IoN-ICM PhD & Post-Doc 2017 Workshop - Program · 2018-05-15 · IoN-ICM PhD & Post-Doc 2017...

IoN-ICM PhD & Post-Doc 2017 Workshop

Institute of Neurology, University College London

Queen Square, WC1N 3BG, London, United Kingdom

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IoN-ICM PhD & Post-Doc 2017 Workshop .............................................................................. 1

Detailed program ....................................................................................................................... 4

Wednesday 25th October ....................................................................................................... 4

Thursday 26th October ........................................................................................................... 7

Friday 27th October .............................................................................................................. 11

Workshops ............................................................................................................................... 14

Abstracts .................................................................................................................................. 16

PI talks ................................................................................................................................. 16

PhD and Post-doc Oral presentations .................................................................................. 25

Session 1 .......................................................................................................................... 25

Session 2 .......................................................................................................................... 33

Session 3 .......................................................................................................................... 35

Session 4 .......................................................................................................................... 39

Session 5 .......................................................................................................................... 45

Poster sessions ..................................................................................................................... 51

Session 1 .......................................................................................................................... 51

Session 2 .......................................................................................................................... 80

Session 3 ........................................................................................................................ 101

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Detailed program

Wednesday 25th October

ICM Presentation (11.30-12.30)

Talk1: Welcome - Lindsay JH Rondot & Lea R’Bibo

Talk2: General Presentation of ICM. Pr. Alexis Brice

Talk3: Research at the ICM. Dr. Alberto Bacci

PhD & Postdoc Talk Session 1 (14.00-15.30)

Talk1: Development of biofluid biomarkers for Huntington's disease. Lauren Byrne

Talk2: Spatacsin regulates calcium homeostasis and lysosome function. Maxime Boutry

Talk3: Hypoxia as a therapy for Friedreich’s ataxia. Gilbert Thomas-Black

Talk4: Deciphering the cellular and molecular events leading to a successful remyelination in

multiple sclerosis patients. Charles Sanson

Talk5: Investigation of the role of LRRK2 in monocytic cells. Iqra Nazish

Talk6: ON-OFF response of microglia to purinergic stimulation. Giampaolo Milior

Poster session 1 (14.30-16.25)

Poster1 - Investigating postzygotic de novo mutations and somatic mosaicism in

monozygotic twins discordant for complex disorders. Nirmal Vadgama

Poster2 - In vitro modelling of mitochondrial disease using human induced pluripotent stem

cell derived myotubes harbouring mtDNA mutations. Ben O’Callaghan

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Poster3 - Tracking Progression in Friedreich’s Ataxia (FRDA) to Establish Biomarkers for

Clinical Trials. Gilbert Thomas-Black

Poster4 - Specific Neuronal Vulnerability in SCA1 is Not Associated with CAG Instability

between Different Brain Regions. Heather Ging

Poster5 - High-dimensional inference on damaged human brain. Tianbo Xu

Poster6 - Focus on Dopamine. Stephanie Hirschbichler

Poster7 - Neurotrophins and the balance between retrograde signalling and autophagic flux

in the axon. Oscar Lazo

Poster8 - Spinal Cord Injury- Translational approach to treatments. Modinat Liadi

Poster9 - The involvement of the motor system in self-recognition. Matan Mazor

Poster10 - Movement Disorder genetics and the role of ageing. Sebastian Schreglmann

Poster11 - Multimodal analysis of primary progressive aphasia. Alexandre Routier

Poster12 - Assessing brain-behaviour relationship using mediation analyses. Jules Brochard

Poster13 - Investigation of the diversity of neurosecretory compounds released in the

cerebrospinal fluid by contacting neurons. Hugo Marnas

Poster14 - Vangl2, a core component of the Wnt Planar Cell Polarity pathway regulates

mammalian neuromuscular junction formation. Myriam Boex

Poster15 - Analysis of neuronal dysfunctions in a murine model of Hereditary Spastic

Paraplegia. Baptiste Wilmet

Poster16 - The battle for self-confidence: a tug-of-war between prospective gains and losses.

Emmanuelle Bioud

Poster17 - Modeling Macrophage Activation in Multiple Sclerosis Patients. Jennifer

Fransson

Poster18 - Study of the involvement of autophagy (in cell death of motor neurons) in ALS.

AM Negulescu

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Poster19 - Neuronal substrate of a complex behavioral transition. Thomas Topilko

Poster20 - Cellular resolution view of the transcriptional landscape of a developing eye.

Radolsaw Ejsmont

Poster 21 - Study of Gpr88 as a therapeutic target for the non-motor symptoms of

Parkinson’s disease. Benjamin Galet


Talk1: 3D Cerebral Organoids as in vitro Models for Alzheimer’s disease. Christopher

Lovejoy

Talk2: Role of spatacsin and its interactors in the metabolism of lysosomes: implication in

hereditary neurodegenerative diseases. Alexandre Pierga

Welcome to IoN (17:00-17:30) Pr. Nicholas Wood

Presentation will be followed by welcoming drinks and nibbles in the Old Board Room of the

National Hospital of Neurology and Neurosurgery (NHNN)

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Thursday 26th October

PI talks session 1 (09.00-10.30)

Talk1: Complete mapping of cellular brain activity and axonal projections by tissue clearing

and automated volume analysis. Nicolas Renier

Talk2: Using stem cells and light to restore function to paralysed muscles. Pr.Linda

Greensmith

Talk3: Facing others: Brain dynamics of the perception of faces and social facial cues.

Nathalie Georges


Talk1: Real gait and postural control modulate neuronal activity in the human subthalamic

nucleus. Antoine Collomb-Clerc

Talk2: Sensorimotor Processing in Post-Stroke Fatigue. William De Doncker

Talk3: REM sleep respiratory behaviours might reflect mental content through cortical

inputs in narcoleptic lucid dreamers. Delphine Oudiette

Talk4: Genetic Determinants of Impulse Control Disorders in Parkinson's disease. Richard

Rees

Workshop sessions (13.00-15.00)

Inherited ataxia. Suran Nethisinghe. 13:00-14:00 - 7QS Teaching Room

Super resolution microscopy. Janosch Heller. 13:00-14:00 and 14.00-15.00 - Meet in QSH

lobby

Introduction to principles and techniques of electrophysiology. Marisol Sampedro-

Castaneda and Gareth Morris. 13.00-13.45 - Meet in QSH lobby

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Electrophysiology practical demo. Marisol Sampedro-Castaneda 13:45-15:00 - Meet in

QSH lobby

A practical introduction to the fly model. Angelique Lamaze 13:30-15:00 - Meet in QSH

lobby

How to communicate/present to the public. Elodie Chabrol 14:00-15:00 - 33 QS LT

Poster session 2 (15.00-15.55)

Poster1 - TBC. Natalie Welsh

Poster2 - Rare variants associated with schizophrenia and bipolar disorder. Mariam Aleissa

Poster3 - Development of biofluid biomarkers for Huntington's Disease. Lauren Byrne

Poster4 - Modifiers of age:at:onset penetrance of LRRK2 G2019S Parkinson's Disease.

Emmeline Brown

Poster5 - Constructing confidence in the absence of feedback. Marion Rouault

Poster6 - Genetic modifiers of trinucleotide repeat diseases. Michael Flowers

Poster7 - Correlation between GAA expansion length and frataxin upregulation in

Friedreich’s ataxia. Sean McAteer

Poster8 - Identifying early ALS pathology in a mouse model. Alan Maza

Poster 9 - Nanoscopy of tripartite synapses. Janosch Heller

Poster10 - A neuronal circuit linking temperature to day sleep onset. Angelique Lamaze

Poster11 - Identification of novel pathogenic mechanisms involved in mTOR:related

epilepsy. Alexandre Bacq

Poster12 – TBD. Stephanie Jouannet

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Poster13 - Learning distributions of shape trajectories: a hierarchical model on a manifold of

diffeomorphisms. Alexandre Bone

Poster14 - Molecular profiling of DCN neuronal circuit development. Iryna Mohylyak

Poster15 - Mechanisms of neuronal death in Parkinson’s disease: impact of Parkin deficiency

on the mitochondrial stress response. Emeline Hamon

Poster16 - GABAA receptor diversity and dendritic inhibition from neocortical interneurons.

Cristina Donato

Poster17 - Synaptic changes upon removal of extracellular perineuronal nets in adult visual

cortex. Giulia Faini

Poster18 - Looking for predictors in MI:based BCI. Marie-Constance Corsi

Poster19 - Characterization of the endosomal compartment in Alzheimer’s disease. Laura

Xicota

Poster20 - The neuroinflammatory components in C9:FTD/ALS. Julie Smeyers


Talk1: Motivational control of decision making. Doug Lee.

Talk2: The genetic architecture of dementia with Lewy bodies. Tatiana Orme

Talk3: Infusion of incidental affect on consumption experiences. Aiqing Ling

Talk4: Decision making in the human motor cortex and impulsivity in Parkinson's disease.

Vishal Rawji

Talk5: Reticulospinal connectivity map and speed control. Martin Cabo Tano

Talk6: Seeing the bigger picture: visual art, the social brain and dementia. Janneke van

Leeuwen

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PI talks Session 3 (17:30-18:30)

Talk1: Mitophagy modulation as a potential therapeutic target for neurodegenerative

diseases. Dr. Helene Plun-Favreau

Talk2: Social cognition: humans, primates and machines. Jean Daunizeau

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Friday 27th October

PI Talks session 4 (09:30-11:00)

Talk1: Insights into the Molecular Basis of Huntington’s Disease. Pr.Gill Bates

Talk2: Functional and neurophysiological basis of pathological repetitive behaviors. Dr. Eric

Burguiere

Talk3: Human stem cell models of tauopathy. Dr.Selina Wray

Poster Session 3 (11.00-11.55)

Poster1 - Apolipoprotein E is necessary for plaque-‐associated synapse loss in a transgenic

mouse model of Alzheimer’s disease. Claudia Cannavo

Poster2 - A longitudinal Biomarker, Imaging and Psychometric Study of mild Traumatic

Brain Injury (Concussion) in sports. Etienne Laverse (TBC).

Poster3 - Microglial exosome secretion coupled to TREM2. Anna Mallach (TBC)

Poster4 - A new rodent model of social exclusion in depression. Anna Fall (TBC)

Poster5 - Modelization of intrinsic motor neuron defects in Amyotrophic Lateral Sclerosis

with human induced pluripotent stem cells. Cynthia Lefebvre

Poster6 - Investigating the physiological function of APP in Drosophila Melanogaster and its

relevance to Alzheimer’s disease. Irini A. Kessissoglou

Poster7 - Spg11 knockout mouse, a model of slowly progressive Amyotrophic Lateral

Sclerosis with juvenile onset. Julien Branchu

Poster8 - The vmPFC signal: a common neural currency for reward, effort and confidence.

Nicolas Clairis

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Poster9 - Multilevel Modeling for Classification from Imaging Genetics data. Pascal Lu

Poster10 - Chd7 and Chd8 chromatin remodelers cooperate to induce oligodendrocyte

precursor differentiation and survival. Corentine Marie

Poster11 - How do perineuronal nets control glutamatergic synaptic transmission and

influence the plasticity rules in parvalbumin interneurons in adult visual cortex ?. Lucie

Gallet

Poster12 - Identification and functions of a novel mutation in PRKCA in Chordoid Gliomas.

Bertille Bance

Poster13 - Identification of new biomarkers in status epilepticus. Aurélie Hanin

Poster14 - C9ORF72 insufficiency leads to FTD-like anomalies without motor neuron

disease. Morwena Latouche

Poster15 - TBD. Rozier Camille

Poster 16 - Assessing the specific impact of REM sleep onto memory consolidation and

problem solving. Célia Lacaux

Poster 17 - Self in the other: social contact enhances bodily self-awareness. Nesrine Hazem

Poster 18 - Yet Another ADNI Machine Learning Paper? Paving The Way Towards

Fully:reproducible Research on Classification of Alzheimer’s Disease. Jorger Samper-

Gonzales

Poster 19 - Exponential random graph model for brain networks. Catalina Obando

Poster 20 - Physiopathology of autoimmune encephalopathy linked to anti:LGI1 antibodies.

Paul Baudin

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PhD Talk Session 5 (12.00-13.00)

Talk1: Biomarkers in Spinocerebellar Ataxia Type-3/Machado-Joseph Disease. Hector

Garcia-Moreno

Talk2: A comparison of simultaneous and sequential binary bi-dimensional decision making.

Chen Hu

Talk3: Investigation of brain mosaicism due to somatic mutations in sporadic parkinson’s

disease. Melissa Salazar

Talk4: Predictive models for Parkinson’s Disease. Raphael Couronne

Conclusion and Farewell (13.00-13.30). Pr. Michael Hannah

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Workshops

Inherited ataxia . Suran Nethisinghe 13:00-14:00

Hereditary ataxias are a group of genetic disorders characterised by a slowly progressive

incoordination of gait. Research interest into inherited ataxias has grown in recent years, with

the identification of many of the genes responsible alongside natural history studies helping

in refining the clinical definition of the ‘ADCA and ARCA’ pathologies. This workshop aims

at presenting the state of research surrounding inherited ataxias and at prompting discussions

around the difficulties and potential solutions in studying repeat disorders. 

Super resolution microscopy - Janosch Heller. 13:00-14:00 and 14.00-15.00 (2 sessions)

The interaction of proteins in pre- and post-synaptic elements happens on the nanoscale

which is not resolvable with conventional light microscopy techniques. Therefore, super-

resolution microscopy (2004 Nobel prize) has gotten much interest recently and provided

novel insight into the nano-world of synapses. During the workshop, I could show a small

group of people how single molecule localisation microscopy is performed. I could give a

short presentation on the history of super-resolution microscopy and its different methods,

followed by a presentation of some imaging and image reconstruction.

Introduction to principles and techniques for electrophysiology. Marisol Sampedro-

Castaneda and Gareth Morris 13:00-13:40

This workshop will provide an overview of electrophysiological techniques, focusing on the

practical applications and questions that we can answer with each one.

Electrophysiology practical demo. Marisol Sampedro-Castaneda 13:45-15:00

Marisol will demonstrate her work on the functional characterization of ion channel mutants

in neurological and neuromuscular diseases and its importance in genetic diagnostics and

counselling. Specifically she will take participants through two electrode voltage clamp

recordings in xenopus oocytes from prep to analysis.

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A practical introduction to the fly model. Angelique Lamaze 13:30-15:00

In this workshop, I will present a history of the model, a general presentation of the

behavioural output we are using in the lab, which is sleep. Students will learn the basic of fly

genetic (recognition of female vs male and the most common markers and genetic tools

used), and a bit of brain dissection (larvae and adult).

How to communicate/present to the public. Elodie Chabrol 14:00-15:00

You have to give a talk but you’re lost… General public is a exciting audience but it can be

scary because it’s not usual, I’ll give you tips to make a great presentation directed at the

public without stress!

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Abstracts

PI talks Inhibitory control of cortical microcircuits

Alberto Bacci

ICM - Institut du Cerveau et de la Moelle épinière; CNRS UMR 7225 - Inserm U1127 - UPMC-P6 UMR S

1127; 75013 Paris, France

In the mammalian neocortex, inhibitory interneurons encompass a vast number of cell

subclasses, and this rich diversity results in an efficient division of labor within neuronal

circuits that governs virtually all forms of cortical activity. Some interneuron types control

principal neuron (PN) dendritic integration of distal excitatory inputs, whereas perisomatic

targeting interneurons control PN output and synchronize them during network oscillations

underlying several cognitive functions. In this presentation, I will focus on perisomatic-

targeting, parvalbumin (PV)-expressing basket cells. I will describe: i) their connectivity

patterns within cortical circuits; ii) their role in organizing the information transfer across

cortical networks during the emergence of γ-oscillations, and iii) the mechanisms and

functional roles of a specific form of long-term plasticity of their GABAergic inhibitory

synapses.

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Complete mapping of cellular brain activity and axonal projections by tissue clearing

and automated volume analysis

Nicolas Renier1

1 Laboratory of Neuronal Network Dynamics, The Brain and Spine Institute, Hôpital de la Pitié Salpétrière

75013 Paris, France

Understanding how neural information is processed in physiological and pathological states

would benefit from a precise detection, localization and quantification of the activity of all

neurons across the entire intact brain, which has not to date been achieved in the mammalian

brain. We introduce a pipeline for high speed acquisition of brain activity at cellular

resolution through profiling immediate early gene expression using immunostaining and

light-sheet fluorescence imaging, followed by automated mapping and analysis of activity by

open-source software. We validated the pipeline first by comprehensive analysis of

pharmacologically-activated brain regions. We are now combining activity mapping with

axon tracing to uncover new brain regions differentially activated during parenting behaviors,

and even to map synaptic densities in various brain regions. We hope to be able with these

tools to uncover consequences of large-scale plastic events affecting brain connectivity in

adult animals.

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Using stem cells and light to restore function to paralysed muscles

Barney Bryson and Linda Greensmith

Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square

Accurate control of muscle function is essential for human behaviour and survival. Thus

impairment of motor function and muscle paralysis can severely impact quality of life and

may even be life-threatening, as occurs in many cases of traumatic spinal cord injury (SCI)

and in patients with Amyotrophic Lateral Sclerosis (ALS). To date, efforts to induce

regeneration of trauma-induced lesions within the CNS that affect motor function have been

unsuccessful, and there are no therapies that can delay or reverse the progressive motor

neuron degeneration that occurs in ALS, which ultimately results in death. Therefore

alternative strategies are being studied to artificially restore function to specific muscle

groups to enable essential motor tasks.

We have recently shown that engraftment of embryonic stem cell-derived motor neurons

(ESC-MNs) into injured peripheral nerves of mice can functionally reinnervate paralysed

muscles. Importantly, the expression of channelrhodopsin-2 (ChR2) enables these ESC-MNs

to confer finely-controlled muscle contraction using optogenetic stimulation. We now also

have evidence that that these ESC-MNs can survive in mice that model ALS and can

innervate muscles in vivo in these ALS mice, even up until late-stage disease.

Currently, we are continuing the development of this novel therapeutic strategy to overcome

paralysis, including the combined use of a sophisticated implantable optical stimulator, as

well as fully evaluating its translational potential for patients. By using an implanted optical

pacemaker one application of this technique would be to restore function to hand muscles, or

even the diaphragm in ALS patients suffering from respiratory insufficiency, thereby

enabling them to breathe without a mechanical ventilator. Ultimately, the ability of this novel

biological interface to control complex motor functions such as hand movement is limited

only by the sophistication of the optical control device.

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Facing others: Brain dynamics of the perception of faces and social facial cues.

Nathalie GEORGE

Institut du Cerveau et de la Moelle épinière, ICM, CNRS UMR 7225 - Inserm U1127 - UPMC-P6 UMR S 1127,

75013 Paris, France

Faces are very rich social stimuli that convey paramount information on the identity, the

direction of attention, and the emotion of others. How does the human brain process this rich

and multiple information? There has been increasing interest in the dynamics of the

processing of social cues conveyed by faces (such as gaze and emotion) over the recent years.

I will review some of the findings in this domain, which are based on electromagnetic

imaging methods.

Magnetoencephalography (MEG) and electroencephalography (EEG) are unique tools to

study complex cognitive functions because they allow investigating the unfolding in time of

information processing and integration. I will review a series of MEG and EEG studies that

we have performed to investigate the spatiotemporal dynamics of the processing of faces and

social facial cues. These studies highlight the exquisite sensitivity of the human brain to

social signals conveyed by faces.

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Mitophagy modulation as a potential therapeutic target for neurodegenerative diseases

Dr Helene Plun-Favreau

Molecular Neuroscience department

Institute of Neurology, UCL

The selective autophagy of damaged mitochondria (mitophagy) is critical for cell survival as

it maintains optimal cellular energy production whilst avoiding the toxic accumulation of

damaged mitochondria. Important information about the control of mitophagy has come from

the study of the genes associated with autosomal recessive Parkinson’s disease (PD). Like

other neurodegenerative disorders, PD is progressive, devastating and incurable. While

studies of both sporadic and genetic cases of PD show that mitochondrial dysfunction is an

important feature of pathogenesis, much of what is known about the disease process, in

particular mitophagy, comes from the study of the rare genetic forms of the disease. Of

particular interest, PINK1 (mitochondrial kinase) and Parkin (E3-ubiquitin ligase) have been

found to play crucial roles in mitophagy. PINK1 accumulates selectively at the surface of the

damaged/depolarised mitochondria where it phosphorylates ubiquitin and activates Parkin,

recruiting autophagy receptors and triggering the engulfment of damaged mitochondria in

autophagosomes, and further fusion with lysosomes. PD-causing mutations in PINK1 and

Parkin disrupt mitophagy, emphasising the importance of mitochondrial dysfunction in PD

pathogenesis. We have developed a wide range of tools and methods to detect mitophagy in

induced pluripotent stem cells (iPSC)-derived neurons and we have optimised some high

content screening platforms in order to identify genes and compounds that are able to

modulate mitophagy. Our ultimate aim is to understand further the mitophagy process in

human neurons and identify compounds that can modulate mitophagy. Upregulating

mitophagy and restoring a functional mitochondrial pool, with consequent recovery of

neuronal function, may represent a feasible strategy for disease modifying therapy.

