary for the establishment of long term memory as well as for the maintenance of long-term potentiation in vivo in rat (Suzuki et al, 2011). By further addressing its mechanism of action on neurons, we found that lactate has a direct stimulatory effect on the expression of plasticity-related genes (e.g. Arc, Zif268, BDNF), both in primary cortical neurons and in vivo (Yang et al. 2014). Biochemical and electrophysiological results showed that this effect is due to the potentiation by lactate of ionotropic NMDA receptor activity and the downstream Erk1/2 signaling cascade. These results provide insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived lactate in long-term memory and reveal a previously unidentified action of L-lactate as a signaling molecule for neuronal plasticity (see Figure).

Finally, we characterized the neuro-protective properties of lactate using Digital Holographic Microscopy, a new 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 ATP signaling on purinergic receptors.

EPFL School of Life Sciences - 2014 Annual Report

Team Members

Scientists Igor Allaman Pascal Jourdain Sylvain Lengacher (CTI) Jean-Marie Petit

Postdoctoral Fellows Maha Elsayed Charles Finsterwald (CTI) PhD Students Benjamin Boury-Jamot Monika Tadi Manuel Zenger

Technicians Cendrine Barrière Elena Gasparotto Evelyne Ruchti Trainee Nathalie Bigler Administrative Assistant Monica Navarro Suarez

Group Digital Holographic* Microscopy* Pierre Marquet

PhD Students* Keven Bourgeaux Kaspar Rothenfusser

Professor Emeritus* Christian Depeursinge

Technician* Sandra Borel

Scientist* Stéphane Chamot

BMI - Brain Mind Institute

Senior Scientist Gabriele Grenningloh

Astrocytic glycogen-derived lactate in synaptic plasticity processes. Following learning-dependent tasks, astrocytic glycogen is mobilized, leading to lactate transfer to neurons. Lactate potentiates NMDA receptor activity promoting expression of synaptic plasticity-related genes in neurons (NA-noradrenaline).

Selected Publications » » » »

Cotte Y, Toy F, Jourdain P, Pavillon N, Boss D, Magistretti P, Marquet P, Depeursinge C. Marker-free phase nanoscopy. Nat. Photonics. 2013; 7(2): 113-117. Magistretti PJ. Synaptic plasticity and the Warburg effect. Cell Metab. 2014;19(1):4-5. Marquet P, Depeursinge C, Magistretti PJ. Exploring neural cell dynamics with digital holographic microscopy. Annu Rev Biomed Eng. 2013;15:407-31. Perreten Lambert, H., Zenger, M., Azarias, G., Chatton, J.Y., Magistretti, P.J., Lengacher, S. Control of Mitochondrial pH by Uncoupling Protein 4 in Astrocytes Promotes Neuronal Survival. J Biol Chem. 2014;289(45):3101428. » Petit JM, Gyger J, Burlet-Godinot S, Fiumelli H, Martin JL, Magistretti PJ. Genes involved in the astrocyte-neuron lactate shuttle (ANLS) are specifically regulated in cortical astrocytes following sleep deprivation in mice. Sleep. 2013 ;36(10):1445-58. » Yang, J., Ruchti, E., Petit, J.M., Jourdain, P., Grenningloh, G., Allaman, I., Magistretti, P.J. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci U S A. 2014 Aug 19; 111(33):12228-33.

EPFL School of Life Sciences - 2014 Annual Report

Markram Lab Henry Markram

Full Professor - Director of the Blue Brain Project - BBP

http://markram-lab.epfl.ch

Introduction

Henry Markram is the Principal Investigator of the LNMC, Director of the Blue Brain Project and Co-Director of the FET flagship Human 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.