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Social cognition: humans, primates and machines

Daunizeau J.

ICM (Paris, France).

A defining feature of human social cognition is our insight that others' behaviour is driven by

their beliefs and preferences, rather than by what is objectively true or good for them. In fact,

a great deal of our social interactions is concerned with guessing others' mental states. But

what are the specific computational processes underlying human "mentalizing", if any? Can

we find traces of these processes in brain activity? Do they change over the lifespan? Does

their adaptive fitness depend upon the type of social interactions (e.g., competitive versus

cooperative) agents engage in? Can one infer on the candidate evolutionary forces that acted

upon mentalizing by comparing its sophistication across different (here: seven) primate

species? How does this relate to the specific "cognitive style" of people suffering from autism

spectrum disorders? These are the questions we address in this work, by combining

computational modelling with experimental investigations of mentalizing in dyadic games.

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Insights into the Molecular Basis of Huntington’s Disease

Professor Gill Bates

Sobell Department of Motor Neuroscience, Institute of Neurology, UCL

Huntington’s disease (HD) is an inherited neurodegenerative disorder with a mean age of

onset of 40 years of age that manifests with movement disorders, psychiatric symptoms and

cognitive decline. The disease is caused by a CAG/polyglutamine repeat expansion in exon 1

of a large gene (HTT) containing 67 exons. Expansions of ≥ 40 CAGs are fully penetrant and

of approximately ≥ 65 CAGs cause the juvenile form of the disease with childhood or

adolescent onset. The CAG repeat expansion is unstable and the length increases in certain

brain regions with age. We have developed a wide range of complementary mouse models

and used these to uncover molecular events triggered by the HD mutation. We have found

that incomplete splicing of the HTT gene leads to the production of a highly aggregation-

prone and pathogenic exon 1 huntingtin protein. Strategies to uncover the extent to which this

contributes to disease pathogenesis are in progress.

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Functional and neurophysiological basis of pathological repetitive behaviors

Eric Burguière

Institut du Cerveau et de la Möelle épinère (ICM), Paris

Increasing evidence points to abnormalities in cortico-basal ganglia circuitry as central to the

pathophysiology of disorder characterized by repetitive behaviors, such as Tourette syndrome

or Obsessive compulsive disorder. Functional origins of such dysfunctional behaviors could

be diverse, such as deficit in behavioral inhibition, flexibility or uncertainty monitoring. I will

present our comprehensive approach in animal models that aim at studying these different

cognitive functions, and their related neurophysiological substrates.

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Human stem cell models of tauopathy

Dr. Selina Wray



The development of human induced pluripotent stem cells (iPSC) and their subsequent

differentiation into neurons has provided new opportunities for the generation of

physiologically-relevent in vitro disease models. Despite the advantages they offer to create

"disease in a dish" models of tauopathy, there are several challenges associated with their use,

particularly the fact that aspects of tau biology such as phosphorylation and splicing are

subject to developmental regulation. I will discuss our finding that the developmental

regulation of tau splicing is conserved in iPSC-neurons, but disrupted by FTD-associated

splicing mutations in MAPT. The developmental phosphorylation of tau is also conserved in

our model, and I will discuss our progress using long-term neuronal cultures to understand

the earliest pathological changes to tau in cells from patients with mutations in MAPT, APP

and PSEN1 in 2D and 3D cultures.

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PhD and Post-doc Oral presentations

Session 1

Development of biofluid biomarkers for Huntington's Disease

Lauren Byrne

Neurodegenerative Diseases


Background

Blood biomarkers of neuronal damage could facilitate clinical management of and

therapeutic development for Huntington's disease (HD). We investigated whether

neurofilament light protein (NfL) in blood is a potential prognostic marker of

neurodegeneration in patients with Huntington's disease.

Methods

In the 3-year, 298-participant TRACK-HD cohort, we did a retrospective analysis of the

relationship between plasma NfL and clinical and neuroimaging measures previously

identified as being the strongest predictors of HD progression. Cross-sectional and

longitudinal relationships were analysed using random effect models of within-subject

correlation. In a separate 37-participant cohort we quantified NfL in cerebrospinal fluid

(CSF) and plasma.

Results

Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation

carriers than in controls (3.63 [SD 0.54] log pg/mL vs 2.68 [0.52] log pg/mL, p<0.0001) and

the difference increased with disease stage. At any given timepoint, plasma NfL correlated

with clinical and MRI findings. In longitudinal analyses, baseline plasma NfL also correlated

significantly with subsequent decline in cognition (SDMT r=–0.374, p<0.0001; SWR r=–

0.248, p=0.0033), TFC (r=–0.289, p=0.0264), and brain atrophy (caudate r=0.178, p=0.0087;

whole-brain r=0.602, p<0.0001; grey matter r=0.518, p<0.0001; white matter r=0.588,

p<0.0001; and ventricular expansion r=–0.589, p<0.0001). All changes except SWR and TFC

remained significant after adjustment for age and CAG repeat count. In premanifest HD

individuals, plasma NfL at baseline was associated with subsequent clinical onset during the

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3-year follow-up period (hazard ratio 3.29 per log pg/mL, 95% CI 1.48–7.34, p=0·0036).

Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0.868,

p<0.0001).

Interpretation

NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and

progression in Huntington's disease.

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Spatacsin regulates calcium homeostasis and lysosome function

Maxime Boutry1-5, Raphaël Matusiak1-4, Julien Branchu1-4, Yoan Ibrahim1-4, Khalid Hamid El

Hachimi1-5, Alexis Brice1-4, Giovanni Stevanin1-6, Frédéric Darios1-4

1: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France. 2: Inserm, U1127, F-

75013, Paris, France. 3: CNRS, UMR 7225, F-75013, Paris, France. 4: Institut du Cerveau et de la Moelle

épinière, ICM, F-75013, Paris, France. 5: Ecole Pratique des Hautes Etudes, PSL Research University,

Laboratoire de Neurogénétique, F-75013, Paris, France. 6: Centre de référence de Neurogénétique, Fédération

de génétique, APHP, La Pitié-Salpêtrière Hospital, F-75013, Paris, France

Abstract: Mutations in SPG11 account for the most common form of autosomal recessive

hereditary spastic paraplegia (HSP), characterized by a gait disorder and cognitive

impairment associated with various brain alterations. Mutations in the same gene are

involved in rare forms of amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease.

Experiments in cellular models have shown that loss of spatacsin, the protein encoded by

SPG11, impairs the recycling of lysosomal membrane after autophagy and leads to

accumulation of autolysosomes. In the lab, we have generated a Spg11 knockout mouse

model that recapitulates the main features of the human pathology. Loss of spatacsin cause

lipids accumulation in lysosomes, but the physiopathological mechanisms are unknown. An

electron microscopy analysis on cortex of 2 month-old mice showed that beside accumulation

of lipids in lysosomes, the number and size of contacts between endoplasmic reticulum and

plasma membrane were increased in Spg11-/- animal. These contacts are involved in

extracellular calcium import by a mechanism called Store-Operated Calcium Entry (SOCE).

Using mouse embryonic fibroblast (MEFs), we showed that import of calcium by SOCE was

increased in Spg11-/- cells and it was responsible for a rise in cytosolic calcium concentration.

Lysosomal calcium concentration was also upregulated and this could be caused by a weaker

calcium release by lysosomal calcium channels. We also showed that alteration of calcium

homeostasis in Spg11-/- cells was responsible for accumulation of cholesterol in lysosomes,

consistent with the accumulation of lipids we previously demonstrated. Interestingly,

alteration of lysosomal membrane recycling and accumulation of autolysosomes observed in

absence of spatacsin were rescued by reducing extracellular calcium import by SOCE. Our

results therefore support that spatacsin regulates lysosome function through an action on

calcium homeostasis.

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Hypoxia as a therapy for Friedreich’s ataxia

Gilbert Thomas-Black



Friedreich’s Ataxia (FRDA) is the commonest inherited ataxia (3 per 100,000). A GAA

repeat expansion in intron 1 of the gene encoding frataxin decreases its expression, and leads

to progressive cellular mitochondrial dysfunction, and thence to sensory and cerebellar

ataxia, skeletal muscle weakness, cardiac failure and premature death. No effective therapy

exists. However, motor function was recently witnessed to improve remarkably in a FRDA

patient upon ascent above 3500m, where the partial pressure of oxygen is significantly lower.

This might be explained by the fact that frataxin gene expression in the normal gene appears

induced by HIF-1α, the cellular master transcriptional regulator of the hypoxic response. We

aim to confirm whether this is true in FRDA patients, and whether this effect can be

replicated by use of a drug class (the PHD inhibitors) which upregulates HIF1α expression.

To do so, we will expose the peripheral blood mononuclear cells and fibroblasts of FRDA

patients to hypoxia, and to a PDH inhibitor (available for human use). We have investigate

the effects on frataxin in relevant organs by exposing WT mice to prolonged hypoxia and

determined whether hypoxic exposure induces frataxin expression in normal human skeletal

muscle in vivo. Subsequent to these analyses, we will use live confocal microscopy and

cellular respiratory control to determine whether up regulation of HIF-1α can rescue

mitochondrial function in patient derived fibroblasts.

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Deciphering the cellular and molecular events leading to a successful remyelination in

multiple sclerosis patients

C. Sanson1, M. El Behi 1, J. Fransson 1, C. Bachelin 1, L. Guillot-Noël 1, V. Damotte1, V. Guillemot 1,

H. Abdi 3, I. Cournu-Rebeix 1, B. Fontaine 1-2, V. Zujovic 1.

1- Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital,

75013 Paris, France. 2- Assistance Publique-Hôpitaux de Paris, Neurology Department Pitié Salpétrière

University Hospital. 3- School of Brain and Behavioral Sciences, the University of Texas, Dallas.

Inflammation in the central nervous system leads to demyelination and neurodegeneration in

patients with multiple sclerosis (MS). While the etiology of the disease is not known, genetic

studies have highlighted 110 genetic variants responsible for MS susceptibility. The processes responsible for the spectrum of disease severity are not well understood.

However, the severity of MS is closely correlated with the efficacy of myelin repair, or

remyelination, a process whose effectiveness is very heterogeneous among patients. Why

remyelination fails or succeeds in patients remains largely unknown, mainly because this

process has never been addressed in a humanized pathological context. To tackle this

question, we developed a new model combining focal demyelination in nude mice and graft

of MS or healthy donor (HD) lymphocytes (LT). We were able to reproduce at least partially

remyelination heterogeneity, with some patients LT inducing a defect in remyelination and

some others inducing a myelin repair comparable to HD. Comparing the secretory profile of

patient LT according to their repair capacities, we highlighted an heterogeneous cytokine

response to the same stimulus, leading to a differential microglial activation and ultimately an

efficient or inefficient differentiation of precursor cells during remyelination. To decipher why LT from patients have differential abilities to respond to a stimulus, we

hypothesized that the genetic variants known for MS susceptibility could also drive disease

severity by influencing LT functions and therefore remyelination. We found that the

interaction of variants associated with genes responsible for T Folicular Helper and naïve Th0

cells functions induce the secretion by patient LT of a secretory profile inducing a pro-

inflammatory activation in microglia, leading to remyelination failure. Overall, we discovered a new role for LT in remyelination: they orchestrate MIG activation

and are therefore at least partially responsible for the success or failure of the myelin repair

process. Capitalizing on patients with high repair capacities to understand the cellular and

molecular actors leading to successful remyelination in pathological conditions seem to be a

key approach to develop therapeutical targets.

30

Investigation of the role of LRRK2 in monocytic cells

Iqra Nazish Reta Lila Weston Institute of neurological Studies


Background: Mutations in the LRRK2 gene are commonly linked to familial Parkinson’s

disease (PD) and LRRK2 risk variants are also associated with idiopathic PD. LRRK2 is also

linked to cancer, leprosy and Crohn’s disease. LRRK2 protein harbours active GTPase and

kinase activities and is expressed variably in several cell types with higher levels observed in

immune cells. How LRRK2 dysfunction causes PD remains ambiguous.

Aims: To establish a link between LRRK2 dysfunction and signalling mechanisms in

RAW264.7 and T1348N cells and the pathological processes in PD.

Methods: Using RAW264.7 and T1348N cells, we tested LRRK2 phosphorylation dynamics

following treatment with LPS, paraquat, hydrogen-peroxide and also after inhibition of

LRRK2 kinase activity using GNE-7915. LRRK2 phosphorylation at different phospho-sites

was monitored using immunoblotting with specific antibodies. Statistical significance was

analysed using ANOVA and t-test using Graph-PAD prism.

Results: We observed significant upregulation of LRRK2 phosphorylated at Ser935 (and not

Ser910) with LPS treatment from 2hr-24hr time points. A dose dependent increase of

phosphorylation of LRRK2-Ser935 was observed after treatment with LPS and paraquat.

Treatment with paraquat only showed downregulation of LRRK2 levels. Treatment with

hydrogen peroxide (0.2-0.6mM) for 1 and 3hrs did not alter the phosphorylation levels of

LRRK2-Ser935. GNE-7915 downregulated phosphorylation which was reversed significantly

when treated with LPS.

Conclusion: 1) LPS stimulates phosphorylation of LRRK2 in RAW264.7 cells. 2) Treatment

of RAW264.7 cells with LPS and paraquat induced LRRK2 phosphorylation even further

whilst treatment with PQ only decreased LRRK2 levels. 3) GNE-7915 downregulated

phosphorylation in RAW264.7 cells which was reversed significantly when treated with LPS.

31

Future work: Results following the inhibition of LRRK2 kinase activity using GNE-9605 are

currently being analysed and LRRK2 dysfunction and signalling mechanisms in another cell

line, LRRK2 K.O., is currently being investigated.

32

ON-OFF responses of microglia to purinergic stimulation

Giampaolo Milior1, Farah Chali 1, Etienne Savary1, Caroline Le Duigou1, Vincent Navarro 3, Bertrand

Mathon 3, Johan Pallud 2 Stéphane Clemenceau 3, Mélanie Morin-Brureau1 & Richard Miles1 Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMR S1127, Institut du Cerveau et de la Moelle épinière,

Paris 75013, France; 2 CENTRE HOSPITALIER SAINTE ANNE PARIS, Université Paris Descartes, CHU de Grenoble 3 AP-HP, GH

Pitie-Salpêtrière-Charles Foix, Epilepsy Unit (VN, MB, SD), Neuropathologie (FB), Neurochirurgie (BM, SC), Paris 75013, France

Microglia are resident macrophages of the brain. In physiological conditions, their ramified

processes move constantly, surveilling the space around them (Dailey & Waite, 1999;

Nimmerjahn, Kirchhoff & Helmchen, 2005). Microglia adopt distinct activated shapes and

phenotypes in brain pathologies (Rock and Peterson, 2006; Choi and Koh, 2008). They may

liberate inflammatory molecules and so determine the spatial and temporal extent of an

inflammatory response (Wyss-Coray & Mucke, 2002; Hanisch & Kettenmann, 2007; Vesce

et al., 2007; Viviani et al., 2007). Alternatively microglia in a diseased brain may adopt a

distinct phenotype corresponding to a protective role.

Identification of microglia to study their shape, mobility and motility or to make electrical

recordings has been greatly advanced by the development of genetically modified animals

where these immune cells express a fluorescent marker. However human brain pathologies

may be best studied in human tissue, and an alternative technique to label microglia is needed

for such studies.

We developed a reliable protocol to stain the microglial cells in acute human slices in order to

do live two photon microscopy imaging.

Purinergic stimulation (ATP, ADP) induces chemotaxis and cytokine release via the P2Y and

P2X classes of purine receptor How do human microglia respond to purinergic stimulation?

When do they release cytokines? There is very little data on living microglia from human

brains in pathological states.

Using 2-photon live imaging of microglia from acute slices of human cortical and

hippocampal tissue from epileptic patients with MTLE-HS, glioma and dysplasia we show

that:

• Purine stimulation induces responses including membrane ruffling and process

extension or retraction.

• Stopping purinergic stimulation induces an exuberant chemotactic process extension.

• Inflammatory cytokines, including IL-8, IL-1A, IL-1B and IL-6, are secreted during

chemotaxis.

33

Session 2

3D Cerebral Organoids as in vitro Models for Alzheimer’s Disease

Christopher Lovejoy



The pathological hallmarks of Alzheimer’s disease (AD) are extracellular plaques composed

of amyloid beta and intracellular tangles composed of aggregated tau protein. Our

understanding of how these pathologies contribute to neuronal death would be greatly

enhanced by models that recapitulate these pathologies in vitro in a human, neuronal system.

To address this, we have generated induced pluripotent stem cells (iPSC) from patients with

familial AD caused by mutations in APP and PSEN1 and differentiated these into 3D cerebral

organoids to investigate pathology and disease mechanisms. Methods: iPSC lines from an

APP patient with the V717I mutation and PSEN1 R278I, Y115H and E280G mutations

patients were generated using non-integrating episomal plasmids expressing OCT3/4, SOX2,

KLF4, MYC (Okita et. al. 2011). These, together with existing lines from an unrelated APP

V717I carrier, two further PSEN1 lines (M139V and Δ intron 4 mutations) and three control

lines, were used to generate cerebral organoids as described previously (Lancaster et. al.

2013). Results: iPSC lines were tested for pluripotency using immunostaining, episomal

integration via PCR and karyotypic stability before being used in any experiments. 3D

cortical organoids were cryo-sectioned at day 30, 60 and 100 post-differentiation and

immunofluorescence was used to confirm the presence of mitotic neuronal precursors (Pax6,

Ki67, phosphor vimentin) and forebrain, post-mitotic cortical neurons (Tbr1, FoxG1, Ctip2,

Satb2). Ongoing work aims to characterise Aβ deposition and tau expression and post-

translational modifications using western blot and immunofluorescence. Conclusions: We

have successfully generated 3D cerebral organoids from patients with familial AD caused by

mutations in APP and PSEN1. Current works aims to determine if these organoids

recapitulate early signs of AD pathology. iPSC-derived 3D tissue and organoids represent a

powerful tool in dementia research for the study of pathology and early disease mechanisms.

34

Role of spatacsine and its interactors in the metabolism of lysosomes: implication in

hereditary neurodegenerative diseases

Alexandre Pierga1-4, Maxime Boutry1-5,- Alexis Brice1-4, Frédéric Darios1-4

1: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France. 2: Inserm, U1127, F-

75013, Paris, France. 3: CNRS, UMR 7225, F-75013, Paris, France. 4: Institut du Cerveau et de la Moelle

épinière, ICM, F-75013, Paris, France. 5: Ecole Pratique des Hautes Etudes, PSL Research University,

Laboratoire de Neurogénétique, F-75013, Paris, France

Hereditary Spastic Paraplegias (HSP) are a group of neurodegenerative diseases characterized

by a pyramidal syndrom linked to severe motor disorders. These disorders are caused by the

retrograd degeneration of motoneurons axons from the corticospinal tract. The most frequent

autosomal recessive form of HSPs is caused by mutations of the SPG11 gene coding for the

spatacsin protein. This form is characterized by ataxia and mental retardation. Loss-of-

fonction of spatacsin has been studied in animal models, with the mice showing cognitive and

motor disorders worsening with age reminding of human symptoms. The loss of spatacsin

function triggers an accumulation of autolysosomes (lysosomes fused with autophagosomes)

that are involved in autophagy process. This accumulation is caused by a decrease in

lysosome recycling after termination of autophagy suggesting a role of spactacsin in

lysosome’s recycling. Moreover, our results have shown an accumulation of lipids (such as

cholesterol) in lysosomes of mice neurons in absence of spatacsin. The aim of the PhD

project is to understand how spatacsin regulates lipid accumulation in lysosomes and why its

loss-of-function alters lysosomes recycling in neurons.

35

Session 3

Real gait and postural control modulate neuronal activity in the human subthalamic

nucleus

Antoine Collomb-Clerc

In animals, modulations of the activity from the cortex, the basal ganglia or the brainstem can

trigger locomotor behaviours and postural and balance modifications. The subthalamic

nucleus (STN) may be a key structure in the associated network as it receives direct

excitatory inputs from the cortex, indirect inhibitory inputs from the striatum, and direct

excitatory inputs from mesencephalic locomotor structures. The latter likely include the

pedonculopontine nucleus (PPN) and the cuneiform nucleus, and receives inhibitory afferents

from the basal ganglia and projects excitatory descending inputs to the spinal cord. In patients

with Parkinson's disease (PD), gait and balance disorders have been related to both the loss of

dopaminergic neurons leading to STN dysfunction. Deep brain stimulation (DBS) of the STN

alleviates motor signs of PD but its effect on gait and balance disorders is controversial with

some patients being even aggravated. As the role of the STN in the control of locomotion and

posture in human is still poorly understood, we proposed to record their neuronal activity

during gait initiation. For this, we recorded local field potentials during gait initiation from

the STN in 23 patients with PD both without and with dopaminergic drug treatment and 3

patients with obsessive-compulsive disorder (OCD). Electrophysiological signals were

acquired simultaneously with kinetic signals from a force platform covering at least the two

first steps. A principal component analysis driven on kinetic parameters highlighted three

main components of gait initiation performance. Then, we identified the correlations between

the scores within these components and the corresponding activity of the STN. Our results

suggest that the STN contributes both to reduce movement inhibition to promote gait

initiation and drive locomotor performance, two processes partly dependent upon the

dopaminergic level.