The Laboratory of Neural Microcircuitry (LNMC) is dedicated to understanding the structure, function and plasticity of the microcircitry of the neocortex. To investigate these neocortical microcircuits, LNMC makes use of state-of-the-art technologies including: multineuron and automated patchclamp, multielectrode arrays, 2-photon and ultramicroscopy, 3D reconstruction, high throughput, single neuron gene expression profiling (mRNAseq) and multiplex RTPCR, microfluidics and supercomputers. Transcriptomics of neuron populations and single cells - The aim of this research project is to correlate the electrical and structural properties of individual neurons with the genes they express. The Channelome project aims to characterize the biophysics of these ion channels in a controlled and consistent environment with an automated patch clamp setup. Neuroanatomy - Using 3D reconstructions of neurons in slices combined with immunohistochemistry and whole mount imaging of brains, our goal is to map the complete set of cortical neuron morphologies and the relative composition of cortical neuron subtypes. Electrophysiology & Microcircuits - We use up to 12 multipatch setups to study the individual neuronal properties and quantify the principles of local connectivity in these microcircuits. Plasticity - LNMC studies short and long term plasticity, occurring under different time scales ranging from few milliseconds to hours. Neuromodulation - the LNMC has engaged in a consortium (DDPDGENES) that aims to characterize the properties of dopaminergic (DA) cells across development and aging in both mouse and human tissue. Autism - The aim of our group is to address if neural microcircuitry hyperfunctioning is at the heart of the neuropathology of autism, as predicted by the Intense World Theory.

Keywords

Results Obtained in 2014

Recent results obtained by the Laboratory of Neural Microcircuitry were multiple and diversified. Our neuroanatomy team completed the reconstruction over 1000 neuron morphologies from the somatosensory cortex and we are expanding to other areas and also acquiring human neuronal morphologies. In the Channelome project we now have more than 120 stable cell lines expressing individual ion channels, which are ready for biophysical and/ or drug screening. Channelpedia (www.channelpedia.net), has been developed to systematically store and share the data generated by the Channelome project as an online resource. In the transcriptomics project, we have introduced a high-throughput protocol that enables us to obtain ~100 single cell transcriptional (SCT) profiles in one experiment. With this protocol we are currently generating SCT profiles from dopaminergic cells of the brain stem and cortical neurons in the mouse. With this data we can unravel the neuronal diversity in these two brain regions based on the gene expression of individual cells. To correlate this with the electrophysiological properties, we are adjusting our SCT protocol to work with cells harvested with patch clamp setups, such that the gene expression profile can be obtained from single cells after electrophysiological characterization. With this data we aim to build neuron models that reproduce the measured electrophysiological properties based on their expressions of relevant channels and receptors. The microcircuitry of Layer I of the somatosensory cortex was extensively described at the level of neurons, synapses and cellular morphologies. We have also published our study on the effects of extracellular electric activity and how neuronal activity gives rise to such extracellular signals, an example of successful collaboration between theoreticians and experimentalists of leading institutions, using numerous experimentally obtained measurements and morphological reconstructions and the power of novel supercomputers.

Neurons, synaptic plasticity, neural microcircuits, neuronal coding, patch clamp, signal integration, electrophysiology, single cell gene expression, ion channels, neuron morphology, modeling, autism. 38

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Ayah Khubieh Jean-Pierre Ghobril Monica Favre Technical Staff Deborah La Mendola Julie Meystre Mirjia Herzog

Trainees Dejan Jovandic Dimitri Christodoulou Karim Achouri Nittin Khanna Oh Hyeon Choung Quentin Herzig Valérie Tâche

Visiting Professor Giogio Innocenti

Administrative Assistant Christiane Debono

External Employee Michele Gigliano

BMI - Brain Mind Institute

Postdoctoral Fellows Emmanuelle Logette Jesper Ryge Kamila Markram Maurizio Pezzoli Ferdinando Michela Marani Olivier Hagens Rajnish Ranjan Rodrigo Perin Sara Gonzalez Andino Séverine Petitprez

Intra- and extracellular biophysics of individual neurons. (Top row) reconstructed and connected L4 (red) and L5 (green) pyramids and basket cells (blue). (Second row) Connection probability as a function of distance. (Bottom) Extracellular action potentials for the three neural types considered.