36

Sensorimotor Processing in Post-Stroke Fatigue

William De Doncker

Motor Neurosci & Mov Disorders

Institute of Neurology

Post-stroke fatigue is a debilitating, persistent symptom with significant impact on stroke

survivors. We previously showed that post-stroke fatigue is associated with low levels of

motor cortex excitability at rest. In this study we map the motor cortex excitability over time

during the performance of a simple reaction time task and correlate excitability profile to

fatigue levels. The prediction is that those with high fatigue will show decreased excitability

prior to movement.

First time non-depressed stroke survivors, at least 3 months post-stroke, with minimal

physical and cognitive impairment were recruited into the study. Fatigue levels were

measured using the Fatigue Severity Scale – 7. Single pulse transcranial magnetic stimulation

was used to measure excitability of the motor cortex as follows. Standard protocols as

previously described were used to measure hotspot and threshold for eliciting a response in

the affected side FDI. The intensity to obtain a 0.5 mV response in the affected side FDI was

determined. The individual’s reaction time was measured when the participant performed a

ballistic finger abduction in response to an auditory ‘go’ cue. 70 trials of finger abduction

were performed when TMS was delivered. Participants prepared to move when they heard

the warning cue prior to the ‘go’ cue, which was the signal to perform a ballistic finger

abduction. TMS was delivered at various time points between the warning cue and the ‘go’

cue and at 70% into the reaction time of the participant. Two more conditions, one where no

warning cue was provided and other where no ‘go’ cue was provided

Based on our previous results we proposed that post-stroke fatigue may be a disorder of

sensorimotor control and less of a psychiatric problem. The data from our current study, thus

far, lends support to this idea.

37

Hold your breath! REM sleep respiratory behaviors might reflect mental content

through cortical inputs in narcoleptic lucid dreamers

Delphine Oudiette1, Pauline Dodet1, Thomas Similowski2, Isabelle Arnulf1 1 Sleep disorders unit, Team 'Abnormal movements and basal ganglia: physiopathology and experimental

therapeutics. Move’it’(Brain and Spine Institute, Paris) 3 Pierre and Marie Curie University, Pulmonary and critical care unit (Inserm , UMRS1158) ; Pitie-Salpetriere

Hospital, APHP, Paris

Breathing is irregular in rapid eye movement (REM) sleep while it is stable in non REM

sleep. Why it is so is still mysterious. We propose that irregular breathing has a cortical origin

and reflects the mental content of dreams, which often accompanied REM sleep.

We tested 21 patients with narcolepsy, who had the exceptional ability to lucid dream in

REM sleep, a condition in which one is conscious of dreaming at the moment of the dream, is

able to control the dream scenario, and to signal lucidity with an ocular code. Sleep and

respiration were monitored during multiple naps. Participants were instructed to modify their

dream in such a way that the dream scenario involved vocalizations or an apnea (e.g. diving

under water), -two behaviors that require a cortical control of ventilation when executed

during wake.

Most patients with narcolepsy (86%) were able to signal lucidity in at least one nap. In 50%

of the lucid naps, we found a clear congruence between the dream report (e.g. holding one’s

breath to avoid smelling poison in a sarin attack) and the observed respiratory behavior

(central apnea). Central apneas were surrounded by the ocular code, and in several cases

preceeded bya preparatory breath.

This suggests that the respiratory-related cortico-subcortical networks involved in the

preparation of voluntary respiratory movements are preserved during REM sleep, and that

breathing irregularities during this stage have a cortical/subcortical origin that reflects dream

content.

38

Genetic Determinants of Impulse Control Disorders in Parkinson's Disease

Richard Rees

Clinical Neuroscience


Introduction: Impulse control disorders (ICD) are a potentially devastating behavioural side

effect of dopamine replacement treatment in Parkinson’s disease. They include

hypersexuality, pathological gambling, compulsive shopping and compulsive eating. There

are also impulse related behaviours (IRB) including punding and hobbyims, walkabout and

dopamine dysregulation syndrom. Recognised risk factors include young age of onset,

disease duration, and personal or family history of addictive behaviours.

Methods: Participants in the UK-wide Tracking Parkinson’s/PRoBaND study completed the

Questionnaire for Impulse Control Disorders in Parkinson’s (QUIP), at baseline, 18 months

and 36 months. We also undertook DNA testing using a customised Illumina Humancore

Exome array. After QC steps, we imputed SNPs with a MAF >0.05. Cases were defined as

ICD positive, IRB positive or QUIP positive. We used two cutoff paramaters: any positive

response to a behaviour (lax) or 2/2 positive responses per behaviour (strict). We undertook

candidate SNP association analyses and genome-wide association analyses.

Results: We genotyped 1603 people with PD. Using the different lax criteria, the case/control

allocations were ICD – 430/1172, IRB – 469/1133, any – 672/930. With the strict criteria

they were: ICD – 178/1425, IRB 435/1168, any – 508/1095. From the candidate analysis we

found rs4867798 in DRD achieved nominal significance for both the lax ICD (p=0.025) and

lax IRB (p=0.031) and a trend to nominal significance in the strict IRB (p=0.055).

rs11214613 in DRD2 also achieved nomial significance (p=0.033) in the lax ICD analysis.

Two genes approached genome-wide significance – in the lax QUIP analysis PABPC4L

(p=5.19x10-7) and in the strict IRB analysis GFPT2 (p=9.05x10-7). Several more genes had

p<10-6. 7 genes were found in ≥1 analysis.

Conclusions: Impulsive behaviours are common in PD, altough the QUIP is a blunt

instrument for diagnosis. There are likely to be genetic factors, although none of our analyses

withstand Bonferroni correction. Interestingly, none of the candidate genes from previously

implicated neurotransmitter systems were found on genome-wide association tests.

39

Session 4

Motivational Control of Decision Making

Douglas LEE, Jean DAUNIZEAU

Sorbonne-Universités-UPMC 06, INSERM, CNRS, UMR ICM-75-1127-7225, 47 boulevard de l'Hôpital, 75013

Paris, France

Thinking hard about a decision should lead to an optimal decision, yet we often fail to make

use of all information available to us, relying instead on heuristics that lead to systematic

biases in judgment. I aim to provide an understanding of how mental resources are allocated

when making decisions, framed around the idea that it is in proportion to the expected value

of the allocation. In sum, I propose to develop a computational model to provide quantitative

predictions regarding the impact of decision features (e.g., difficulty, incentive, constraints)

onto behavioral outcomes (e.g., choice, confidence, response time). Time permitting, I will

use my model to advance the understanding of the neural bases of decision-making control,

using both neuropsychological investigations of patients and neuroimaging experiments.

40

The genetic architecture of dementia with Lewy bodies

Tatiana Orme


Dementia with Lewy bodies (DLB) is the second most common form of dementia after

Alzheimer’s disease. However, despite this fact, only a few risk loci have been identified to

date and so far, only a multiplication of the SNCA gene has been shown to cause disease.

By undertaking a comprehensive genetic analysis of this disorder, by analysing the exome

sequencing data of a large cohort of 1053 DLB cases and 1433 controls, I aim to better

understand the genetic architecture of DLB. This shall be achieved by adopting several

approaches: first, studying common variability, to identify common variants that have modest

effect sizes on disease risk.  Second, by studying rare variability - for variants which are not

common in the general population and are thus predicted to impart a greater burden on

disease. Third, by studying the frequency and type of variants seen in genes already

recognised to cause neurodegenerative diseases - to discover the role, if any, they play in

DLB, and finally, to determine if certain biological pathways underlie the disease

pathobiology. In addition, I will analyse a small DLB kindred, as investigation of the genetics

of patients with familial DLB may uncover Mendelian causes of disease. Finding either risk

modulating or causative genes will aid in the identification of pathways involved in disease

pathophysiology. This, is turn, will help establish targets for novel therapeutic drugs, in

addition to improving our understanding of the molecular basis of not only DLB, but also

Parkinson’s and Alzheimer’s diseases.

41

Infusion of Incidental Affect on Consumption Experiences

Aiqing Ling1, Nathalie George1, Baba Shiv2, Hilke Plassman1

1.Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMR S1127, Institut du

Cerveau et de la Moelle épinière, Paris 75013, France. 2. Stanford University

Extent of research in social psychology has demonstrated that incidental affect, i.e., feelings

that are unrelated to the decisions at hand, could infuse individuals’ preferences at time of

choice (i.e., expected and decision utility). However, it is unclear whether and how incidental

affect might infuse how individuals experience the products (i.e., experienced utility). In two

studies combining functional magnetic resonance imaging (fMRI), skin conductance

recording (SCR), and facial affective recording (FAR), we investigated whether and how

individuals’ reported consumption experiences were altered by incidentally obtaining

monetary rewards across sensory modalities (i.e., taste and visual domains). The behavioral

data provided convergent evidence across sensory domains that positive incidental affect

increases individuals’ enjoyment of the consumption experiences. In the first study, by using

fMRI, we identified the brain mediators and moderators that underlie how incidentally receipt

of a monetary reward increased enjoyment of wines. These brain mediators and moderators

were key brain regions involved in coding values and arousal. In the second study, we

decomposed affect into valence and arousal by applying psychophysiological measures to

sample these two constructs (i.e., FAR for valence and SCR for arousal). We provided novel

evidence that the valence of affect mediates affect infusion on aesthetic evaluation of images,

and that the extent of such mediation is moderated by the arousal of affect. In a third study,

we manipulated the arousal state and the valence state of the participants separately to further

test how the effectiveness of incidental affect on enjoyment of music is changed. We found

that controlling the level of valence, higher arousal state led to greater enjoyment of the

music. Collectively, these studies identified the neurophysiological mechanism on how

incidental affect infuses individuals’ consumption experiences.

42

Decision making in the human motor cortex and impulsivity in Parkinson's disease

Vishal Rawji, Professor John Rothwell, Tom Foltynie and Marjan Jahanshahi

Sobell Department of Motor Neuroscience and Movement Disorders


Behavioural inhibition is a key component of normal human functioning, serving to supress

inappropriate or unwanted actions. Different types of motor inhibition are employed

depending on the behavioural demands. Reactive inhibition is employed when applying the

brakes of a car if someone walks out into the road. It is cued by external events and requires

rapid cancellation of ongoing motor activity. Proactive inhibition is a prospective and goal

orientated type of behavioural inhibition, concerned with responding under restraint. For

example, driving slower than normal around a school in anticipation of children running out

into the road.

Models of response inhibition posit that the basal ganglia exerts its inhibitory effect on

behaviour by inhibiting the inputs into the motor cortex (M1). Studies of response inhibition

in humans however have only assessed the effect of response inhibition on the outputs of

M1.

Using a task designed to probe response inhibition (conditional stop signal task) with a novel

form of TMS (cTMS), we present evidence showing that response execution and inhibition

may utilise different inputs to modulate M1 output.

As expected, we found that subjects slow down their responses when they expect that they

may need to cancel their movement. The physiological mechanisms of this slowing down, a

manifestation of proactive inhibition, are still elusive. Drift diffusion models suggest that this

slowing down is due to two mechanisms: 1) a higher decision threshold and 2) slower rise of

corticospinal excitability when subjects are asked to respond under restraint (i.e. when they

may need to stop). Using the stop signal task and cTMS, we set out to test this hypothesis.

Interestingly, we found that there was no difference in the threshold at which responses were

made or difference in rise of corticospinal excitability when subjects responded under

restraint, despite the same behavioural slowing down.

43

Reticulospinal Connectivity map and Speed Control

Martin Carbo Tano, Claire Wyart

Institut du Cerveau et de la Moelle épinière (ICM), Paris, France.

Modulation of locomotion speed is critical for survival, different gaits have to be engaged in

order to cope to the changing environment. Motor circuits in the brain select the set of

movements to execute based on sensory inputs, while circuits in the spinal cord (SC) referred

to as central pattern generators (CPGs) produce oscillatory activity of motor neurons leading

to the complex pattern of muscle contractions. Spinal circuits involved in rhythm generation

are organized in modules according to speed in aquatic and terrestrial vertebrates. In the

hindbrain, reticulospinal neurons (RSNs) form a class of neurons conserved across

vertebrates and constitute the major descending motor control system that integrates sensory

inputs and relays motor commands to spinal circuits. In larval zebrafish, lesion experiments

and calcium imaging reflecting neuronal activity suggest that subpopulations of RSNs are

implicated in the initiation of visual prey capture, fast escape, optomotor response, forward

swimming and struggling.

While spinal CPGs networks controlling speed of locomotion are rather well identified in

swimming animals, the pattern of projections of distinct RSNs onto spinal targets in order to

set locomotor speed remain unresolved. My postdoc project in the Wyart lab aims to establish

the RSN to SC map and a mechanistic model explaining how spinal circuits are recruited by

descending command signals to control speed of locomotion. I will talk you about my plan of

action and how I intent to achieve three main goals: 1) Establish the relevant RSN-SC map

for speed selection, 2) Probe the dynamic recruitment of synapses from RSNs onto their SC

targets in the slow and fast modules 3) Investigate the level of convergence and divergence

from RSNs onto the speed-dependent SC targets.

44

Seeing the bigger picture: visual art, the social brain and dementia.

Janneke van Leeuwen


We know that the value of art is dependent on a complex interaction between cultural

context, knowledge and personal preferences. An increasing body of neuroimaging studies

suggest that engaging with visual art activates many of the same brain networks involved in

complex social behaviour. Therefore, the way we relate to art may reflect our social identity.

Neuroscientific research has also found evidence that dementia has a particularly strong

impact on these social brain networks. This study brings together these two strands of

research; investigating what visual art can tell us about the impacts of dementia on the social

brain and whether different forms of dementia might have distinct effects.

Research with healthy people has shown that people prefer different colours in different

contexts, but little is known about how variations in spatial and material properties might

influence how people with dementias experience colour. The Colour Rooms project will

begin to explore these questions. A set of 25 miniature monochromatic room models was

built and then photographed with a wide-angle lens to look like life-size spaces. The rooms

vary in hue, lightness and saturation and include the alleged ugliest colour in the world. By

initially presenting the rooms as photographic images, rather than real life spaces, the role of

spatial imagination in the perception of colour can be studied. There are also suggestions that

dementia can cause changes in colour preferences, which will be focused on in relation to

patterns of altered neuronal activity in different types of dementia. The material experience of

colour is also of great interest and will be addressed by presenting the Colour Rooms both as

digital images on a monitor and as high-quality photographic prints. Experiments with larger

scale constructions will further explore the differences between virtual and material

experiences of colour in space.

45

Session 5

Biomarkers in Spinocerebellar Ataxia Type-3/Machado-Joseph Disease.

Hector Garcia-Moreno



Spinocerebellar ataxia type-3/Machado-Joseph Disease (SCA-3) is the most common

autosomal dominant cerebellar ataxia. The “European Spinocerebellar Ataxia type-

3/Machado-Joseph Disease Initiative (ESMI)” study is a multicentric study in partnership

with different centres in Germany (Bonn, Tubingen), the Netherlands (Nijmegen) and

Portugal (Azores, Coimbra). The study has two main aims: stablish a ready cohort of

presymptomatic and early-stage patients for future clinical trials, and create a model for the

disease evolution based on different biomarkers.

The different biomarkers will be based on: validated scales and inventories based on

neurological examination (SARA- Scale for the Assessment and Rating of Ataxia-, INAS-

Inventory of Non-Ataxia Signs-, MoCA- Montreal Cognitive Assessment), functional

composites (SCAFI- Spinocerebellar Ataxia Functional Index, CCFS-Composite Cerebellar

Functional Severity Score), questionnaires (EQ-5D, PHQ-9, PSQI), analysis of lifestyle,

analysis of levels of mutant protein and differential gene expression in blood and CSF, brain

MRI (volumetry and analysis with Diffusion Tensor Imaging).

Different studies have shown the potential role of Neurofilaments light chain (NfL) as

biomarkers in different neurodegenerative conditions (Alzheimer’s disease, Progressive

Supranuclear Palsy, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis). Recently,

NfL have been shown as a promising biomarker in Huntington’s disease (HD), since they

correlate with the stage of the disease, the number of CAG, the score in some

neuropsychological test and the volume of some areas of the brain. In addition, they seemed

to be useful to track the evolution of the disease, since the rate of progression in the HD-

premanifest group was superior to the rate in the control group.

Polyglutamine diseases are caused by an increase of the number of CAG repeats in certain

genes, resulting in proteins with a stretched polyglutamine tract. This alteration confers

46

deleterious properties to these proteins. Both HD and SCA-3 belong to the Polyglutamine

disease family, and, therefore, they could share common physiopathological mechanisms.

We aim to study the levels of NfL in blood and CSF to unravel their role as a potential

biomarker in SCA-3 patients.

47

A comparison of simultaneous and sequential binary bi-dimensional decision making

Chen Hu1, 2, 3, Mathias Pessiglione 1, 2

1.Institut cerveau moelle épinière (ICM), 2. Institut national de la santé et de la recherche médicale (INSERM).

3. Université Pierre et Marie Curie (UPM

It is widely acknowledged that ventral medial prefrontal cortex (vmPFC) is crucial for

valuation process in primates. Abundant literature has converging evidence that during

valuation phase, the activity of vmPFC signals the value of options of various categories,

ranging from primary rewards (e.g. food items) to rewards with abstract aesthetic value (e.g.

paintings). Nevertheless, in a binary choice, how values of two options are compared and

represented is still under debate. Existing studies identified that vmPFC would register the

value difference between the chosen versus unchosen option. However, this account failed to

provide a pre-choice signal to aid agents reach a decision. Another theory tried to model the

value comparison process as the value of the attended minus unattended option; nonetheless,

the implicit assumption that there is little influence from people’s prior preference is

unsatisfying. Previous results in our lab found that vmPFC represented the value of people’s

default option minus the value of the alternative option, where the default option was defined

by people’s prior preference (e.g. people’s favorite music genre or food category).

Participants demonstrated behavioral bias towards the default option; they chose the default

option more frequently and with shorter response time.

Building on previous findings, our work tries to identify whether default policy can be

created on the fly by sequential presentation of choice information. The working hypothesis

is that sequential presenting will create a situational default which might bias one option or

one dimension depends on the relative magnitude and presenting order. Thus, people can

generate a pre-commit like tendency to accept or reject the option that has a temporal

primacy, which would facilitate them to choose between the two. Since this processing fits

into the above-mentioned value comparison scheme, people would be more efficient under

informative sequential frame compare to uninformative sequential frame or simultaneous

frame. We compared people’s choice and response time from four frames; including

simultaneous presentation of effort and reward information of two options, sequential

dimension presenting (i.e. present either effort or reward information first), sequential option

presenting (i.e. present one option first) and sequential control presenting (i.e. present effort

information for one option while reward information for the other option). We found that

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during informative sequential presenting (the sequential dimension and sequential option

frame), people are shorter in response time compare to the other two frames. Meanwhile

choice accuracy remains at the same level. This suggests that there is a gain in information

processing efficiency above and beyond the low level feature of sequential presenting (such

as cutting reading time). Several model families are proposed and compared using variational

Bayesian inference approach to answer questions: 1) how decision values are constructed in

different frames; 2) how a potential default policy might bias the information integration

process. We had identified that during sequential presenting, depending on how informative

the first piece of information is (compare to a running average across the choice pair history),

people might upregulate or downregulate the weight of the second piece of information in

their decision. We are currently applying these models to neuroimaging data to further

specify the value comparison scheme in vmPFC.

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Investigation of brain mosaicism due to somatic mutations in sporadic Parkinson’s

disease

Melissa Salazar

Clinical Neuroscience


Although the mechanisms of neurodegeneration could be explained by the occurrence of

somatic mutations in brain and different types of variations have been reported in different

brain areas, the pathological role of somatic mutations remains undetermined. We aim to

optimise a robust sequencing method for sensitive detection of somatic variation in sporadic

Parkinson’s Disease (PD) samples.

Sequencing libraries were prepared by using a Haloplex HS panel (Agilent) targeting SNCA

and coding exons of 10 PD genes, including GBA. Six artificial mosaics, consisting of

dilutions of a brain sample carrying known variants, were sequenced on the HiSeq 2500

platform from Illumina. 13 controls, 27 PD and 3 multiple system atrophy patients were

included in this study, and when available frontal cortex, cerebellum and blood samples were

also analysed. Sequencing data was processed by Surecall, which takes advantage of the

molecular barcode technology to remove duplicates and generate consensus sequences that

replicate the original DNA fragments. LoFreq and MuTect were compared to validate the

results from Surecall. An IGV-based methodology was developed to discard false positives

by carefully scrutinising each of the variant calls from Surecall in artificial mosaics and

samples. With >2000x coverage, no false positives were detected at 0.5% in two artificial

mosaics and the detection limit was set at 0.33% after finding four false positives at ~0.29%.