Selected Publications » Camacho S, Michlig S, de Senarclens-Bezençon C, Meylan J, Meystre J, Pezzoli M, Markram H, le Coutre J. (2015) Anti-Obesity and Anti-Hyperglycemic Effects of Cinnamaldehyde via altered Ghrelin Secretion and Functional impact on Food Intake and Gastric Emptying. Sci Rep. 2015 Jan 21;5:7919. » Pezzoli M, Elhamdani A, Camacho S, Meystre J, González SM, le Coutre J, Markram H. (2014) Dampened neural activity and abolition of epileptic-like activity in cortical slices by active ingredients of spices. Sci Rep. 4:6825. » Toledo-Rodriguez M, Markram H. (2014) Single-cell RT-PCR, a technique to decipher the electrical, anatomical, and genetic determinants of neuronal diversity. Methods Mol Biol. 1183:143-58. » Muralidhar S, Wang Y, Markram H. (2014) Synaptic and cellular organization of layer 1 of the developing rat somatosensory cortex. Front Neuroanat 7:52. » Perin R, Markram H. (2013) A computer-assisted multi-electrode patch-clamp system. J Vis Exp. (80):e50630. » Delattre V, La Mendola D, Meystre J, Markram H, Markram K. (2013) Nlgn4 knockout induces network hypo-excitability in juvenile mouse somatosensory cortex in vitro. Sci Rep. 3:2897. » Favre MR, Barkat TR, Lamendola D, Khazen G, Markram H, Markram K. General developmental health in the VPA-rat model of autism. (2013) Front Behav Neurosci. 7:88. » Reimann MW, Anastassiou CA, Perin R, Hill SL, Markram H, Koch C. (2013) A biophysically detailed model of neocortical local field potentials predicts the critical role of active membrane currents. Neuron. 79(2):375-90. » Loebel A, Le Bé JV, Richardson MJ, Markram H, Herz AV. (2013) Matched pre- and post-synaptic changes underlie synaptic plasticity over long time scales. J Neurosci. 33(15):6257-66.

EPFL School of Life Sciences - 2014 Annual Report

Petersen Lab Carl Petersen

Full Professor

http://lsens.epfl.ch/

Introduction

Carl Petersen studied physics as a bachelor student in Oxford (1989-1992). During his PhD supervised by Prof. Sir Michael Berridge in Cambridge (1992-1996) 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 (1999-2003), 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.

Carl Petersen joined the Brain Mind Institute of the Faculty of Life Science at the Ecole Polytechnique Federale de Lausanne (EPFL) in 2003, setting up the Laboratory of Sensory Processing to investigate the functional operation of neural circuits in mice during quantified behavior. The goal is to obtain a causal and mechanistic understanding of sensory perception and associative learning at the level of individual neurons and their synaptic interactions within the complex neural circuits of the mammalian brain. Our experiments focus primarily on tactile sensory perception in the mouse whisker sensorimotor system. To understand sensory processing at the level of individual neurons and their synaptic connections, we make electrophysiological recordings combined with imaging techniques and molecular interventions. These studies are carried out both in vitro and in vivo. We want to know how specific neuronal networks contribute to learning and processing of sensory information ultimately leading to behavioural decisions. We are currently working on several complementary areas of research: - 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 genetargeted mice.

Keywords

Sensory perception, motor control, sensorimotor integration, learning, neocortex, neural circuits, synaptic transmission, whole-cell membrane potential recording, optogenetics, two-photon microscopy.

Results Obtained in 2014

Research in the Laboratory of Sensory Processing during 2013-2014 contributed to three important areas of neuroscience: Neuromodulation of cortical function (Eggermann et al., 2014): Mice actively move their tactile whiskers to explore their immediate environment. During such periods of active sensing, there is a profound change in brain state. The pattern of neocortical activity changes from the slow, large-amplitude fluctuations observed during quiet wakefulness to a desynchronised state during whisking. Part of this state change is driven by the thalamus. Here, in addition, we report that acetylcholine (ACh) is released in the somatosensory neocortex during active whisker sensing and that the released acetylcholine hyperpolarises cortical membrane potential (Vm), thus contributing to blocking the slow cortical activity. Target-specific function of cortical projection neurons (Yamashita et al., 2013): Excitatory pyramidal neurons in the superficial layers of primary somatosensory can project to motor cortex or secondary somatosensory cortex. Yamashita et al. (2013) describe functional differences between these two types of projection neurons, finding that neurons projecting to motor cortex rapidly signal the onset of tactile sensory stimulation, whereas neurons projecting to secondary somatosensory cortex have slower but sustained activity during repetitive touch. Membrane potential correlates of sensory perception (Sachidhanandam et al., 2013): In this study we investigated cortical function in mice performing a simple goal-directed sensorimotor task. Mice had to lick a spout to obtain a reward in response to a detected whisker stimulus. Membrane potential recordings in primary somatosensory cortex revealed two components to the sensory response, an early initial response invariant to behavioural outcome and a later secondary depolarisation which was enhanced on hit trials.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Senior Scientist Sylvain Crochet PhD Students Matthieu Auffret Pierre Le Merre Semihcan Sermet Varun Sreenivasan Angeliki Vavladeli

Master’s Students Lucie Eberhard Achille Othenin-Girard Yifei Zhang

Technicians Eloïse Charrière Katia Galan

Administrative Assistant Severine Janot

BMI - Brain Mind Institute

Postdoctoral Fellows Emmanuel Eggermann Célia Gasselin Taro Kiritani Natalya Korogod Yves Kremer Alexandros Kyriakatos Damien Lapray Johannes Mayrhofer Aurélie Pala Shankar Sachidhanandam Tanya Sippy Takayuki Yamashita

Mice actively move their tactile whiskers to explore their environment. Eggermann et al. (2014) ﬁnd that acetylcholine (ACh) is released in the somatosensory neocortex during active whisker sensing and that the released acetylcholine blocks slow cortical membrane potential (Vm) ﬂuctuations.

Selected Publications » » » » » »

Eggermann, E., Kremer, Y., Crochet, S. and Petersen, C.C.H. (2014). Cholinergic signals in mouse barrel cortex during active whisker sensing. Cell Reports 9: 1654-1660. Petersen, C.C.H. (2014). Cortical control of whisker movement. Annu. Rev. Neurosci. 37: 183-203. Tomm, C., Avermann, M., Petersen, C.C.H., Gerstner, W. and Vogels, T.P. (2014). Connection-type specific biases make random network models consistent with cortical recordings. J. Neurophysiol. 112: 1801-1814. Yamashita, T., Pala, A., Pedrido, L., Kremer, Y., Welker, E. and Petersen, C.C.H. (2013). Membrane potential dynamics of neocortical projection neurons driving target-specific signals. Neuron 80: 1477-1490. Sachidhanandam, S., Sreenivasan, V., Kyriakatos, A., Kremer, Y. and Petersen, C.C.H. (2013). Membrane potential correlates of sensory perception in mouse barrel cortex. Nat. Neurosci. 16: 1671-1677. Petersen, C.C.H. and Crochet, S. (2013). Synaptic computation and sensory processing in neocortical layer 2/3. Neuron 78: 28-48.

EPFL School of Life Sciences - 2014 Annual Report

Sandi Lab Carmen Sandi

Full Professor - Director of Brain Mind Institute - BMI

http://lgc.epfl.ch

Introduction

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. 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. After 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 behavior. She has presided the European Brain and Behavior Society and is Editor-in-Chief of the journal Frontiers in Behavioral Neuroscience.

• 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, computer-based tests) and neuroimaging approaches.

Keywords

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

Results Obtained in 2014

Stress is a risk factor for the development of psychopathologies characterized by cognitive dysfunction and deregulated social behaviors. We have investigated mechanisms linked to the immediate impact of chronic stress and to the programming effects of exposure to early life adversity. We have identified two cell adhesion molecules, neuroligin-2 (NLGN-2) and nectin-3, in the hippocampus as critically implicated in behavioral and functional alterations induced by exposure to chronic stress. NLGN-2 is reduced by stress throughout the hippocampus; and viral-induced gene expression and pharmacological treatments targeting NLGN-2 confirm its role in sociability and aggression. Nectin-3 is reduced in the perisynaptic CA1, but not in the CA3, compartment and was found to be implicated in the effects of stress in social exploration, social recognition and a CA1-dependent cognitive task. We further identified NMDA-induced proteolytic processing of nectin-3 by matrix metalloproteinase-9 (MMP9) involved in nectin-3 cleavage and chronic stress-induced social and cognitive alterations. Early life stress is investigated in our laboratory through a rodent model of peripubertal stress-induced psychopathology that leads to increased emotionality, decreased sociability and pathological aggression. While the orbitofrontal cortex shows hypoactivation in social confrontations, the amygdala, particularly its central nucleus, is hyperactivated in this model, consistent with evidence implicating this nucleus in the regulation of social and aggressive behaviors. We have identified alterations in both brain areas in the gene expression of molecular markers of excitatory and inhibitory neurotransmission, as well as NLGN-2. Our findings highlight peripuberty as a period in which stress can lead to long-term programming of the genes involved in excitatory and inhibitory neurotransmission in brain regions that play a key role in the regulation of social, emotional and cognitive behaviors.