By using our optimised methods, we achieved >92% sensitivity in Surecall when detecting

1% variants and >80% sensitivity for 0.5% variants. From all samples analysed, 31 coding-

somatic variant candidates have been found and for further validation.

Deep sequencing of PD samples using Haloplex HS allows for sensitive detection of variants

at >0.33% allele frequency. The results from this capture-sequencing analysis will be

validated by ddPCR or Amplicon-seq, which had proven high sensitivity in previous

mosaicism studies.

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Predictive models for Parkinson’s Disease

Raphaël Couronne, ARAMIS Team, ICM

We aim to develop statistical and algorithmic methods for clinical decision support with patients at risk or already diagnosed with Parkinson’s Disease. Using multimodal (clinical, genomic, imaging) and longitudinal data from both ICM (NucleiPark, Iceberg) and the international cohort PPMI, our first goal is to create a data-driven model of the disease progression. To this end we will make use of a Bayesian mixed-effects model that estimates the temporal progression of a biological phenomenon from observations oberved at multiple time points. A stochastic version of the Expectation-Maximization algorithm, namely MCMC- SAEM is used to estimate the a posteriori estimates of the parameters. This model allows to estimate a group average trajectory in the space of measurements as well as personnalized trajectories for each patient. It was first used to model the progression of neurological tests for Alzheimer’s disease, providing insight on the ordering of the decline of cognitive functions. Leveraging this model for Parkinson’s Disease, we intend to better identify and understand the sequence of symptoms as well as the impact of genetic factors on the disease progression. Ultimately we wish to identify pathological subgroups, and be able to predict future symptoms or treatment response for a patient.

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Poster sessions

Session 1 Poster 1

Investigating postzygotic de novo mutations and somatic mosaicism in monozygotic

twins discordant for complex disorders

Nirmal Vadgama, John Hardy

Monozygotic (MZ) twins were long thought to be genetically identical, however recent

studies have demonstrated genetic differences between them. To test the hypothesis that early

post-twinning mutational events leads to phenotypic discordance, thirteen MZ twins

discordant for a range of complex disorders were investigated at the genomic and proteomic

level.

All single nucleotide variants (SNVs), indels and copy-number variations (CNVs) identified

by exome sequencing and microarray analysis were evaluated for functional consequence,

evolutionary conservation, population frequency and overlap with known disease-

susceptibility genes.

Twenty-two putative discordant SNVs and indels, but no discordant structural variants, were

identified. Parent-offspring trio analysis was implemented to assess potential association of

germline de novo mutations with susceptibility to disease. A rare, highly conserved de novo

mutation in RASD2 was detected in twins discordant for attention deficit hyperactivity

disorder (ADHD). RASD2 is enriched in the stratum and involved in the modulation of

dopaminergic transmission. In the twins discordant for Tourette’s syndrome, an inherited stop

loss mutation was detected in AADAC, a known candidate gene for the disorder. Further, a

de novo CNV duplication was identified in a twin pair discordant for ADHD overlapping

CD38, a gene implicated in social amnesia and autism. When analysing the burden of shared

CNVs among the twins, a rare hemizygous deletion in region 15q13.2 was detected in twins

with schizophrenia, overlapping ARHGAP11B, a human-specific gene involved in basal

progenitor amplification and neocortex expansion.

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To investigate potential downstream consequences of (epi)genetic mechanisms and

underlying biochemical pathways, proteomic profiling of serum samples obtained from an

MZ twin pair discordant for ischaemic stroke was analysed through a label-free pipeline.

Biological processes overrepresented in the affected twin predominantly corresponded to

stroke-related processes, including wound healing, blood coagulation and haemostasis.

Further, a comparison of blood chemistries showed a >10- and >18-fold elevation of γ-

glutamyltransferase (GGT) and erythrocyte sedimentation rate (ESR) levels respectively in

the affected twin.

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Session 1 Poster 2

In vitro modelling of mitochondrial disease using human induced

pluripotent stem cell derived myotubes harbouring mtDNA mutations

Ben O’Callaghan1, Michael G. Hanna1, Jennifer Morgan2, Henry Houlden1, Monika Madej1 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, 2Dubowitz Neuromuscular

Centre, UCL Great Ormond Street Institute of Child Health, London

Background: At present no treatment has been shown to effectively alter the clinical course of

mitochondrial disease patients and instead treatment is largely symptomatic. A useful model

for exploring disease pathomechanisms and the testing of future therapeutics is therefore

desired.

Aims: To investigate the effect that mtDNA mutations causing MERRF and MELAS

syndromes have on mitochondrial function in disease relevant myogenic cell types.

Methods: Fibroblasts obtained from patient biopsies harbouring the m.8344A>G MERRF and

m.3243A>G MELAS mutations have been reprogrammed using non-integrating delivery

methods. hIPSC lines are being differentiated into myotubes using defined factors which

recapitulate the developmental stages of myogenesis.

Results: Isogenic hIPSCs with differing heteroplasmy levels have been established from a

MELAS m.3243A>G and three unrelated MERRF m.8344A>G patients during

reprogramming. hIPSCs are being differentiated into MyHC+/Titin+/Myogenin+ myotubes

which retain a non-proliferative PAX7+/Ki67- satellite-like cell niche. Differentiation

efficiency is affected by mtDNA mutation load. Preliminary results of mitochondrial function

assessed by live cell imaging will be presented.

Conclusions: This in vitro model will provide new insight into pathomechanisms of

mitochondrial disease in muscle. Intermediate metabolites affected by mitochondrial

mutations may show promise as a supplement based therapy for mitochondrial disease

patients.

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Session 1 Poster 3

Tracking Progression in Friedreich’s Ataxia (FRDA) to Establish

Biomarkers for Clinical Trials.

Thomas-Black G, Giunti P et al.

Introduction: Clinical trials using a variety of promising therapeutic compounds have been

carried out in FRDA. The primary endpoints have included well established measures such

as; clinical rating scales, echocardiography and one study included MRI of iron deposition in

the dentate nucleus of the cerebellum, but none have demonstrated statistically significant

improvement despite patients reporting subjective benefits (Perlman, 2012). This has led the

scientific community to investigate novel trial designs and explore the identification of new

biomarkers that could more reliably capture progression of disease.

Methods: This study aims to investigate new ways of measuring disease progression in

Friedreich's Ataxia. Innovative and quantitative MRI measures in the brain and spinal cord of

up to 24 patients and 6 control subjects will be analysed alongside high resolution imaging of

the retina using optical coherence tomography (OCT) and visual acuity checks performed on

up to 70 patients. The procedures will be carried out across 3 time points, spanning 22

months. This will be the largest study of its kind to date and should assist in clinical trial

development.

Results: We will have collected and analysed data from the first time point and will be able to

report on the following:

• Comparison of controls vs FRDA patients using our novel MRI measures.

• Confirm/negate findings of previous studies looking at OCT data in FRDA.

• Correlations of OCT and MRI data with clinical scores

Conclusions: We have been able to demonstrate correlations between general retinal nerve

fibre layer thickness and age of onset, GAA repeat sequence length, SARA score and INAS.

Trends towards significant correlations were observed between certain MRI measures of the

spinal cord and general RNFL thickness, we hope to increase our numbers to confirm this

relationship.

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Session 1 Poster 4

Specific Neuronal Vulnerability in SCA1 is Not Associated with CAG

Instability between Different Brain Regions

Heather Ging , Paola Giunti

Introduction: SCA1 results from an expanded polyglutamine tract, encoded by CAG

trinucleotides, within ATXN1, with symptoms due to cerebellar degeneration, specifically

degeneration of the Purkinje cells and neurons within the brainstem and spinal cord. A major

determinant of SCA1 pathology is the repeat size, which has an inverse relationship to

disease age of onset and severity. We have previously shown that interruption of the

expansion by missense (CAT) mutations is a significant modulator of the disease phenotype,

with interruptions delaying the age at onset such that the length of the longest contiguous

stretch of pure CAG repeats inversely correlates with age at onset (Menon et al., 2013). This

study aims to understand the somatic differences between human blood and various brain

regions from two SCA1 patients, differentially involved in the neurodegenerative process,

and their phenotypic effect.

Methods: DNA was extracted from the brain and blood of two SCA1 patients. This DNA was

fragment sized, cloned and sequenced, as previously described (Menon et al., 2013).

Results: Somatic mosaicism was investigated in eight brain regions of two SCA1 patients by

fragment analysis, sizing both the mode and largest expansions, and confirmed by cloning

and DNA sequencing. Sequencing analysis established the exact size and configuration of the

CAG repeats and found them to be largest in the caudate nucleus and shortest in the

cerebellum. This argues against a direct association between the degree of somatic mosaicism

and the selective neurodegeneration in SCA1.

Conclusions: Peripheral blood DNA CAG repeat size is a good indicator of repeat size in the

cerebellum and validates its use in the diagnostic setting. Furthermore, this work

demonstrates that selective neuronal vulnerability correlates poorly with the observed somatic

instability throughout the different tissues examined.

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Session 1 Poster 5

High-dimensional inference on damaged human brain

Tianbo Xu, Parashkev Nachev

Though consistency across the population renders the extraordinarily complex functional

anatomy of the human brain surveyable, the inverse inference—from common functional

maps to individual behaviour—is constrained by marked individual deviation from the

population mean. Such inference is fundamental to the evaluation of therapeutic interventions

in focal brain injury, where the impact of an induced structural change in the brain is

quantified by its behavioural consequences, inevitably refracted through the lens of lesion-

outcome relations. Current therapeutic evaluations do not incorporate inferences to the

individual outcome derived from a detailed specification of the lesion anatomy, relying only

on reductive parameters such as lesion volume and crudely discretised location. Examining

1172 patients with anatomically-registered focal brain lesions, here we show that such low-

dimensional models are highly insensitive to therapeutic effects. In contrast, high-

dimensional models supported by machine learning dramatically improve sensitivity by

leveraging complex individuating patterns in the functional architecture of the brain. The

failure to replicate in humans positive interventional effects in experimental animals is thus

revealed to have a remediable inferential cause, forcing a radical re-evaluation of therapeutic

inference in the human brain.

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Session 1 Poster 6

Focus on Dopamine

Stephanie Hirschbichler, Prof. Rothwell, Sanjay Manohar

Studying eye movements can provide important insights into the pathophysiology of

neurological disorders. The speed-accuracy trade-off is a well-studied law obeyed by a broad

variety of behavioral tasks including saccadic eye movements. This law can be overcome by

monetary reward, which simultaneously invigorates movements and improves response

precision (Manohar et al. 2015). Dopamine may be a key neuromodulator in such

motivational effects. Accordingly, patients suffering from Parkinson disease, a condition

characterised by a dopaminergic deficit, demonstrate reduced reward sensitivity suggesting a

higher cost for controlling intrinsic neuronal noise in PD. Here I test whether the cost of

controlling noise extends to decision making. When we have to choose between a larger

number of options, our responses become slower, according to the logarithm of the number of

alternatives (Hick’s law). To test whether reward can violate this law of decision-making, I

ask healthy volunteers to make a saccade to one of a variable number of targets, while

varying the monetary incentive available. If there is a cost for improving the effective signal-

to-noise-ratio in saccadic decisions, motivation by reward and loss should result in RT

scaling that is faster than that predicted by Hick’s law (Holmes et al 2006). (Results are

currently being collected and will be ready for poster presentation by the date of the

workshop.)

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Session 1 Poster 7

Neurotrophins and the balance between retrograde signalling and

autophagic flux in the axon

Oscar Lazo, Gipi Schiavo

Neurotrophins are secreted by target tissues and regulate several neuronal functions, which

rely on the axonal transport of activated receptors aboard signalling endosomes. Most of them

are regulated by the GTPase Rab7, but at any given time some carriers lack this Rab, raising

the possibility that different pools of signalling endosomes are generated. Accordingly, we

found that Rab10 is recruited to axonal carriers and is required for the transport of p75NTR

receptors. In addition, Rab7 also regulates maturation and retrograde flux of autophagosomes.

How the sorting of internalized receptors to these different compartments and their axonal

trafficking are regulated remains unknown. Using a combination of biochemical and live-cell

imaging tools, this project aims to determine whether Rab10 defines a novel population of

retrograde carriers with distinct signalling output and whether BDNF signalling regulates the

recruitment of Rab7 and Rab10 to different transported organelles.

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Session 1 Poster 8

Spinal Cord Injury- Translational approach to treatments

Modinat Liadi Professor Ying Li

Transplantation of olfactory ensheathing cells is a promising candidate in aiding recovery

after spinal cord injury. Clinical application by our collaborator showed positive outcome for

axonal regeneration, where functions were regained after transplantation of autologous

olfactory bulb ensheathing cells (OB-OECs) to the site of injury. However, when treating

large injuries the yield of OB-OECs from the limited mass of biopsy tissue will not be

sufficient to bridge the severed connections. To overcome this limitation we here present our

work on the use of collagen as a scaffold for human OB-OECs to investigate: (1) if human

OB-OECs can be grown and integrated in 3-dimensional collagen; (2) can collagen

encourage human OB-OECs to aid axon regeneration in our brain slice model; (3) can

collagen act as a viable scaffold for human OB-OECs in our vivo spinal injury model. Our

preliminary study shows (1) human OB-OECs can be grown and integrated into 3-

dimensional collagen; (2) this scaffold encourages to an extent axon regeneration in slice

culture; (3) use of this collagen scaffold improved the handling during transplantation and

also increased the ability to treat injury sites without a large yield of OECs in the in vivo

model.

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Session 1 Poster 9

The involvement of the motor system in self-recognition

Matan Mazor, Steve Fleming, Karl Friston

Most traditional approaches to behavioral and neuroimaging data analysis treat temporal

dependence of measurements as a limiting factor that needs to be controlled for. To overcome

potential interactions between consecutive measurements, trial-order randomization is

employed. Here we propose an alternative method (TWISTER: TWo Independent Stimulus

Traits Evenly Randomized), that takes advantage of such temporal interactions to elevate

statistical power. In this method, experimental trials are randomly dispersed in time within an

experimental run. The temporal structure is maintained across different runs, but

experimental events are twisted across one or two desired experimental dimensions.

Differences in sensitivity to certain dimensions are captured by asymmetries in the degree of

inter-run temporal consistency of response patterns. Responses can be behavioral (e.g.

reaction times) or physiological (e.g. BOLD signal) depending on the question of interest.

Importantly, since this method compares the temporal consistency across, and not within,

experimental runs, it is robust to any serial interaction of measurements that may exist within

a single run.

This method is oblivious to the single-subject effect sign (+/-), making group-level inference

resistant to idiosyncratic differences across subjects. Furthermore, when dealing with

physiological time-series data, it obviates the need in a generative model of the signal.

We present results of applying TWISTER in an fMRI experiment and discuss its application

to behavioral paradigms.

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Session 1 Poster 10

Movement Disorder genetics and the role of ageing

Sebastian Schreglmann, K. Bhatia

Background: Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid

beta (GBA) gene causes autosomal-recessive Gaucher`s disease (GD), the most common

lysosomal storage disorder. GBA mutations are associated with an increased risk to develop

Parkinson`s Disease and are its most common known genetic risk factor, while an association

with dystonia has not been reported so far.

Goal: To report on the observation of decreased levels of GCase in peripheral blood in a

series of individuals presenting with dystonia without signs of parkinsonism.

Methods: The data for the study was collected between 2014-2016 from patients with isolated

dystonia and clinical red flags indicating a secondary cause to their presentation. All patients

were screened for structural, acquired and degenerative causes of dystonia including

neuroimaging, blood tests for copper, caeruloplasmin, genetic analysis and white cell

enzymes as part of their diagnostic work-up. Lysosomal enzyme activity measurements were

performed using a fluorescence-based essay. Sequencing of GBA exons 8-11 was performed

using a standard Sanger Sequencing protocol.

Results: After exclusion of possible alternative aetiologies, n=27 patients (m/f=13/14) with

dystonia of variable forms (n=18 focal/segmental; n=9 generalized/hemi) without

parkinsonism and abnormal GCase activity were identified. Cases showed GCase activity

within the range typical for heterozygous (normal range: 2.5-8.9μmol/l/h, n=24) and

homozygous (0.29-2.5; n=3) GBA mutations, while Chitotriosidase was found elevated in

n=2. No other lysosomal enzyme activity was found abnormal. Age at onset differed between

cases with enzyme levels typical for heterozygous (28.1yrs) and homozygous (50.3yrs) GBA

mutations. Alternative genetic causes like mutations in DYT1, Parkin, SCA1,2,3,6,7,

mitochondrial genes and GCH1 were excluded dependent on presentation in n=22. A

significant proportion of cases displayed a positive family history for PD (n=6), dystonia

(n=3) and other neurological conditions such as tremor, autism, epilepsy and ADHD (n=15).

On Sanger sequencing (n=22), one pathogenic mutation (het. N370S) was found in a male

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patient with isolated foot dystonia (onset aged 52), congenital cataract and GCase levels in

the homozygous range.

Conclusion: While lysosomal dysfunction due to decreased GCase activity is recognized to

be a causative risk factor for PD, the observation of decreased GCase activity levels in this

series of dystonia patients provides evidence that lysosomal dysfunction may be associated

with dystonia too. The epidemiology and mechanism of this remain to be established.

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Session 1 Poster 11

Multimodal analysis of Primary Progressive Aphasia

Alexandre Routier a,b; Olivier Colliot a ; Marie-Odile Habert d,e ; Marc Teichmann b,c a Aramis team (CNRS - ICM - Inserm - Inria - UPMC), b Frontlab team (CNRS - ICM - Inserm - UPMC), c

Department of Neurology, Centre de référence ‘Démences Rares’, Hôpital de la Pitié Salpêtrière, AP-HP, d

Department of Nuclear Medicine, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, AP-HP. e

Laboratoire d’Imagerie Biomédicale (CNRS - Inserm - UPMC)

Primary Progressive Aphasia (PPA) is a group of rare neurodegenerative diseases affecting

language abilities in approximately 6000 people in France (usually before 65 years old). So

far, three main variants (Gorno-Tempini et al., 2011) have been identified: the non-fluent

PPA affecting some phonological and syntactic processes due to an atrophy of the inferior

frontal cortex, the logopenic PPA defined by a lexical disorder and a decrease of the the

verbal working memory affecting the temporopariatal junction, and the semantic PPA

characterized by an erosion of the system of word meanings at anterior temporal cortex.

There is also a heterogeneity in disease processes and underlying pathologies including

'frontotemporal lobar degeneration' (FTLD, tauopathies, TDP-43) and Alzheimer disease.

Finally, several gene mutations have been described in familial forms (progranulin, MAPT,

TARDBP).

This complex heterogeneity from a clinical, anatomical and biological point of view

represents an important challenge for the classification of patients (e.g., Mesulam et al., 2014)

and encourages the development of multimodal analysis of different forms of PPA in order to

provide a classification of integrative diagnostic tools. This complexity opens a new way to

use PPA as lesional models for accurate exploration of the anatomy of different neural

processes and computational components of language. Finally, the biology varying in PPA

could identify biological vulnerability of different neural networks and define among others

the predominant target of Alzheimer pathology.

The aim of the thesis is to provide a characterization of different forms of APP on the

anatomical functional / metabolic but also biologically and linguistically. Current studies are

often from small cohorts will exploit data PHRC 'CAPP'. We have in this large cohort of 89

patients followed longitudinally and having different data from behavioral and language

assessment and neuroimaging. Among the imaging data, we will study first the structural

MRI (which allows eg to quantify atrophy of anatomical structures) and impaired white

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matter using diffusion imaging. For this, we will rebuild the fibers of the white matter

tractography by a process for determining the set of neuronal connections. Subsequently, we

will analyze the metabolic activity observed during a TEP-18 FDG acquisition (radiolabeled

glucose). The statistical analysis of these different neuroimaging modalities will be

performed in a transverse and longitudinal approach and will take into account the biology

and linguistics analysis.

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Session 1 Poster 12

Assessing brain-behaviour relationship using mediation analyses

Jules BROCHARD and Jean DAUNIZEAU 1 Université Pierre et Marie Curie, Paris, France. 2 Institut du Cerveau et de la Moelle épinière, Paris, France. 3

INSERM UMR S975

Typical fMRI experiments aim at identifying brain regions whose activity dynamics correlate

(in time) with some stimulus or task factor of interest. Here, we extend this approach by

asking whether one can identify brain regions that contribute to the transformation of such

task factors into overt behaviour. We show how to adapt so-called “mediation analysis” to

neuroimaging data, identify its statistical properties and highlight its potential interpretational

pitfalls. For example, we disclose non-intuitive sensitivity issues that arise when pairwise

correlations between task factors and either brain activity or behaviour increase. We also

propose post-hoc tests that can discriminate between proper mediating regions and regions

that respond to both task factors and behavioural changes. We demonstrate our approach

using an fMRI investigation of the impact of monetary reward onto (physical) effort

management.

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Session 1 Poster 13

Investigation of the diversity of neurosecretory compounds released in the

cerebrospinal fluid by contacting neurons

Hugo Marnas*,1, Feng Quan*,1, Lydia Djenoune1, Andrew Prendergast1, Laura Desban1,

Pierre-Luc Bardet1 and Claire Wyart1

1.Institut du Cerveau et de la Moelle épinière (ICM), 47 bld hospital, 75013 Paris, France. * equal contribution

Arousal locomotion varies as a function of our inner states as well as cues from the

environment. The initiation of locomotion relies on descending command from the brain as

well as the excitability of spinal circuits themselves. The mechanisms allowing the CNS to

monitor the interplay between generating motor activity and integrating sensory inputs during

locomotion remain unclear. Our team investigates a novel interoceptive pathway relying on

spinal sensory neurons called cerebrospinal fluid contacting neurons (CSF-cNs), which were

described by Kolmer and Agduhr in more than 200 vertebrates species. Due to their location,

at the interface between the cerebrospinal fluid (CSF) and the central nervous system, these

neurons are good candidate for a sensorimotor loop in the spinal cord. CSF-cNs are

GABAergic neurons expressing the transient receptor potential PKD2L1. We have evidence

that CSF-cNs respond to variations of CSF pH and flow, and modulate locomotion and

posture via projections on spinal targets. Recently, we performed a transcriptome analysis of

CSF-cNs and identified a wide repertoire of peptides and secreted proteins. We took

advantage of the zebrafish embryo transparency to validate the expression of peptides and

small proteins by fluorescent in situ hybridization coupled with immunohistochemistry using

PKD2L1 as a CSF-cNs marker. We showed that peptide expression was mainly localized in

the spinal cord in the embryonic and larval stages. Few peptides remain expressed around the

central canal in the spinal cord in adult zebrafish, possibly in adult CSF-cNs. To investigate

the putative CSF-cNs peptides contributing to the modulation of locomotion and posture, our

team developed tools to monitor endogeneous peptidic release in vivo and generated mutants

for all peptides and key elements of the neurosecretory machine. We currently investigate the

phenotypes of such neurosecretory mutants in multiple behavioral assays. Altogether, our

data indicate that secreted peptides released by CSF-cNs in the cerebrospinal fluid could

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modulate widely physiology via regulating the molecular content of the CSF in addition to

locally impact locomotion and posture.

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Session 1 Poster 14

Vangl2, a core component of the Wnt Planar Cell Polarity pathway

regulates mammalian neuromuscular junction formation

Myriam Boex, Julien Messéant, Stéphanie Bauché, Bertrand Fontaine and Laure Strochlic INSERM UMR_S1127, Brain and Spinal Cord Institute, Paris, 75627 Cedex 13, France.

The development of the neuromuscular junction (NMJ), a cholinergic synapse between the

axon terminal of a motoneuron and a specialized region of the skeletal muscle fiber requires a

dynamic communication via various reciprocal signaling processes between the two elements

that are only partially understood. Numerous studies have recently highlighted the emerging

and complex role of Wnt signaling at the NMJ. Secreted Wnt ligands (notably Wnt4 and

Wnt11) signal through interaction with the Frizzled-like cysteine rich domain (CRD) of the

muscle-specific tyrosine kinase MuSK to activate both canonical/β-catenin dependent and

core Planar Cell Polarity (PCP) signaling pathways. First evidence for a role of Wnt PCP

signaling during NMJ formation comes from studies in Zebrafish showing that both Wnt4a

and Wnt11r cooperate to initiate NMJ formation likely by stimulating PCP-dependent MuSK

endocytosis. In mice, we previously demonstrated that one of the key PCP core component,

namely Van Gogh-Like protein 2 (Vangl2), is expressed in both pre- and postsynaptic

compartment of the NMJ, interacts with extracellular Wnt4 and Wnt11 and is required to

shape the neuromuscular synapse. However, the molecular determinants of Vangl2 signaling

at the NMJ still largely remain unknown. To assess the role of Vangl2-dependent PCP

signaling at the NMJ, we first examined in vivo the NMJ phenotype of diaphragms from

Vangl2 knock-out (Vangl2-/-) mice embryos and showed that the absence of Vangl2 induces

pre- and postsynaptic differentiation defects characterized by a decrease in the number and

volume of acetylcholine receptors (AChRs) and overgrowth of motor axon within the target

field. We further demonstrated that only muscle (-HSA) but not motoneuronal (-HB9)

specific conditional KO (cKO) of Vangl2 recapitulates both pre- and postsynaptic defects of

the Vangl2-/- mice embryos suggesting that Vangl2 acts in the muscle to regulate NMJ

formation. Finally, Vangl2 forms a complex with MuSK independently of its CRD and loss

of Vangl2 function inhibits Wnt11-mediated AChRs clustering in primary muscle cells. All

together, these results demonstrate that a Wnt/PCP signaling pathway relying on

MuSK/Vangl2 interaction contributes to the establishment of mammalian neuromuscular

connectivity.

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Session 1 Poster 15

Analysis of neuronal dysfunctions in a murine model of Hereditary Spastic

Paraplegia

Baptiste Wilmet1 under the direction of Dr. Morwena Latouche1 and Pr. Giovanni Stevanin1

1:Ecole Pratique des Hautes Etudes, Paris

Hereditary Spastic Paraplegia (HSP) is a group of Motor Neuron Disease (MNDs)

characterized by progressive spasticity and paralysis of lower limbs. Degeneration of cortico-

spinal tract is the main pathophysiological characteristic responsible for the observed

symptoms. In complex forms of the disease, motor issues are associated with cognitive

deficits. Mutations in SPG11 gene coding for Spatacsin are a major cause of these complex

forms. For a better understanding of SPG11-related HSP mechanisms, our team generated a

Knock-Out mouse model (spg11-/-) which mimics the cognitive and motor deficits correlated

with histologic alterations. In Vivo EEG recordings of spg11-/- motor cortex highlighted the

emergence of spike discharges-like events, concomitantly to a NeuN+ cells loss, suggesting a

disturbance of excitability of cortical networks. Ex vivo Electrophysiological recordings of

spg11-/- hippocampi displayed reduced short and long-term potentiation and fibers

excitability, correlated with a lack of spatial and fear-related memories, suggesting an

impairment in pre and/or post-synaptic elements. This project aims to decipher the biological

causes of those electrophysiological deficits. We hypothesized 1) that alterations in motor

cortex are due to a disturbance of excitation/inhibition balance and 2) cerebral networks loss

of efficiency is due to an issue in pre and/or post-synaptic elements. To check the validity of

these hypotheses, we propose by using histology and electrophysiology to 1) test the

functioning and integration of cortical interneurons and motor neurons and 2) study the pre

and post-synaptic elements related to synaptic transmission function such as Action Potential

propagation, neurotransmitters vesicles and synaptic electrophysiological properties.

Altogether, the results of these experiments will decipher the roles of Spatacsin in the

pathogenesis of HSP as well as pathophysiological pathways of interest for all motor neurons

diseases.

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Session 1 Poster 16

The battle for self-confidence: a tug-of-war between prospective gains and

losses

Emmanuelle Bioud, Jean Daunizeau and Mathias Pessiglione Motivation, Brain & Behavior (MBB) team, Institut du Cerveau et de la Moelle (ICM), Inserm Unit1127,

Hôpital de la Pitié-Salpêtrière, Paris

When estimating their chances of succeeding at a task or a project, healthy people tend to

exhibit a desirability bias: they are inclined to perceive as relatively more likely events that

are desirable, such as hitting the center of a target in a dart game, or launching a successful

company in the future. More specifically, the more desirable the outcome attached to a

success (the higher the potential benefit), the more confident people are in their chances.

Several interpretations have been suggested to such phenomenon. The rosy-outlook

hypothesis simply postulates that people distort their confidence judgment, in proportion to

potential benefit, to feel better about their future, and avoid stress or anxiety. The

motivational reasoning hypothesis assumes that people intend to adjust their resources

depending upon potential benefit: ‘There is a lot to win here, therefore I’m particularly

motivated to succeed, therefore I will try harder at the task, therefore I’m more likely to

succeed.’ In any case, the notion of desirability bias implies that confidence judgments

should correlate positively not only with prospective gain in case of success, but also with

prospective loss in case of failure, because the perspective of avoiding larger losses also

makes success more desirable. However, recent findings in decision neuroscience would

yield a different prediction. The same brain region (namely, the vmPFC) was found to

represent both the likeability of various stimuli and confidence in the selected response

(probability of success). Moreover, some spillover effects, such as the impact of background

music on painting evaluation, may be mediated by changes in vmPFC baseline activity. This

contamination mechanism could be extended to a contamination of confidence judgments by

outcome values: confidence would follow vmPFC baseline, being positively biased by

prospective gains and negatively biased by prospective losses. In order to disentangle

between desirability bias and contamination mechanisms, we conducted a series of 4

behavioral experiments, where participants rated their confidence prior to performing a motor

precision task, equivalent to a dart game. Critically, we varied both the expected gain

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associated to success, and the expected loss associated to failure. We observed that

confidence ratings were positively correlated with gains and negatively correlated with

losses, as predicted by the contamination mechanism. Importantly, these distortions of

confidence judgments were dissociated from the actual performance (success rate), which

was not affected by expected gains and losses. Thus, our findings challenge the notion of

desirability bias and suggest instead a contamination mechanism through which the value of

any contextual feature may bias confidence judgment. This might be a consequence of the

vmPFC functional properties, which we are presently investigating using fMRI.

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Session 1 Poster 17

Modeling Macrophage Activation in Multiple Sclerosis Patients

Jennifer Fransson

Multiple sclerosis (MS) is a neuroinflammatory disease in which myelin loss leads to

neurodegeneration. In response to myelin loss, remyelination can occur, limiting

degeneration and reducing clinical symptoms. However, remyelination capacity varies

greatly between patients for unknown reasons. Understanding why the repair process is

successful in some patients and fails for other is of utmost importance. While macrophage

and lymphocyte infiltration into the CNS initiates myelin loss, these cells are also essential

for induction of remyelination. In particular, the pro- and anti-inflammatory activation states

of macrophages induce distinct parts of the process. For this project, the aim is to model the

activation of macrophages from patients and controls in order to determine if faulty activation

could be responsible for part of the disease progression. Macrophages were obtained through

activation of peripheral monocytes from blood samples from 8 patients and 8 controls, and

after pro- or anti-inflammatory stimulation the cells were analyzed through RNA sequencing.

These data were analyzed using methods for multivariate analyses with high-dimensional

data to assess the interaction between disease status and macrophage activation. Preliminary

results suggest that the difference between patient and control macrophages vary between

different activation states, and that this interaction varies between different groups (relating to

the function) of genes. Moving forward, these analyses will be performed on a larger dataset

to increase power and to include comparisons between different groups of patients. Also, the

impact of the altered groups of genes on macrophage function will be studied further focusing

on biological read-outs relevant for remyelination: estimation of myelin phagocytic activity

and effect of macrophage conditioned media on oligodendrocyte precursor cell

differentiation. Explaining and correcting macrophage responses in MS could be the first step

to improve remyelination and, as a result, quality of life for patients with few or no treatment

options available today.

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Session 1 Poster 18

Study of the involvement of autophagy (in cell death of motor neurons) in

ALS

AM Negulescu1 and E. Kabashi1

1Institut du cerveau et de la moelle épinière (ICM)- Paris, France

The amyotrophic lateral sclerosis (ALS) is a progressive illness caused by the

neurodegeneration of the motor neurons, traduced in locomotory weakness and finally in

respiratory failure. It appears that the autophagy plays a critical role in this disease, as various

reports show defective cleansing of specific proteins, due to impaired autophagy. It is worth

saying that the autophagy is a process of self-degradation of defective cytoplasmic proteins or

organelles via double membrane vacuoles called autophagosomes. This mechanism is

essential for the development and the survival of normal neural cells as these cells are

incapable of diluting toxic intracellular components via cell division. Many studies show that

dysfunctional autophagy can lead to many diseases, including neurodegeneration. The project

that I am going to develop during the postdoc that I recently started at the ICM aims to

investigate the role of the autophagy using in vivo and in vitro models of ALS.

The experience in the autophagy field was acquired during my PhD, when I showed that the

transmembrane receptor Kremen1 could be a putative tumor suppressor, able to induce

autophagic cell death due to its dependence receptor function (receptors that have the ability

to induce a survival pathway whenever they are interacting with their ligand and cell death in

the absence of the same ligand). By analysing TCGA RNAseq datasets, I observed that the

Kremen1 receptor is lost in a large spectrum of cancers. Re-establishing Kremen1 expression

in breast cancer MDA-MB 231 cell line induced cell death in 2D in vitro cell culture and

inhibited growth in soft agar. Furthermore, I observed by transmission electron microscopy

(TME) that this Kremen1 induced cell death has autophagic features. Enhanced accumulation

of autophagomes may lead to autophagic cell death. In this context, biochemistry

investigation revealed that LC3-I was converted to LC3-II, an autophagy marker, and

treatment with a specific inhibitor of autophagy, 3-methyladenin (3-MA), blocked Kremen1

induced cell death, confirming the necessity of autophagy during this event. In addition, a

shRNA screen revealed the implication of proteins involved in autophagosome formation

(ATG4, Beclin1) or lyososome degradation (cathepsine B and G) in this process of

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autophagic cell death. I will utilize the tools and expertise accumulated during this PhD

project to define the role of autophagy in ALS.

During this workshop I will be presenting the common features of autophagy, some of my

PhD results and will develop on my future postdoc project in Edor Kabashi’s team.

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Session 1 Poster 19

Neuronal substrate of a complex behavioral transition

Thomas TOPILKO 1,2, Florine VERNY 2, Nicolas RENIER 1,2 1 : Université Pierre and Marie Curie-Paris 06, 2 : Institut du Cerveau et de la Moelle-épinière, ICM,

INSERM/CNRS U-1127/UMR-7225

Animal behaviors can change throughout life, to adapt to seasonal rhythms or reproductive

fitness for instance. Nest building is a well-documented behavior in mice that is essential for

thermoregulation as well as shelter and reproduction. Interestingly, while adult mice always

build nests, their structural complexity dramatically increases during pregnancy in mice. This

confirms the widely reported fact that, during pregnancy in the mouse, neuronal plasticity can

shape the output of certain neuronal networks to tune the execution of a behavior. While most

studies on adult brain plasticity have so far focused on rapid changes affecting neuronal

excitability or synaptic recycling at a small scale, it has been shown that plasticity can also

manifest itself on a larger scale in the adult brain following sensory deprivation, by the

remodeling of complete axonal branches. However, the functional role of large-scale

plasticity events and their molecular control are poorly characterized. By using the transition

towards parental nest building as a model behavior, my aim is to decipher the mechanisms

supporting large-scale changes in the structure of adult brain networks, and how they

translate into long-lasting behavioral adaptations. My preliminary data indeed confirmed

findings previously reported that virgin female mice build simple flat nests with high

frequency, whereas pregnant females build complex tridimensional covering nests more

consistently. Using an unbiased method of brain-wide mapping of neuronal activity with

tissue clearing and light sheet microscopy, I identified two brain regions significantly more

active during maternal nest building behavior than non-parental nest building: the Preoptic

area (POA), and the Edinger-Westphal nucleus (EW). Although the POA was already linked

to parenting behaviors, the EW had not been implicated so far. The anatomical distribution of

neurons active during parental nest building within the EW suggest that they might be

centrally projecting neurons (EWcp) expressing the neuropeptide Urocortin1 (Ucn1).

Therefore, my preliminary results suggest that the LPOA and the EW are part of a common

neuronal network, that is implicated in the transition towards a parental nest building

behavior in mice. I hypothesize that the improved performances of nest-building in pregnant

mice are the result of plastic changes in the connectivity or activity of this circuit. These

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changes could be the result of a large-scale structural reorganization of a few long-range

neuronal projections, or a modification of the responsiveness of these neurons to internal and

outside cues. The aim of my project is to find how these plastic changes can shape the

execution of a complex nesting behavior. To do so, I will take advantage of the recently

developed novel tools for the unbiased study of neuronal activity and connectivity in the

brain.

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Session 1 Poster 20

Cellular resolution view of the transcriptional landscape of a developing

eye

Radolsaw Ejsmont

Specification of cell identity is a multi-step process that is governed by key

transcription factors, many of which have been identified, however their targets

remain largely unknown or were only analyzed bioinformatically. It is also not clear yet,

whether the binding of a transcription factor immediately results in expression of the target

genes. In this project, we aim to identify the sequence of quantitative changes in gene

expression which govern the development of the neural retina in Drosophila.

The sequence of events in early retinal differentiation is governed by 3 master control

transcription factors, namely Eyeless, Atonal and Senseless. We will analyze the targets of

Ato that controls the transition from eye disc intermediate cell to R8 photoreceptor neurons.

We will analyze the targets of Ato that controls the transition from eye disc intermediate cell

to R8 photoreceptor neurons. The fly retina offers the unique advantage of allowing the

imaging of cells as they transition through differentiation in vivo. We will utilize

recombineering and genomic engineering to tag all predicted Ato targets with new

transcriptional reporters.  Analysis of putative target gene expression in Ato knock-out

background will confirm true downstream targets. Functional analysis of the regulated genes

will provide an unprecedented insight into the genetic control of the transition from neural

precursor cells to neurons.

The cascade of Ey, Ato and Sens forms a backbone of the network, governing transitions

from progenitor (Ey) to precursor (Ato) to differentiated cell (Sens). Direct regulation of ato

by Ey and of sens by Ato has been previously described, however the molecular

program executed by these factors still remains to be discovered. While the retinal

determination network is conserved across species, its key members were discovered in

insects. Their homologs play crucial role in the development of the vertebrate eye, act as

tumor suppressors or regulators of apoptosis. Understanding regulation and function of

genes within the network will therefore give insight not only into insect eye development, but

also development of the vertebrate eye, other sensory organs and cancer.

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In our project, we propose an in toto approach to reconstruct the regulatory networks

governing sequential cell fate transitions. We will combine a novel direct method for

assessing control of a particular gene by transcription factors with subsequent functional

analysis. Such an approach will provide new unbiased insight into the regulatory network

structure, as well as into the function of genes within it. This project answers fundamental

questions about how gene regulatory networks shape development on a systems level and at

the cellular resolution.

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Session 1 Poster 21

Study of Gpr88 as a therapeutic target for the non-motor symptoms of

Parkinson’s disease.

Benjamin Galet, Manuela Ingallinesi, Jonathan Pegon, Nicole Faucon-Biguet, Anh Do Thi,

Philippe Ravassard and Rolando Meloni. Biotechnology and Biotherapy Group, Brain and Spine Institute/CNRS UMR 7225/INSERM 1127/UPMC

UM75, Paris, France

Although Parkinson's Disease (PD) is commonly defined as a progressive motor disorder, it

entails many non-motor symptoms (NMS) such as apathy, depression and cognitive

alterations. L-DOPA, the gold standard treatment for PD, slows down the progression of

motor symptoms but its potency is limited in time and does not prevent the cognitive decline

many patients endure. In this regard, Gpr88, an orphan G-protein coupled receptor, may be of

interest as a potential therapeutic target for PD. Gpr88 expression is mainly restricted to the

striatal medium spiny neurons, and is modulated by dopamine, glutamate, GABA as well as

by L-DOPA and psychoactive drugs. Moreover, we have recently shown that the knock-down

(KD) of Gpr88 in the ventral striatum (STR) normalizes motor and cognitive alterations in a

rat model of psychosis. In light of these results, we are now evaluating the potential of Gpr88

as a therapeutic target for the non-motor symptoms of PD.

To this end, a rat non-motor model of PD was obtained by lesioning dopamine afferences to

the dorsolateral striata through bilateral injections of 6OHDA. Lentiviral vectors expressing

micro-RNA (miR) sequences were later injected for Gpr88-KD either in the dorsolateral,

dorsomedial or ventral subregions of the STR. The effects both procedures were then

evaluated with behavioural testing as well as cellular and molecular analyses.

Results indicate that the Gpr88-KD in discrete striatal regions differentially affects the

disease phenotype. Interestingly, these effects are highly dependent on the dopaminergic state

of the animals, suggesting an interplay between Gpr88 and dopamine. Upcoming studies will

help identify the cellular and molecular bases for these effects, and shed some light on

Gpr88’s function and relevance as a therapeutic target for the NMS of PD.

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Session 2 Poster 1

TBC. Natalie Welsh

Session 2 Poster 2

Rare variants associated with schizophrenia and bipolar disorder

Mariam Aleissa, Andrew Mcquillin

The microcephalin 1 gene (MCPH1) plays an important role in DNA damage and repair and

cell cycle arrest, with the BRCT1 domain being important for centrosomal localization

throughout the cell cycle. A low frequency MCPH1 variant rs61749465 A>G (p.Asp61Gly)

showed evidence for association with schizophrenia (SCZ). We further explored this variant

in 2,300 bipolar disorder (BPD), 1,930 SCZ subjects and 1,820 normal comparison subjects

and report evidence for association with BPD (P=0.0009). Notably the variant allele of

rs61749465 was absent in the 1,820 comparison subjects tested. rs61749465 is located in the

N-terminal BRCT1 domain of MCPH1 and bioinformatic analysis predicted the Asp61Gly

substitution to be damaging to MCPH1 protein function. A second MCPH1 BRCT1 domain

variant (rs199422124 C>G; p.Thr27Arg), reported to cause autosomal recessive

microcephaly, was also genotyped however the variant was not detected in any of the

subjects tested.