EPFL School of Life Sciences - 2014 Annual Report

Team Members Postdoctoral Fellows Alexandre Bacq Samuel Bendahan Fiona Hollis Thomas Larrieu Orbicia Riccio Wicht John Thoresen Michael van der Kooij Ioannis Zalachoras

PhD Students Damien Huzard Leyla Loued-Khenissi Laura Lozano Montes Aurélie Papilloud Alina Strasser Sophie Walker

Technicians Jocelyn Grosse Marie-Isabelle Guillot de Suduiraut Olivia Zanoletti

Master’s Students Victoire Gorden Jennifer Mackay Kévin Meng

Administrative Assistant Barbara Goumaz

Trainee Biology Lab Assistants Timothée Naegeli Elodie Schranz

BMI - Brain Mind Institute

Social exploration in two rats unfamiliar to each other. Exposure to early life stress or to chronic stress in adulthood reduces animals’ sociability, as evidenced by reduced interest in exploring conspeciﬁcs.

Selected Publications » van der Kooij, M.A., Fantin, M., Rejmak, E., Grosse, J., Zanoletti, O., Fournier, C., Ganguly, K., Kalita, K., Kaczmarek, L. and Sandi, C. (2014) Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations. Nat. Commun. 5:4995. » Tzanoulinou, S., Riccio, O., de Boer, M. and Sandi, C. (2014) Peripubertal stress-induced behavioral changes are associated with altered expression of genes involved in excitation and inhibition in the amygdala. Transl. Psychiatry, 4, e410. » van der Kooij, M.A., Fantin, M., Kraev, I., Korshunova, I., Grosse, J., Zanoletti, O., Guirado, R., Garcia-Mompó, C., Nacher, J., Stewart, M.G., Berezin, V. and Sandi, C. (2014) Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression. Neuropsychopharmacology 39(5):1148-1158. » Márquez, C., Poirier, G.L., Cordero, M.I., Larsen, M.H., Groner, A., Marquis, J., Magistretti, P.J., Trono, D. and Sandi, C. (2013) Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Transl. Psychiatry 3:e216. » Poirier, G.L., Imamura, N., Zanoletti, O. and Sandi, C. (2014) Social deficits induced by peripubertal stress in rats are reversed by resveratrol. J. Psychiatr. Res. 57:157-164. » Veenit, V., Riccio, O. and Sandi, C. (2014) CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors. J. Psychiatr. Res. 53:1-7. » Cordero, M.I., Ansermet, F. and Sandi, C. (2013) Long-term programming of enhanced aggression by peripuberty stress in female rats. Psychoneuroendocrinology, 38(11):2758-2769.

EPFL School of Life Sciences - 2014 Annual Report

Schneggenburger Lab Ralf Schneggenburger

Full Professor

http://lsym.epfl.ch/

Introduction

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 MaxPlanck 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.

The main interest of the lab lies in understanding the cellular and molecular mechanisms of neuronal communication at synapses. We investigate basic mechanisms of transmitter release and its short- and long-term plasticity, and we study signaling mechanisms which determine synapse connectivity and synapse function in neuronal circuits. This research aims to gain insight into neuronal network function, and it might help to understand the pathophysiology of neuropsychiatric and neurodevelopmental disorders, many of which represent diseases of the synapse.

Keywords

Synaptic transmission, nerve terminal, neurotransmitter, exocytosis, shortterm plasticity, synapse development, synapse connectivity.