We sought to characterize the functional effects of these variants on MCPH1 function. Cell

viability and cell count assays indicated that the variant allele of rs199422124 had a larger

impact on cell survival compared to the variant allele of rs61749465, however neither of the

variant alleles significantly altered DNA damage or mRNA stability. Analysis of gene

expression data from RNA sequencing experiments suggested that rs61749465 expression

altered the expression of a number of genes involved in protein translation and in the

Alzheimer's disease pathway. Confirmation of the findings presented here could further our

understanding of the role of genetic variants in the risk of developing a psychotic disorder.

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Session 2 Poster 3

Development of biofluid biomarkers for Huntington's Disease

Lauren Byrne, Ed Wild

Background: Blood biomarkers of neuronal damage could facilitate clinical management of

and therapeutic development for Huntington's disease (HD). We investigated whether

neurofilament light protein (NfL) in blood is a potential prognostic marker of

neurodegeneration in patients with Huntington's disease.

Methods: In the 3-year, 298-participant TRACK-HD cohort, we did a retrospective analysis

of the relationship between plasma NfL and clinical and neuroimaging measures previously

identified as being the strongest predictors of HD progression. Cross-sectional and

longitudinal relationships were analysed using random effect models of within-subject

correlation. In a separate 37-participant cohort we quantified NfL in cerebrospinal fluid

(CSF) and plasma.

Results: Mean concentrations of NfL in plasma at baseline were significantly higher in HTT

mutation carriers than in controls (3.63 [SD 0.54] log pg/mL vs 2.68 [0.52] log pg/mL,

p<0.0001) and the difference increased with disease stage. At any given timepoint, plasma

NfL correlated with clinical and MRI findings. In longitudinal analyses, baseline plasma NfL

also correlated significantly with subsequent decline in cognition (SDMT r=–0.374,

p<0.0001; SWR r=–0.248, p=0.0033), TFC (r=–0.289, p=0.0264), and brain atrophy (caudate

r=0.178, p=0.0087; whole-brain r=0.602, p<0.0001; grey matter r=0.518, p<0.0001; white

matter r=0.588, p<0.0001; and ventricular expansion r=–0.589, p<0.0001). All changes

except SWR and TFC remained significant after adjustment for age and CAG repeat count. In

premanifest HD individuals, plasma NfL at baseline was associated with subsequent clinical

onset during the 3-year follow-up period (hazard ratio 3.29 per log pg/mL, 95% CI 1.48–

7.34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation

carriers (r=0.868, p<0.0001).

Interpretation: NfL in plasma shows promise as a potential prognostic blood biomarker of

disease onset and progression in Huntington's disease.

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Session 2 Poster 4

Modifiers of age-at-onset penetrance of LRRK2 G2019S Parkinson's

Disease

Emmeline Brown, Nicholas Wood

The G2019S mutation in the LRRK2 gene predominantly causes late-onset typical

Parkinson’s disease. It is the single most common single nucleotide polymorphism implicated

in the disease. The mutation exhibits reduced age-at-onset penetrance, with starkly varying

onset ages: some carriers get the disease before age 30, whereas others are never affected

despite living into advanced age. In recent years, estimates of penetrance have fallen (likely

due to biasing features of early study design), sometimes to levels associated with risk factors

(25-42.5% at age 80). It is hypothesised that genetic factors play a strong role in modifying

the age-at-onset of motor symptoms of Parkinson’s disease. A number of studies have

attempted to find these factors, most recently Farrer et al (2016) propounded modification by

DNM3 and the LRRK2 trans haplotype. However, as a late-onset disease, there is significant

scope for environmental factors to impact outcome, which complicates the discovery of

genetic modifiers. Accruing sufficient sample size also poses a challenge.

We performed survival analysis, using age-at-onset of motor symptoms, on the LRRK2 trans

haplotype for 55 G2019S carriers (who all carried the same ancestral pathogenic haplotype),

and on DNM3 (using 38 G2019S carriers). No association with altered age-at-onset was

discovered. DNM3 has been refractory to replication efforts by other laboratories. A more

refined and extensive phenotypic measure (than age-of-onset) will likely be important in the

discovery of Parkinson’s disease genetic modifiers.

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Session 2 Poster 5

Constructing confidence in the absence of feedback

Marion Rouault, Steve Fleming

Accurately evaluating our decisions is essential to adaptive behavior. Metacognition refers to

this ability to monitor, assess and learn about our own cognitive operations. Metacognition is

particularly useful since most real-life decisions lack immediate feedback: evaluation can be

ambiguous, delayed, may only occur after a whole sequence of subsequent decisions, or

might just never occur at all. Yet, previous behavioral and neural evidence suggest that we

are able to evaluate our own choices in the absence of feedback, for instance detecting errors

long before we are informed. Although learning from explicit feedback has been extensively

studied, less is known about the behavioral and computational mechanisms underlying

metacognitive learning in the absence of feedback. Our study examines this question.

In short learning blocks, human subjects (N=29) performed two perceptual tasks (interleaved

trials). Each pair of tasks was chosen according to a 2 by 2 factorial design crossing task

difficulty (easy, difficult) and feedback (present, absent). At the end of a block, we measured

subjects’ confidence in their facility in each task, either indirectly (as a choice between the

two tasks) or directly (via ratings). We found that objective task performance and reaction

times were similar with and without feedback. However, even though performance was no

different, participants were significantly less confident in the absence of feedback, by either

direct or indirect report.

When we replicated the experiment (N=29), whilst varying the length of each block, we

found that feedback influenced the course of learning. With feedback, a longer learning phase

increased the difference in confidence between easy and difficult tasks. In contrast, the

amount of learning had no influence on confidence in the absence of feedback.

To understand how subjects build “global” beliefs about self-ability from local task

experience, we are developing a hierarchical model. A local module based on normative

Bayesian models of perceptual decisions was able to explain trial-by-trial perceptual choices,

and provided an index of local confidence. This local module was embedded into a global

learning scheme in which beliefs about self-ability on each task were constructed from local

confidence across trials. Initial simulations and model comparison suggest that local

confidence may act as a learning signal in the absence of feedback, allowing subjects to

develop insight into their abilities.

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Session 2 Poster 6

Genetic modifiers of trinucleotide repeat diseases

Michael Flower, Sarah Tabrizi

There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but

analysis is inevitably limited by advanced disease and postmortem changes. However, mutant

HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily

available and contains cells that are dysfunctional in HD, could act as a surrogate for brain

tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD

cohorts, and performed gene set enrichment analysis using public databases and weighted

correlation network analysis modules from HD and control brain datasets. We identified

dysregulated gene sets in blood that replicated in the independent cohorts, correlated with

disease severity, corresponded to the most significantly dysregulated modules in the HD

caudate, the most prominently affected brain region, and significantly overlapped with the

transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and

use of gene sets likely surmounted the limitations of previously inconsistent HD blood

expression studies. Our results suggest transcription is disrupted in peripheral cells in HD

through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with

Alzheimer’s disease, suggesting a common pathogenic mechanism involving macrophage

phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic

approaches

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Session 2 Poster 7

Correlation between GAA expansion length and frataxin upregulation in

Friedreich’s ataxia

McAteer S1, Bayot A, Abeti R1, Thomas-Black G1, Nethisinghe S1, Giunti P1 1Department of Molecular Neuroscience, Institute of Neurology, UCL, Ataxia Centre, London UK

Friedreich’s ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused

by a mutation in the frataxin (FXN) gene, which encodes for the protein frataxin. In FRDA

patients the repeat triplicate GAA expansion located within the first intron leads to inhibited

gene expression. The length of the shorter (GAA)n expanded allele has previously been

shown to positively correlate with disease severity and negatively correlate with age of

symptom onset. The molecular pathogenesis of FRDA involves epigenetic modifications that

result in transcriptional silencing of FXN. Therefore, therapeutics in FRDA research have

focused on targeting these mechanisms to develop potentially suitable treatments. However,

the results from both in vivo and in vitro investigations have been variable. In this study, we

looked to investigate a potential correlation between the GAA repeat expansion length and

treatment dependent frataxin upregulation in FRDA. To determine a possible relationship,

peripheral blood mononuclear cells were extracted from FRDA patients and healthy controls

and subsequently treated with the three drug compounds: RG2833, thiamine, and BIX-1294.

Both FXN mRNA and protein concentration were analysed for treatment induced changes

and potential correlation with GAA expansion size. Both R2833 and BIX-01294 were found

to have variable levels of FXN mRNA upregulation. In addition, we report a lack of

therapeutic efficacy of thiamine treatment at both FXN mRNA and protein levels in PBMCs

of FRDA and control subjects. We report no apparent correlation between the GAA repeat

sizes of our investigation and the changes in either FXN mRNA expression or protein

concentration, due to the treatment with RG2833 or BIX-01294. However, this was to be

expected given as our FRDA cohort as was limited in minimal differences in GAA repeat

length. Further studies recruiting patients with much larger expansions are required to

elucidate the role of these compounds in improving frataxin expression in more severely

affected FRDA patients.

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Session 2 Poster 8

Identifying early ALS pathology in a mouse model

Alan Maza, Elizabeth Fisher

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset motor neurone disease characterised

by progressive degeneration of upper and lower motor neurones (UMN, LMN respectively).

Clinical signs of ALS start focally as an asymmetrical muscle weakness and fasciculation

(spinal-onset) or dysarthria, aphasia and tongue fasciculation (bulbar-onset), but then rapidly

progress to paralysis and eventual death typically within 3-5 years of diagnosis. Interestingly,

cognitive alterations can also occur in ALS, particularly in those cases where fronto-temporal

dementia (FTD) is also found. The principle aim for my PhD research is to characterize the

earliest changes in the peripheral and central nervous system in our novel FUS animal model

(“FUS Delta14 model”) carrying a de novo FUS splice-site mutation reported in a sporadic

ALS patient28. This FUS Delta14 model carries one copy of the endogenous truncated FUS

protein lacking the NLS domain and the FUS gene is under control of the endogenous

promoter (submitted article). So far, this FUS Delta14 model has progressive LMN loss,

motor alteration at 18 months of age together with denervation of NMJ at 18 months with no

other symptoms. Finally, by transcriptomic analysis we have found alteration in genes

involved in ribosomal and mitochondrial functions at 12 months but not at 3 months of age,

suggesting these changes are associated with the progression of ALS-like disease. Hence,

FUS Delta14 model represents a highly valuable tool to study the earliest stage of ALS.

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Session 2 Poster 9

Nanoscopy of tripartite synapses

Janosch Heller, Dmitri Rusakov

Astrocytes play an active role in shaping and maintaining neuronal circuits. In addition to

their long-established role in extracellular potassium buffering and glutamate uptake, these

cells can also regulate the activity of local synaptic circuits through secretion and clearance of

neurotransmitters. Whilst the molecular signal exchange between astroglia and synapses

occurs in a highly heterogeneous microenvironment on the nanoscale, the spatial subcellular

distribution of the underlying molecular machineries remains poorly understood.

We have therefore employed super-resolution microscopy techniques such as dSTORM

(direct stochastical optical reconstruction microscopy) to visualise the 3D positions of

neurotransmitter receptors and transporters in astrocytes. This imaging technique relies on the

sequential activation, imaging and bleaching of a sparse subset of fluorescent molecules.

Thus, images can be obtained with sub-diffraction resolution by localising individual

activated molecules in each frame. Using dSTORM, we were able to localise cytoskeletal

proteins as well as clusters of receptors and transporters in astrocytic and neuronal

membranes in fixed cultured cells and in brain slices. Moreover, through multi-colour

imaging, the positional relationship between synapses and astroglial receptors and

transporters can be assessed. We are currently attempting to determine whether the astroglial

coverage of excitatory as well as inhibitory synapses is altered in different conditions

compatible with long-term synaptic potentiation or depression.

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Session 2 Poster 10

A neuronal circuit linking temperature to day sleep onset

Angelique Lamaze, James Jepson

Day and night sleep are differently regulated. This suggests that they use different neuronal

and molecular circuits for their regulation. In particular, we have recently shown how a warm

temperature affects specifically day sleep onset via the clock neurons DN1p (A. Lamaze et

al., Sci. Rep., 2017). In order to understand how day sleep is regulated by the environment

(here a warm temperature), I looked for the neuronal target of the DN1p. Here, I found that a

group of neurons receives a direct inhibitory input from the DN1p in the anterior optical

tubercle (AOTU). These neurons are sleep-promoting, but at warm temperature they are

inhibited in the morning by the DN1p. Based on the Two-process model developed by A.

Borbély, sleep regulation can be explained via the interaction of two processes, the circadian

clock (process C) and sleep drive (process S). Here, I propose a model that integrates the

increase of temperature into this model of sleep regulation.

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Session 2 Poster 11

Identification of novel pathogenic mechanisms involved in mTOR-related

epilepsy.

Bacq A1, Ribierre T1, Marsan E1, Muraca G1, Leguern E1 and Baulac S1. 1Genetics and Physiopathology of Epilepsy, Institut du Cerveau et de la Moelle Épinère, INSERM UMR 1127,

Paris, France.

The laboratory of S. Baulac is passionate about the focal familial epilepsy. While earlier

genetic studies suggested a strong contribution of ion channel and neurotransmitter receptor

genes in the development of the disease, recent work revealed alternative pathways among

which emerges the mechanistic target of rapamycin (mTOR) signal transduction pathway. In

this pathway, DEPDC5 gene (whose mutations were first identified by Dr Baulac’s team) is

known to be the most frequently mutated gene in inherited focal epilepsies. The majority of

mutations are loss-of-function and many of the patients (up to 78%) are resistant to

conventional antiepileptic drugs.

Focusing on DEPDC5, my project aims to identify novel pathogenic mechanisms involved in

focal epilepsy and neurodevelopmental comorbidities. DEPDC5 is part of the GATOR1

complex, a repressor of the mTOR complex 1 signaling pathway, master regulator of cellular

functions. However, the specific function of DEPDC5 in the brain and its role in epilepsy

remain unknown. To successfully conduct this promising investigation, I am planning to

combine state-of-the-art molecular, cellular, and behavioral approaches in genetic mouse

models. In one part, I will study the neuronal function of DEPDC5, dependent and

independent of mTOR pathway. And in another part, I will characterize a relevant animal

model of the pathology, by combining generalized and focal inactivation of DEPDC5.

Altogether, this project should provide significant insights towards the understanding of

epileptogenesis and a clinical impact for patients with the subsequent opportunities of new

therapies development to control refractory seizures.

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Session 2 Poster 12

Stephanie Jouannet

Gliomas are the most frequent primary brain tumors in adults and also the most aggressive,

with overall poor survival. They are classified by the world health organization (WHO)

according to their malignancy grade (I-IV) and resemblance to normal glial cells (astrocytes

and oligodendrocytes). The gene mutation of IDH (Isocitrate DesHydrogenase) results in the

formation of a neo-enzyme producing a large amount of D-2-Hydroxyglutarate (D2HG) in

nearly 2/3 of the low-grade glioma and grade III glioma. This neo-oncometabolite promoting

tumor DNA and histones hypermethylation, and therefore cellular epigenome

reprogramming. Our hypothesis is that the D2HG released could also modify tumors

associated macrophages/microglia (TAMs). Our aim is to investigate the methylome which

could induce a modification of the M1 (pro-inflammatory) vs M2 (anti-inflammatory)

polarization of the TAMs and identified the role of these potential modifications on glioma

progression and treatment resistance.

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Session 2 Poster 13

Learning distributions of shape trajectories: a hierarchical model on a

manifold of diffeomorphisms

Alexandre Bône, Olivier Colliot, Stanley Durrleman (i) Sorbonne Universités, UPMC Université Paris 06, Inserm, CNRS, Institut du Cerveau et de la Moelle (ICM)

-- Hôpital Pitié-Salpêtrière, 75013 Paris, France. (ii) Inria Paris, Aramis project-team, 75013 Paris, France

We propose a mixed effects statistical model to learn a distribution of shape trajectories from

longitudinal data, i.e. the collection of individual objects repeatedly observed at multiple

time-points. Shape trajectories and their variations are defined via the action of a group of

deformations. The model is built on a generic statistical model for manifold-valued

longitudinal data, for which we propose to use a finite-dimensional set of diffeomorphisms

with a manifold structure, an efficient numerical scheme to compute parallel transport on this

manifold and a specific sampling strategy for estimating shapes within a Markov Chain

Monte Carlo (MCMC) method. 

The method allows the estimation of an average spatiotemporal trajectory of shape changes at

the group level, and the individual variations of this trajectory in terms of shape and pace of

shape changes. This estimation is obtained by a Stochastic Approximation of the

Expectation-Maximization (MCMC-SAEM). We show that the algorithm recovers the

optimal model parameters with simulated 2D shapes. We apply the method to estimate a

scenario of alteration of the shape of the hippocampus 3D brain structure during the course of

Alzheimer's disease.

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Session 2 Poster 14

Molecular profiling of DCN neuronal circuit development

Iryna Mohylyak

Our individual variation in behavior is that key feature of our personality. The crucial

question of whether and how our individuality of behavior and its variability in the

population might be reflected in the single brains remains unknown. The Brain works as an

interconnected system where different specialized areas continuously exchange information

through stable synchronous connectivity patterns. Those connectivity map is unique to every

individual, and reflects our personality. The unique connectivity patterns of individuals arise

during development through intrinsically variable axon growth mechanisms. Therefore,

deciphering the mechanisms of axonal growth is important for expanding our understanding

of brain wiring during development.

Using a group of cells in the Drosophila brain called the Dorsal Cluster Neurons it was

shown that the development of higher order neural circuits in the fly visual system is

intrinsically variable, resulting in a range of possible circuit diagrams among genetically

identical individuals. Ongoing work in the laboratory shows that the variation in circuit

wiring predicts the stable innate orientation behavior of an individual fly in an object fixation

task. This wiring variability is regulated by a process of cell-cell signaling mediated by the

Notch signaling pathway. The goal of this project is to determine the differential molecular

state of DCN neurons at two determinative time points, before and after Notch signaling. We

will test if, when and how the intrinsic variation in neuronal circuit wiring is reflected by

variation of gene expression in DCN neurons, as well as if this variation is cause or

consequence of wiring variability. We will do this by identifying and validating DCN specific

differentially expressed genes and test their potential function in DCN wiring and wiring

variability. 

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Session 2 Poster 15

Mechanisms of neuronal death in Parkinson’s disease: impact of Parkin

deficiency on the mitochondrial stress response.

HAMON Emeline1, JACOUPY Maxime1, ERPAPAZOGLOU Zoi1, MOUTON-LIGER

François1, BRICE Alexis1, CORTI Olga1

1.Institut du Cerveau et de la Moelle épinière Paris, France

Parkinson’s disease (PD) is characterized by the specific degeneration of the dopaminergic

neurons of the substantia nigra. Autosomal recessive PD forms are caused by mutations in

the genes encoding the E3 ubiquitin ligase Parkin (PARK2) and the mitochondrial

serine/threonine-protein kinase PINK1 (PARK6). These proteins jointly regulate the

autophagic degradation of damaged mitochondria, a process termed mitophagy. Mitophagy is

a part of a more global response of the cell to mitochondrial stress, involving the activation of

other protective pathways, such as the antioxidant and mitochondrial unfolded protein

responses, translational attenuation and mitochondrial biogenesis. These pathways have

rarely been studied together, and whether PINK1 and Parkin dysfunction affects them more

generally remains to be clarified.

We addressed these questions in primary cortical neurons form wild-type and PARK2 KO

mice treated with the protonophore, CCCP, to induce mitochondrial stress. We studied

mitophagy by following the clearance of markers of submitochondrial compartments. In

parallel, we explored the activation of the other above-mentioned mitochondrial stress

response pathways, by following in time the expression profile of key transcriptional

regulators involved and their downstream targets using real-time RT-qPCR, and validating

key findings by western blot. Our results show that CCCP treatment triggers mitophagy and

is accompanied by the global induction of the targeted stress pathways in wild type neurons.

In contrast, mitophagy was impaired and the transcriptional profiles of most of the genes

studied were altered in PARK2 KO neurons.

Altogether, our studies suggest that neurodegeneration in PARK2-linked PD is caused by the

inability of the cell to appropriately respond to mitochondrial stress.