Results Obtained in 2014

In 2013 and 2014, the lab has made important contributions to the understanding of molecular mechanisms underlying presynaptic plasticity, and the specific development of synapses in the brain. Post-tetanic potentiation (PTP) is a presynaptic plasticity caused by an increased transmitter release with a duration of about one minute. We could show that PTP is mediated by an activity-dependent phosphorylation of the presynaptic protein Munc18 by protein kinase-C (Genc et al., 2014). This discovery was made possible by developing a novel virus-mediated gene replacement strategy, which allowed us to replace the endogenous Munc18 protein with a phosphorylation-deficient mutant in vivo. Furthermore, we could show that de-phosphorylation of Munc18 leads to the termination of enhanced transmitter release. In the lower auditory system of the brain, large excitatory synapses like the calyx of Held form at specific points to mediate ultrafast synaptic transmission. The mechanisms guaranteeing the specific development of calyx synapses has however remained enigmatic. Using methods of cDNA-array analyses of gene expression, we first identified that BMPs were differentially expressed in the target area of calyces of Held, the medial nucleus of the trapezoid body (MNTB). Since BMPs were previously shown to play a role in neuromuscular synapse development in the fruit fly, we then used Cre-lox mediated conditional gene deletion in the auditory circuits, and found that in the absence of BMP-receptor genes, calyces of Held fail to undergo the characteristic mono-innervation of their target neurons. Instead, several smaller pre-calyceal nerve terminals innervate a given MNTB neuron (see Figure). This shows that BMP signaling is necessary for establishing correct synapse connectivity, and correct nerve terminal size in the mammalian brain. The cellular mechanisms of how BMPs act to instruct large synapse growth and the elimination of supernumerary synapses is currently under investigation.

EPFL School of Life Sciences - 2014 Annual Report

Team Members PhD Students Ozgür Genç Enida Gjoni Elin Kronander Wei Tang

Technicians Jessica Dupasquier Heather Murray

Master’s Student Aiste Baleisyte

Administrative Assistant Laure Dayer

BMI - Brain Mind Institute

Postdoctoral Fellows Norbert Babai Brice Bouhours Christopher Clark Michael Kintscher Olexiy Kochubey Evan Vickers

Ultrastructural reconstruction of single calyx of Held synapses in wild-type control mice (top; green structure represents the presynaptic nerve terminal), and in conditional BMP-receptor 1a/1b double-KO mice (bottom). Note the presence of several synaptic terminals in the KO mice, indicating that BMP signaling is both important for synapse elimination, and synapse growth. Taken, with permission, from Xiao et al., 2013.

Selected Publications » Babai N., Kochubey O., Keller D., Schneggenburger R. (2014). An alien divalent ion reveals a major role for Ca2+ buffering in controlling slow transmitter release. J Neurosci. 34:12622-12635. » Genç, O., Kochubey, O., Toonen, R.F., Verhage, M., and Schneggenburger, R. (2014) Munc18-1 is a dynamically regulated PKC target during short-term enhancement of transmitter release. Elife 2014 Feb 11;3: e01715. doi: 10.7554/eLife.01715. » Xiao L., Michalski N., Kronander E., Gjoni E., Genoud C., Knott G., Schneggenburger R. (2013) BMP-signaling specifies the development of a large and fast CNS synapse. Nat Neurosci.16:856-864. » Michalski N., Babai N., Renier N., Perkel D.J., Chédotal A., Schneggenburger R. (2013) Robo3-Driven Axon Midline Crossing Conditions Functional Maturation of a Large Commissural Synapse. Neuron 78: 855-868.

EPFL School of Life Sciences - 2014 Annual Report

Hill Lab Sean Hill

Adjunct Professor

http://hill-lab.epfl.ch

Research Interests

Sean Hill is co-Director of the Blue Brain Project and co-Director of Neuroinformatics in the European Union funded Human Brain Project (HBP). He also serves as the 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 Université 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.

The Hill Laboratory focuses on research in neural systems and neuroinformatics. Key research interests include the use of biologically-realistic models to study the role of emergent phenomena in information processing, as well as network connectivity and synaptic plasticity in the central nervous system, from the neocortical column to the whole brain, and across different arousal conditions including wakefulness and sleep. Other interests include computational approaches to neural tissue interfaces including simulated local field potentials (LFP), electroencephalography (EEG) and transcranial magnetic stimulation (TMS). Prof. Hill leads work on the Human Brain Project’s Neuroinformatics Platform: a collaborative platform for organizing, analysing and predicting neuroscience data including multi-scale brain atlases, machine learning, machine vision, data and text mining, cluster analysis and data-driven ontologies.