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Session 2 Poster 16

GABAA receptor diversity and dendritic inhibition from neocortical

interneurons

Cristina Donato1, Javier Zorrilla de San Martin1, Carolina Cabezas1, Andrea Aguirre1, Andrea

Barberis2, Marie-Claude Potier1, Alberto Bacci1

1 ICM- Institut du Cerveau et de la Moelle épinière, Groupe hospitalier Pitié-Salpetriere, 47 Boulevard de

l’Hôpital, 75013 Paris, France. 2 IIT – Istituto Italiano di Tecnologia, Department of Neuroscience and Brain

Technologies, Genova, Italy

In the neocortex, inhibition sculpts all forms of cortical activity and is involved in several

brain diseases. Neocortical inhibition is provided by locally projecting GABAergic

interneurons, which encompass a vast number of cell subclasses. Some interneurons, known

as basket cells, innervate the perisomatic region of cortical pyramidal neurons (PNs), whereas

others are specialized in targeting dendrites. Importantly, dendrite-targeting interneurons are

believed to control the integration of glutamatergic synapses onto PNs. We performed

simultaneous patch clamp recordings from connected dendrite-targeting Martinotti cells

(MCs) and PNs in layer 2/3 of mouse somatosensory cortex. We found that these connections

relied on GABAARs, selectively expressing the α5 subunit. In addition, we found that this

GABAAR α subunit was not present at GABAergic synapses formed by other interneuron

subtypes. The α5 subunit is known to be involved in tonic inhibition. Yet, our data on unitary

and spontaneous synaptic responses suggest that in layer 2/3 PNs, α5 majorly contributed to

synaptic phasic inhibition from MCs.

Importantly, it was shown that the treatment with a highly specific α5 inverse agonist

completely rescued learning and memory deficits in Ts65Dn mice, an animal model for

Down syndrome (Braudeau J et al., 2011; Martìnez-Cué et al., 2014), although the actual

mechanism(s) at the synaptic and circuit levels are unknown. Our preliminary results suggest

that MC-PN connections are stronger in trisomic mice, as opposed to their euploid

littermates. We are in the process of establishing the underlying mechanisms and circuit-

specific properties of this enhanced inhibition.

All together results of our experiments will lead to a better understanding of the physiological

properties and function of this specific synapse originating from dendrite-targeting MCs,

fundamentally advancing the general knowledge of neocortical physiology underlying both

normal behaviors and pathological activities.

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Session 2 Poster 17

Synaptic changes upon removal of extracellular perineuronal nets in adult

visual cortex

Faini G.1, Aguirre A.1, Landi S.2, Ratto G.2, Pizzorusso T.3, Deleuze C.1, Bacci A.1

1 ICM, UMR S 112; Inserm U 1127; CNRS UMR 7225, France, 2 Institute Nanoscience, Pisa, Italy; Scuola

Normale Superiore, Pisa, Italy, 3 CNR, Istituto di Neuroscienze, Italy; Dip. NEUROFARBA, Università di

Firenze, Italy

The maturation of sensory processing undergoes a critical period (CP), during which cortical

neural circuits are sculpted and changed by experience. The closure of CP is paralleled by the

accumulation of extracellular perineuronal nets (PNN) around parvalbumin (PV)-positive,

fast-spiking interneurons. These condensed and specialized extracellular matrix composed of

chondroitin sulfate proteoglycans, surround cell body and proximal dendrites of PV cells and

restrains neuronal plasticity. Indeed, the degradation of PNNs in adult animals was shown to

re-open the structural plasticity typical of the CP, but absent during adulthood. Although the

mechanisms underlying CP have been studied, the functional aspects linking PNNs to

activity-dependent plasticity remain obscure.

By combining electrophysiological and optogenetic approaches, together with in vivo

degradation of PNN (stereotaxic injection of the bacterial enzyme Ch-ABC) and sensory

deprivation, we aimed at defining i) the neurophysiological properties of FS interneurons in

layer 4 of primary visual cortex (V1) during the establishment of the CP, and ii) how these

properties are altered by PNN accumulation. PV cells were compared to their glutamatergic

counterparts, the regular spiking (RS) spiny-stellate neurons (referred as principal neurons

PN).

We found a robust age-dependent increase of input-output firing relationships in both cell

types, with no overall change in their passive electrical properties. Importantly, we found that

in vivo PNN removal in V1 in adult mice did not affect the action potential properties and

firing dynamics Importantly, we found that in vivo PNN removal in V1 in adult mice

increased both excitatory and inhibitory transmission selectively onto PV cells, leaving their

excitability intact, and recapitulating younger, pre-CP states. In addition, triggering plasticity

in vivo by monocular deprivation (MD) did not boost the increased activity onto PV

interneurons. Interestingly, paired recordings in layer 4 of V1 showed no changes of

inhibitory unitary connections in the presence and absences of PNNs. In order to understand

96

the circuit mechanisms underlined, we expressed the light-sensitive opsin channelrhodospin 2

in the visual thalamus. We found that PNN removal increases the recruitment of PV cells by

thalamocortical fibers leading to an increase of feedforward inhibition onto PV cells and

possibly onto PN. These results are in agreement with V1 recordings in vivo of visually

evoked potentials in response of increasing contrast. Indeed, PNN disruption caused a

reduction of the slope of the contrast sensitivity curve, indicating a higher recruitment of

inhibition.

In conclusion, we found that PNN removal in adult visual cortex increases the specific

recruitment of PV cells by thalamic fibers. Increased PV cell recruitment results in a neuron-

specific alteration of the E/I balance both in vitro and in vivo. These experiments shed light

on the basic mechanisms underlying cortical plasticity, and its reopening through PNN

removal.

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Session 2 Poster 18

Looking for predictors in MI-based BCI

M.-C. Corsi, F. De Vico Fallani Inria Paris, Aramis project-team, 75013, Paris, France. Sorbonne Universités, UPMC Univ Paris 06, Inserm,

CNRS, Institut du cerveau et la moelle (ICM) - Hôpital Pitié-Salpêtrière, Boulevard de l’hôpital, F-75013, Paris,

France

Non-invasive BCIs are largely used to produce thought-provoked action, by exploiting the

ability of subjects to voluntary modulate their brain activity through mental imagery (MI).

However, it appears to be a learned skill, which needs several sessions to reach significant

performances [1],[15], and a phenomenon such as the “BCI illiteracy” [3] reduces the

usability of MI-based BCIs [4].

This gap has motivated a deeper understanding of mechanisms associated with MI tasks [5]–

[7], to identify features that enhance proficiency of co-adaptive BCI frameworks [8], [9]. The

specificity of the NETBCI project is to perform multimodal (M/EEG, MRI) experiments.

Among the objectives is finding predictors of BCI learning. Typically, they can be sorted in

two categories: neurophysiological [10]–[13] and psychological predictors [14], [15]. Taking

advantage of the longitudinal aspect of this protocol (2 sessions per week, during 2 weeks),

temporal influence can also be studied to see if predictors which influence MI performances

within a session are also involved in the evolution of the performance between sessions.

From very preliminary BCI results obtained from 12 BCI-naive participants (6 females; aged

27,8 ± 4.5), after observing a significant performance improvement from session 3, self-

esteem and motivation tend to have an influence on session performance whereas kinesthetic

imagery tends to be involved in global accuracy improvement.

Time seems to be a parameter to take into account when building a predictive model of MI

performances. At the moment, only psychological predictors have been studied in the frame

of this protocol, whereas neurophysiological predictors, such as mu-rhythm over

sensorimotor areas, need also to be considered to build a proper predictive model. In parallel

of the next experiments, other possible predictors will be studied in the perspective of finding

alternatives features extraction and/or classification tools.

[1] D. J. McFarland, A. T. Lefkowicz, and J. R. Wolpaw, “Design and operation of an EEG-based brain-

computer interface with digital signal processing technology,” Behav. Res. Methods Instrum. Comput., vol. 29,

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no. 3, pp. 337–345, Sep. 1997. [2] J. R. Wolpaw, N. Birbaumer, D. J. McFarland, G. Pfurtscheller, and T. M.

Vaughan, “Brain–computer interfaces for communication and control,” Clin. Neurophysiol., vol. 113, no. 6, pp.

767–791, Jun. 2002. [3] B. Z. Allison and C. Neuper, “Could Anyone Use a BCI?” in Brain-Computer

Interfaces, D. S. Tan and A. Nijholt, Eds. Springer London, 2010, pp. 35–54. [4] C. Zickler and al., “BCI

Applications for People with Disabilities: Defining User Needs and User Requirements,”In proceedings of the

AAATE conference, 2009. [5] J. Toppi et al., “Investigating the effects of a sensorimotor rhythm-based BCI

training on the cortical activity elicited by mental imagery,” J. Neural Eng., vol. 11, no. 3, p. 35010, Jun. 2014.

[6] V. Kaiser et al., “Cortical effects of user training in a motor imagery based brain–computer interface

measured by fNIRS and EEG,” NeuroImage, vol. 85, Part 1, pp. 432–444, Jan. 2014. [7] S. Perdikis, R. Leeb,

and J. del R. Millán, “Subject-oriented training for motor imagery brain-computer interfaces,” Proc. 36th Annu.

Int. Conf. IEEE Eng. Med. Biol. Soc., 2014. [8] C. Vidaurre, C. Sannelli, K.-R. Müller, and B. Blankertz,

“Machine-Learning-Based Coadaptive Calibration for Brain-Computer Interfaces,” Neural Comput., vol. 23, no.

3, pp. 791–816, Dec. 2010. [9] C. Vidaurre, C. Sannelli, K.-R. Müller, and B. Blankertz, “Co-adaptive

calibration to improve BCI efficiency,” J. Neural Eng., vol. 8, no. 2, p. 25009, Apr. 2011. [10] B. Blankertz et

al., “Neurophysiological predictor of SMR-based BCI performance,” NeuroImage, vol. 51, no. 4, pp. 1303–

1309, juillet 2010. [11] A. Bamdadian, C. Guan, K. K. Ang, and J. Xu, “The predictive role of pre-cue EEG

rhythms on MI-based BCI classification performance,” J. Neurosci. Methods, vol. 235, pp. 138–144, Sep. 2014.

[12] M. Grosse-Wentrup, B. Schölkopf, and J. Hill, “Causal influence of gamma oscillations on the

sensorimotor rhythm,” NeuroImage, vol. 56, no. 2, pp. 837–842, May 2011. [13] M. Grosse-Wentrup and B.

Schölkopf, “High γ-power predicts performance in sensorimotor-rhythm brain-computer interfaces,” J. Neural

Eng., vol. 9, no. 4, p. 46001, Aug. 2012. [14] E. M. Hammer et al., “Psychological predictors of SMR-BCI

performance,” Biol. Psychol., vol. 89, no. 1, pp. 80–86, Jan. 2012. [15] C. Jeunet, B. N’Kaoua, S. Subramanian,

M. Hachet, and F. Lotte, “Predicting Mental Imagery-Based

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Session 2 Poster 19

Characterization of the endosomal compartment in Alzheimer’s disease.

Laura Xicota1, Emeline Gallo1, Clément Gauthier2, Julien Lagarde3, Marie Sarazin3 and

Marie-Claude Potier1. 1ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, UPMC, Hôpital de la

Pitié-Salpêtrière, 47 Bd de l’Hôpital, Paris; 2Institut de Recherches Servier, 125 chemin de Ronde, Croissy-sur-

Seine ; 3Unit of Neurology of Memory and Language, Université Paris Descartes, Sorbonne Paris Cité,

INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris.

Alzheimer’s disease (AD) is the most common form of dementia affecting, in 2015, a total of

47.47 million people worldwide. It is characterized by the accumulation of amyloid plaques

in the cerebral parenchyma; such plaques are formed by amyloid peptides, the byproducts of

the cleavage of the amyloid precursor protein. This processing takes place in the early

endosomes, which have proven to be enlarged in brain tissue of individuals with AD, even

before the accumulation of both amyloid plaques and neurofibrillary tangles.

Previous research in our group has shown that this alteration in early endosomes can also be

detected in peripheral cells, namely in peripheral blood mononuclear cells (PBMCs) and in

skin fibroblasts (Corlier et al., 2015). In the case of PBMCs there was a higher percentage of

cells containing larger endosomes in both individuals with mild cognitive impairment (MCI)

and AD. Additionally, endosomal volume in PBMCs and PiB retention positively correlated

in cognitively affected individuals. Similar results were observed in fibroblasts, with AD

individuals having a higher percentage of cells with larger endosomes. These results open the

possibility of a new generation of biomarkers that would allow an early identification of AD.

Following these results, our objective is to better understand the alterations in the endosomal

compartment in MCI and AD in peripheral cells. In particular we will further analyze the

enlargement of early endosomes, their biochemical (Ca2+ concentrations and pH), and

biomolecular characteristics (protein content), with the endpoint of identifying prognostic

peripheral biomarkers. To this end we will use skin fibroblasts from the IMABIO3 cohort

which includes healthy, MCI, and individuals with AD.

Preliminary results obtained from a pilot study, which included three individuals of each

group, support our previous observations showing that individuals with MCI or AD had a

higher percentage of enlarged endosomes. These preliminary results are promising and will

need to be confirmed on additional individuals from the IMABIO3 cohort.

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Session 2 Poster 20

The neuroinflammatory components in C9-FTD/ALS

Julie Smeyers1, Julia Sepulveda-Diaz1, Florencia Gonzales1, Clémence Fournier1, David

Akbar1, Vincent Anquetil1, Isabelle Le Ber1, Morwena Latouche1

1.Brain and spine institute (ICM), 47 bvd de l’hôpital 75014 Paris

Frontotemporal dementias (FTD) are a group of neurodegenerative diseases characterized by

a frontal and temporal cortical lobes atrophy causing cognitive and behavioural troubles in

patients. FTD are associated to Amyotrophic lateral Sclerosis (ALS), a motoneuron disease

that leads to paralysis. Nowadays, there is no cure and life expectancy is less than ten years

for FTD or ALS patients. In fact, a real continuum exists between these two pathologies,

from a clinical, neuropathological and molecular point of view. Mutations in the C9ORF72

gene are the most common cause of familial forms of FTD (25%), ALS (40%) and FTD-ALS

(76%). Mutations correspond to a heterozygous G4C2 non-coding repeat expansion leading

to RNA foci formation and dipeptides repeats (DPR) aggregation. Moreover, the expansion

inhibits the transcription of a complete C9ORF72 mRNA causing protein haploinsufficiency

that could contribute to the pathology. The function of the C9ORF72 protein, though largely

unknown, seems to be linked to innate immunity. This suggests an important contribution of

neuroinflammation in the disease. Moreover, innate immunity can be activated by some

protein aggregates (like aβ and α-synuclein aggregates). In C9ORF72 FTD-ALS as well as in

most forms of FTD (60%) and ALS (90%) inclusions of TDP-43 protein are formed and are

thought to participate in the neuropathological process. Our project aims to determine innate

immunity implication in FTD-ALS caused by C9ORF72 mutations. Therefore, we are

studying in vitro and in vivo (i) if TDP-43 aggregates are involved in microglia activation (ii)

what inflammatory pathways are activated in microglia in FTD-ALS-C9ORF72?

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Session 3 Poster 1

Apolipoprotein E is necessary for plaque-‐associated synapse loss in a transgenic mouse

model of Alzheimer’s disease.

Cannavo, C. (1), Jackson, R. (1), Spires-‐Jones, T. (1), Hudry, E. (2)

(1) UK Dementia Research Institute, Centre for Dementia Prevention, and Edinburgh Neuroscience, The

University of Edinburgh

(2) MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical

School

Alzheimer’s Disease (AD) is the most common form of dementia in the elderly population.

Cognitive impairment is the main clinical symptom of AD, which correlates strongly with

loss of the connections between neurons (synapses), but the molecular mechanisms leading to

synapse loss remain unclear. AD is characterised by the pathological accumulation of

amyloid beta (Ab) in plaques, and the risk of developing AD is greatly increased by

inheritance of the apolipoprotein E epsilon 4 allele. [1]

The presence of toxic Ab oligomers surrounding plaques is associated with synapse loss in

both human AD brain and in mouse models of the disease. Using high resolution imaging of

synapses with array tomography, we previously observed that the apolipoprotein E epsilon 4

isoform (apoE4), which increases the risk of AD, is associated with more synaptic Ab than

the neutral E3 isoform in human AD brain. [2]

In this study, we investigated the relationship between synapse loss, synaptic Ab

accumulation, and apoE by genetically ablating APOE and examining synapse degeneration

around plaques in a mouse model of AD. We hypothesise that knocking out apoE will

reduce plaque-‐associated synapse degeneration. Array tomography imaging demonstrates

that knocking out apoE prevents synaptic loss surrounding amyloid plaques. This confirms

that apoE plays a key role in Ab mediated synapse degeneration, and supports further

investigation into therapeutic targeting of interactions of Ab and apoE to prevent or reverse

synapse loss and cognitive dysfunction.

[1] Kim, Jungsu; Basak, Jacob M; Holtzman, David M “The Role of Apolipoprotein E in Alzheimer’s disease.” Neuron. 2009; 287-‐303

[2] Koffie, Robert M; Hashimoto, Tadafumi; Tai, Hwan-‐Ching; Kay, Kevin R; Serrano-‐Pozo, Alberto; Joyner, Daniel; Hou, Steven;

Kopeikina, Katherine; Frosch, Matthew P; Lee, Virginia M; Holtzman, David M; Hyman, Bradley T; Spires-‐Jones, Tara “Apolipoprotein

E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-‐beta.” Brain. 2012; 2155-‐2168.

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Session 3 Poster 2

A longitudinal Biomarker, Imaging and Psychometric Study of mild Traumatic Brain

Injury (Concussion) in sports.

Etienne Laverse, Prof Huw Morris

Session 3 Poster 3

Microglial exosome secretion coupled to TREM2

Anna Mallach

Session 3 Poster 4

A new rodent model of social exclusion in depression

Anna Fall

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Session 3 Poster 5

Modelization of intrinsic motor neuron defects in Amyotrophic Lateral

Sclerosis with human induced pluripotent stem cells

Cynthia Lefebvre (1), Carine Dalle (2), Boris Lamotte d'incamps (3), Stéphane Blanchard (4),

Guillaume Tournaire (4), Diana Toli (4), Charles Nicaise (5), François Salachas (6), Lucette

Lacomblez (6), Christian Lobsiger (1), Stéphanie Millecamps (1), Séverine Boillée (1),

Delphine Bohl (1). (1) ALS causes and mechanisms of motor neuron degeneration, ICM- INSERM U 1127 - CNRS UMR-7225 –

UPMC, Paris, France. (2) CELIS-E-Phys- ICM- INSERM U 1127 -CNRS UMR-7225 - UPMC- Paris, France.

(3) Ctr. For Neurophysics, Physiol. and Pathology, Paris, France. (4) Neurosciences, Unité Biothérapies pour les

Maladies Neurodégénératives -Inst. Pasteur, Paris, France. (5)Lab. Neurodegeneration and Regeneration,

URPhyMNARILIS, Univ. of Namur, Namur, Belgium. (6) Maladies du Système Nerveux, Ctr. de référence

maladies rares SLA, Hôpital Pitié-Salpêtrière, Paris, France.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by

progressive degeneration and death of motor neurons with no effective therapy. Patients have

only 2 to 5 years of life expectancy after diagnosis. The majority of ALS cases are sporadic

with unknown etiology while around 10% are familial cases. So far, one rodent model

recapitulate the disease and despite several hypotheses regarding the mechanisms leading to

ALS, the genetic heterogeneity make hard the understanding of the exact causes of motor

neuron degeneration. In order to analyze the contribution of ALS causing mutations directly

in human motor neurons, we have generated induced pluripotent stem cells (iPSc) from ALS

patients carrying mutations in the three main genes responsible for ALS (C9ORF72, SOD1,

TARDBP) and patients with sporadic forms, and produced human iPSc-derived motor

neurons in high proportions. Whereas most published reports study patients with one specific

ALS form, our project aims to compare different ALS forms in a same experimental context

in order to identify similarities and differences between the different forms.

Electrophysiological recordings at two time-points of motor neuron cultures suggest that the

excitability of the ALS-derived motor neurons is altered differently in motor neurons derived

from mutant SOD1 and mutant C9ORF72 iPSc than those derived from mutant TARDBP

iPSc. Analysis show that ALS motor neurons cultured in the presence of neurotrophic factors

survive in culture like control ones. However, preliminary data suggest that under stress like

neurotrophic factor deprivation, mutant SOD1 and C9ORF72 motor neurons show growth

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defects and mutant SOD1 and TARDBP motor neurons degenerate. Furthermore, mutant

SOD1 and C9ORF72 motor neurons accumulate neurofilament inclusions but not motor

neurons carrying TARDBP mutation. Interestingly, these accumulations are localized in the

axonal initial segment (AIS), important for maintenance of axonal identity and firing action

potential. Taken together, these results suggest that different pathways to degeneration may

be followed in ALS motoneurons carrying different mutations and draw the hypothesis of a

perturbation of the AIS as a link to motor neuron defect in ALS.