Keywords

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

Team Members In the hiring stage

Selected Publications » Richardet, R., Chappelier, J. C., Telefont, M., & Hill, S. (2015). Large-scale extraction of brain connectivity from the neuroscientific literature. Bioinformatics, btv025. » Reimann, M. W., Anastassiou, C. A., Perin, R., Hill, S. L., Markram, H., & Koch, C. (2013). A biophysically detailed model of neocortical local field potentials predicts the critical role of active membrane currents. Neuron. 79(2), 375-390. doi: 10.1016/j.neuron.2013.05.023 » S. Druckmann, S. Hill, F. Schürmann, H. Markram, and I. Segev, A Hierarchical Structure of Cortical Interneuron Electrical Diversity Revealed by Automated Statistical Analysis. Cerebral Cortex 23 (2013) 2994-3006. » J. DeFelipe, P.L. López-Cruz, R. Benavides-Piccione, C. Bielza, P. Larrañaga, S. Anderson, A. Burkhalter, B. Cauli, A. Fairén, D. Feldmeyer, G. Fishell, D. Fitzpatrick, T.F. Freund, G. González-Burgos, S. Hestrin, S. Hill, P.R. Hof, J. Huang, E.G. Jones, Y. Kawaguchi, Z. Kisvárday, Y. Kubota, D.A. Lewis, O. Marín, H. Markram, C.J. McBain, H.S. Meyer, H. Monyer, S.B. Nelson, K. Rockland, J. Rossier, J.L.R. Rubenstein, B. Rudy, M. Scanziani, G.M. Shepherd, C.C. Sherwood, » J.F. Staiger, G. Tamás, A. Thomson, Y. Wang, R. Yuste, and G.A. Ascoli, New insights into the classification and nomenclature of cortical GABAergic interneurons. Nature Reviews Neuroscience 14 (2013) 202-216. » Hill, S. L., Wang, Y., Riachi, I., Schurmann, F., & Markram, H. (2012). Statistical connectivity provides a sufficient foundation for specific functional connectivity in neocortical neural microcircuits. Proc Natl Acad Sci U S A, 109(42), E2885-2894. doi: 10.1073/pnas.1202128109

EPFL School of Life Sciences - 2014 Annual Report

Schürmann Lab Felix Schürmann

Adjunct Professor

http://schuermann-lab.epfl.ch

Research Interests

The Schürmann Laboratory focuses on research at the interface between in silico neuroscience and computer architectures to guide novel computing substrates.

In silico neuroscience, neurosimulation, high performance computing.

Team Members In the hiring stage

Modern in silico neuroscience can leverage the computational capabilities of some of the largest computers available to science. However, it also has its own special 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, the development of novel techniques for model building and visualization, and new ideas for brain-inspired computing substrates.

Selected Publications » F.Schürmann, F.Delalondre, P.S.Kumbhar, J.Biddiscombe, M.Gila, D.Tacchella, A.Curioni, B.Metzler, P.Morjan, J.Fenkes, M.M.Franceschini, R.S.Germain, L.Schneidenbach, T.J.C.Ward, B.G.Fitch: Rebasing I/O for Scientific Computing: Leveraging Storage Class Memory in an IBM BlueGene/Q Supercomputer. In J.M. Kunkel, T. Ludwig, and H.W. Meuer (Eds.): ISC 2014, LNCS 8488, pp. 331--347. Springer International Publishing Switzerland (2014). » E. Hay, F. Schürmann, H.Markram, , & I. Segev, (2013). Preserving axosomatic spiking features despite diverse dendritic morphology. J Neurophysiol, 109(12), 2972-2981. doi: 10.1152/jn.00048.2013. » S. Druckmann, S. Hill, F. Schürmann, H. Markram, and I. Segev, A Hierarchical Structure of Cortical Interneuron Electrical Diversity Revealed by Automated Statistical Analysis. Cerebral Cortex 23 (2013) 2994-3006. » Hill, S. L., Wang, Y., Riachi, I., Schürmann, F., & Markram, H. (2012). Statistical connectivity provides a sufficient foundation for specific functional connectivity in neocortical neural microcircuits. Proc Natl Acad Sci U S A, 109(42), E2885-2894. doi: 10.1073/pnas.1202128109.

BMI - Brain Mind Institute

Felix Schürmann is co-director of the Blue Brain Project and involved in several research challenges of the European Human Brain Project. He 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 master thesis to the simulation of quantum computing. He studied for 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.

Keywords

EPFL School of Life Sciences - 2014 Annual Report