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Session 3 Poster 6

Investigating the physiological function of APP in Drosophila Melanogaster

and its relevance to Alzheimer’s disease

Irini A. Kessissoglou 1, Ariane Ramaekers 1,2 and Bassem Hassan1,2,3

The Amyloid Precursor Protein (APP) is a structurally and functionally conserved

transmembrane protein. APP is mainly known and studied for its involvement in Alzheimer’s

disease (AD), a neurodegenerative disorder characterised by cognitive impairment and

particularly memory loss. APP is present in high quantities in neurons and undergoes two

proteolytic processes. It gets either cleaved by α secretase, producing sAPPα or, in a non-

canonical state, APP is internalised and gets cleaved by β secretase and subsequently γ

secretase, generating sAPPβ and Amyloid β oligomers. Most research on AD has been

focused on the amyloidogenic pathway, targeting the elimination of Amyloid β plaques.

However, considering that these two proteolytic processes happen in different locations and

compete with each other, a shift towards the amyloidogenic pathway reduces the production

of sAPPα. Therefore, this project will be investigating the biology and in vivo physiological

function of sAPPa, and whether perturbing this function is what actually causes AD.

The aim is to describe the molecular underpinnings of sAPPa function and then its

physiological function in the brain homeostasis throughout ageing. To describe the molecular

mechanism where sAPPa is involved in, we will be using the Drosophila Melanogaster as the

model organism, the sAPPa homologue sAPPL and, more specifically, its involvement in the

development of the mushroom bodies’ αβ neurons. Finally, I will be looking at the

physiological function of sAPPa as a robustness factor, maintaining the cellular homeostasis

in the brain throughout ageing and whilst responding to stress. To answer this question, we

will be using the same model as in development but this time in ageing and after placing the

fruit flies under continuous stress conditions, using Paraquat as an oxidative stress factor.

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Session 3 Poster 7

Spg11 knockout mouse, a model of slowly progressive Amyotrophic Lateral

Sclerosis with juvenile onset

Julien Branchu, Maxime Boutry, Laura Sourd, Céline Léone, Alexandrine Corriger, Raphaël

Matusiak, Magali Dumont, Khalid Hamid El Hachimi, Alexis Brice, Giovanni Stevanin,

Frédéric Darios Inserm U1127, CNRS UMR7225, UPMC UMR_S975, Institut du Cerveau et de la Moelle épinière - Paris –

France

Motor neuron diseases regroup a variety of neurological disorders with overlapping

phenotypes. Among these diseases, Amyotrophic Lateral Sclerosis (ALS) is the most

frequent and is characterized by spasticity, muscle weakness and wasting. The symptoms

generally progress rapidly leading to death due to the loss of both upper and lower motor

neurons. Hereditary Spastic Paraplegias (HSP) constitute the second most frequent group of

motor neuron diseases characterized by progressive weakness and spasticity in the lower

limbs. These symptoms are mainly caused by an axonal degeneration of the upper motor

neurons.

The clinical overlap between these pathologies is supported by the mutations found in the

SPG11 gene, which are the main causes of autosomal recessive HSP and are also responsible

for slowly progressive autosomal recessive ALS with juvenile onset. SPG11 encodes a 2,443

amino acid protein of unknown function named spatacsine which localizes to various cellular

organelles and compartments, including endoplasmic reticulum, lysosomes and microtubules.

To investigate how the loss of spatacsine, the protein encoded by SPG11, leads to motor

neuron degeneration we generated and characterized a Spg11 knockout mouse model. These

mice recapitulate most of the clinical hallmarks observed in SPG11 patients: they showed

progressive gait impairment, coordination problems and motor dysfunction that started early

and worsened with time. All the Spg11 knockout mice also exhibited muscle strength loss

and half of them developed lower limb spasticity and walk with stiff legs.

These behavioral deficits were associated with progressive brain atrophy with loss of neurons

in the primary motor cortex and cerebellum as well as global spinal cord atrophy with loss of

the large surface motor neurons and accumulation of dystrophic axons in the corticospinal

tract. Interestingly, examination of the motor neuron alterations showed that the degeneration

was preceded by an accumulation of autofluorescent lipid material in lysosomal structures.

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We are now investigating the nature of these lipids using lipidomic approaches. This new

mouse model will help to decipher the role of spatacsine and the physiopathology of this

disabling disease.

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Session 3 Poster 8

The vmPFC signal: a common neural currency for reward, effort and

confidence

Nicolas Clairis

Standard decision theory assumes that choices are based on a comparison of subjective values

assigned to potential outcomes of available options. A great wealth of neuroimaging studies

have implicated the ventromedial prefrontal cortex (vmPFC) in signaling such subjective

values. Moreover, the vmPFC has been shown to reflect the subjective value of stimuli from

various categories (money, food, painting, music etc.), giving rise to the notion of a common

neural currency. The positive correlation between vmPFC activity and subjective value has

been observed both for appetitive and aversive items, such as monetary gains and losses.

Recently, it has also been demonstrated that the vmPFC encodes confidence (probability of

being correct), which can be seen as a valuation of the response. However, it remains unclear

whether the vmPFC would also integrate action cost, in particular the amount of effort

associated to potential actions. Here, we addressed this question using fMRI while

participants rate the likeability of both reward and effort items. We found that vmPFC

activity correlates positively with reward rating (how pleasant it would be to be given the

reward) and negatively with effort rating (how unpleasant it would be to be imposed the

effort). Furthermore, vmPFC activity also reflected a quadratic function of both reward and

effort rating, which in a previous study was shown to account for confidence level. These

patterns were observed irrespective of the presentation mode (e.g., rewards presented as texts

or images) and the particular sub-categories of presented items (e.g., food vs. non-food

rewards, or cognitive vs. motor effort). Thus, our findings challenge the hypothesis that the

vmPFC would only valuate dimensions in the goods space (as opposed to the action space)

and extends the notion of common neural currency.

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Session 3 Poster 9

Multilevel Modeling for Classification from Imaging Genetics data

Pascal Lu, Olivier Colliot Sorbonne Universités, UPMC Université Paris 06, Inserm, CNRS, Institut du Cerveau et la Moelle (ICM), AP-

HP - Hôpital Pitié-Salpêtrière, INRIA Paris, ARAMIS Project-Team, 75013 Paris, France

We propose a framework for automatic classification of patients from multimodal genetic and

brain imaging data by optimally combining them. In particular, machine learning methods

have been used to build predictors for heterogeneous data, coming from different modalities

for brain disease diagnosis, such as Alzheimer's disease (AD). However, challenging issues

are high-dimensional data, small number of observations, the heterogeneous nature of data,

and the weight for each modality.

Additive models with unadapt penalties (such as the classical group lasso penalty or L1-

multiple kernel learning) treat all modalities in the same manner and can result in undesirable

elimination of specific modalities when their contributions are unbalanced.

To overcome this limitation, we introduce a multiplicative model:

(i) that combines imaging and genetics and that considers joint effects between these two

modalities for diagnosis prediction,

(ii) that uses several penalties taking into account the structure of the different types of data,

such as a group lasso penalty over the genetic modality and a L2-penalty on imaging

modalities.

Finally, we propose a fast optimization algorithm, based on a proximal gradient descent

method.

Our model has been evaluated on genetic (single nucleotide polymorphisms - SNP) and

imaging (anatomical MRI measures) data from the ADNI database (http://adni.loni.usc.edu),

and compared to additive models [2, 3]. It exhibits good performances in AD diagnosis; and

at the same time, reveals relationships between genes, brain regions and the disease status.

This work has been published in [1]. [1] P. Lu, O. Colliot. Multilevel Modeling with Structured Penalties for Classification from Imaging Genetics data. In Graphs in Biomedical Image Analysis,

Computational Anatomy and Imaging Genetics. LNCS 10551. 2017 (https://arxiv.org/abs/1710.03627) [2] H. Wang, F. Nie, H. Huang, S. L. Risacher, A. J.

Saykin, and L. Shen. Identifying disease sensitive and quantitative trait-relevant biomarkers from multidimensional heterogeneous imaging genetics data via

sparse multimodal multitask learning. In Bioinformatics. Vol 28, n°12, pages 127--136. 2012 [3] F. Aiolli, M. Donini. EasyMKL: a scalable multiple kernel

learning algorithm. In Neurocomputing, vol 169, p. 215--224, 2015

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Session 3 Poster 10

Chd7 and Chd8 chromatin remodelers cooperate to induce oligodendrocyte

precursor differentiation and survival

Corentine Marie1, Magali Frah1*, Adrien Clavairoly1*, Hatem Hmidan1, Jun Yan3, Chuntao

Zhao2, Romain Daveau1, Bernard Zalc1, Jean-Léon Thomas1, Pierre Gressens3, Phillipe

Ravassard1, Ivan Mozser1, Brahim Nait-Oumesmar1, Donna Martin4, Richard Q. Lu2, and

Carlos Parras1

1Sorbonne Universités, UPMC University Paris 06, Inserm U1127, CNRS UMR 7225,GHPitié-Salpêtrière,

Institut du Cerveau et de la Moelle Épinière, ICM, 75013 Paris, France. 2Department of Pediatrics, Division of

Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati,

Ohio, USA. 2Integrative Biology Graduate Training Program, University of Texas Southwestern Medical

Center, Dallas, Texas, USA. 3 XX Robert Debré. 4Department of Pediatrics, University of Michigan, Ann Arbor,

Michigan, USA

*M.F. and A.C. contributed equally to this work.

Oligodendrocytes (OLs) are myelin-forming cells of the central nervous system wrapping

axons and allowing the saltatory conduction of action potentials. In Multiple sclerosis (MS),

myelin sheath is destroyed and effective remyelination by oligodendrocyte precursor cells

(OPCs) diminishes with disease progression. Therefore, a better understanding of the

mechanisms controlling OPC generation and differentiation is essential to develop efficient

remyelinating therapies. Oligodendrogenesis, involving the steps of OPC generation, OPC

differentiation and maturation of OLs, is a process controlled by specific transcription factors

including Ascl1, Olig2 and Sox10 but the mechanisms involved are poorly understood. As it

is known that chromatin remodelers are regulatory factors necessary in the formation of the

promoter-enhancer loop prior to transcription, we focused our study on Chd7

(Chromodomain-Helicase-DNA-Binding 7), a member of the CHD protein family. In a first

study, we showed that Chd7 is highly enriched in the oligodendroglial lineage cells with a

peak of expression during OL differentiation and that Chd7 OPC-conditional deletion impairs

OL differentiation during (re)myelination. In a second study, we used unbiased genome wide

technics in purified OPCs to study Chd7 regulation of genes involved in OPC differentiation,

proliferation and survival. To this aim, we have generated OPC-specific inducible Chd7

knock-out (Chd7-iKO) and analyse the transcriptome (RNA-seq) of purified OPCs from P7

mouse cortices compared to control littermates. We found that Chd7 promote the expression

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genes involved in OPC differentiation and myelination and inhibits apoptosis, without

affecting OPC proliferation. Furthermore, we investigated Chd8, a paralog of Chd7, showing

that it is expressed in the oligodendroglial lineage with a peak of expression in differentiating

oligodendrocytes, similar to Chd7. Genome wide binding (ChIP-seq) profiling for Chd7 and

Chd8 indicate that these two chromatin remodelers bind to common genes related to OPC

differentiation, survival and proliferation. Integrating these datasets with other key

transcriptional regulators of oligodendrogenesis (Olig2, Ascl1 & Sox10), we have built a

model accounting for the time-controlled regulate expression of genes involved in each step

of OL differentiation.

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Session 3 Poster 11

How do perineuronal nets control glutamatergic synaptic transmission and

influence the plasticity rules in parvalbumin interneurons in adult visual

cortex ?

Lucie Gallet

Plasticity within neuronal circuits allows the brain to adapt to its environment and is crucial

for the development of sensory-motor and cognitive functions. During cortical maturation,

sensory information processing is strongly regulated by experience during a developmental

window called critical period (CP). The activity of cortical GABAergic interneurons

expressing parvalbumin (PV interneurons) is known to play a critical role in the development

of cortical plasticity.

CP is associated with maturation of the extracellular matrice, in particular a net-like dense

structure that specifically accumulates around PV interneurons, called « perineuronal nets »

(PNNs), made of chondroitin-sulfate proteoglycans, extracellular matrice and adhesion

molecules. Chemical or genetic PNNs degradation in adult visual cortex leads to re-opening

of the CP. However, the cellular mechanisms underlying the regulation of plasticity by PNNs

are still unknown. Recent works in the lab show that in vivo PNNs enzymatic degradation in

the adult visual system leads to a specific increase of PV interneurons recruitment by

thalamo-cortical afferences, and consequently to an increase in feed-forward inhibition on

glutamatergic principal neurons as well as on other PV interneurons. A paper will soon be

released on this work (Faini et al., prep).

The aim of my thesis project is to characterize the properties and plasticity rules at the

glutamatergic synapse between the thalamus and PV interneurons in the layer 4 of V1 in

adult mice. I will determine how PNN accumulation around PV interneurons regulates

glutamate receptor type and synaptic targeting, and how in turn they affect the plasticity rules

at this synapse.

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Session 3 Poster 12

Identification and functions of a novel mutation in PRKCA in Chordoid

Gliomas

Bertille Bance, Marc Sanson Institut du Cerveau et de la Moelle épinière (ICM), 47 bld hospital, 75013 Paris, France.

Chordoid glioma is a characteristic, slow growing and well-circumscribed diencephalic

tumor, whose mutational landscape is unknown. By whole exome and RNA sequencing, the

lab identified 14 Chordoid gliomas out of 15 harboring a same PRKCA mutation (PRKCAmut).

PRKCA encodes the protein kinase C isozyme alpha (PKCα), member of serine- and

threonine- specific kinases family. PKCα is known to be involved in diverse cellular

signaling pathways and is mutated in a wide range of human cancers. However this mutated

form PRKCAmut is novel and expressed at higher level than the wild-type PRKCA gene in

chordoid glioma. This kinase has been reported to plays roles in many different cellular

processes such as, cell adhesion and proliferation. I’m investigating the characteristics and

functions of this mutation in vitro and in vivo in order to may provide new targeting

opportunities in chordoid gliomas patients.

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Session 3 Poster 13

Identification of new biomarkers in status epilepticus

Aurélie Hanin1, Maria Damiano2, David Luis1, Stéphane Charpier1, Françoise Bismut3,

Maguy Bernard3, Randa Bittar3, Foudil Lamari3 and Vincent Navarro1,2

1Cellular excitability and networks dynamics, Brain and Spine Institute/CNRS UMR 7225/INSERM

1127/UPMC UM75,, Paris, France; 2AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Department of

Neurology; 3AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Department of Biochemistry

Status epilepticus, SE, is a life-threatening prolonged epileptic seizure. Despite initial adapted

molecules, in around 25% of cases, SE may last and become refractory to all molecules.

There is a need to identify valid biomarkers of brain injury in refractory SE. In fact several

biochemical pathways may increase neuronal excitability during seizures and/or SE and

eventually lead to brain injury with neuronal loss, and subsequent irreversible neurological

sequels. For instance, modification in brain cholesterol homeostasis may participate to

neuronal hyperexcitability in SE, through dysfunction of synaptic proteins regulation.

Cholesterol membrane content regulates the functional properties of membrane ion channels

and neurotransmitter receptors. Our team had recently shown that the use of a short hairpin

RNA to suppress expression of the CYP46A1, the protein hydroxylates cholesterol and

facilitates transmembrane extrusion, may lead to cholesterol accumulation, neuronal loss and

epileptic features. We have set up a Liquid Chromatography/ Mass Spectrometry (LC-

MS/MS) method to screen cholesterol content and a wide panel of its precursors and

metabolites in biological samples. We study this pathway in brains from a Kainic Acid

induced SE mouse model and in human refractory SE samples (serum and Cerebrospinal

Fluid (CSF)). A disturbance of the brain cholesterol metabolism has been noticed on the

mouse model of SE (decrease of the concentration of 24-hydroycholesterol in the first days

post SE) and on patients with a refractory SE (increase of cholesterol levels, disturbance of

precursors concentrations,...). The study will be followed during my PhD by another studies

on human refractory SE samples (CSF, serum and brain post mortem tissues), and in a Kainic

Acid induced SE mouse model. We will correlate the biochemical analysis with clinical,

imaging and electrophysiological outcomes. Additionally, we would like to screen human

samples for proteins that may represent biomarkers of the neuronal loss (NSE protein) and

glial cells reactions (S100ß) in SE patients.

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Session 3 Poster 14

C9ORF72 insufficiency leads to FTD-like anomalies without motor neuron disease

Morwena Latouche, Maria-Belen Lopez-Herdoiza, Stephanie Bauché, Baptiste Wilmet,

Caroline Le Duigou, Delphine Roussel, Magali Frah, Jonas Béal, Petra Frick, Delphine

Bouteiller, Sébastien Dussaud, Pierre Guillabert, Carine Dalle, Magali Dumont, Vincent

Anquetil, Gaelle Bruneteau, Phillippe Ravassard, Manuela Neumann, Sophie Nicole, Isabelle

Le Ber, Alexis Brice, Morwena Latouche

The GGGGCC intronic repeat expansion within CORF gene is the most common genetic

cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). The

mutation may lead through disease through multiple mechanisms, of which to a potential

loss-of-function mechanism may play a part as a partial decrease of CORF transcripts and

protein level have been observed in patients. For understanding the implications in both FTD-

ALS of this loss-of-function, we developed and characterized a CORF knock-down mouse

model. We found that these mice do not develop motor neuron disease but show behavioral

anomalies related to FTD. Analysis showed altered autophagy in the brain of these animals

with lysosomal alterations and signs of cellular suffering in the periphery. These findings

suggest that CORF partial loss of function rather contribute to an FTD phenotype while

toxicity from species produced by the expansion may be needed to trigger motor neuron

disease and massive neurodegeneration.

Session 3 Poster 15

Camille Rozier TBA

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Session 3 Poster 16

Assessing the specific impact of REM sleep onto memory consolidation and

problem solving

Célia Lacaux, Delphine Oudiette et Pr. Isabelle Arnulf

Institut du Cerveau et de la Moelle Epinière

Non-rapid-eye movement (NREM) sleep is now well-known to serve memory consolidation

by reactivation newly acquired memories. However, the role of the second main sleep phase,

namely rapid-eye movement (REM) sleep, remains unsettled. REM sleep is characterized by

a mental activity that resembles those of wakefulness but within a paralysed body. Since its

discovery, it has been strongly associated with dreams as 80% of people awakened from

REM sleep report dreaming contents. But why do whanine dream? REM sleep has been

proposed to allow the recombination of memories altogether, potentially resulting in the

emergence of new patterns and associations that may help solving problems and inspiring

insight. A single work has indeed demonstrated that sleeping on a problem increases the

likelihood to find a hidden rule but the specific role of REM sleep has not been carefully

examined. The present research project thus aims at investigating the specific contribution of

REM sleep on memory consolidation and insight. Such an objective is difficult to achieve as

REM sleep ends a sleep cycle, thus being always contaminated by preceding periods of

NREM sleep. To overcome this issue, we will use a unique population: narcoleptics.

Narcolepsy is a sleep disorder characterised by excessive daytime sleepiness, and soften by

direct falling asleep into REM sleep. We will this opportunity to assess the specific

contribution of both sleep phases on memory consolidation and insight. Participants will

perform a spatial memory task, consisting in memorising several objects’ location. Unknown

to them, a hidden rule allows finding novel objects’ position without knowing it. After a

learning session, subjects will be divided into a control and a sleep group (subdivided into

two groups: NREM and REM groups). The impact of sleep onto memory consolidation of old

objects’ location and on new objects’ location will thus be assessed. We hypothesise that

NREM sleep will benefit the memory consolidation process and that REM sleep will increase

the chance of discovering the hidden rule.

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Session 3 Poster 17

Self in the other: social contact enhances bodily self-awareness

Nesrine HAZEM1,2,3*, Morgan BEAURENAUT1,2, Nathalie GEORGE2,3,4,5,6 £, Laurence

CONTY1 £

1 Laboratory of Human and Artificial Cognition (CHArt), Univ Paris Nanterre, Nanterre, France. 2 Institut du

Cerveau et de la Moelle épinière (ICM), Social and Affective Neuroscience Laboratory and Centre MEG-EEG,

Paris, France. 3 Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, Paris, France. 4 CNRS, UMR 7225,

Paris, France. 5 Inserm, U 1127, Paris, France. 6 ENS, Centre MEG-EEG, Paris, France

Human self-awareness is arguably the most important and revealing question of modern

sciences. Converging theoretical perspectives link self-awareness and social abilities in

human beings. In particular, mutual engagement during social interactions—or social

contact—would boost self-awareness. Yet, empirical evidence for this effect is scarce. We

recently showed that the perception of eye contact induces enhanced bodily self-awareness.

Here, we aimed at testing this influence for social contact in auditory and tactile modalities,

to demonstrate that social contact enhances bodily self-awareness irrespective of sensory

modality. In a first experiment, participants were exposed to hearing their own first name (as

compared to another unfamiliar name and noise). In a second experiment, human touch (as

compared to brush touch and no-touch) was used as the social contact cue. In both

experiments, participants demonstrated more accurate rating of their bodily reactions in

response to emotional pictures following the social contact condition—a proxy of bodily self-

awareness. Further analyses indicated that the effect of social contact was comparable across

tactile, auditory and visual modalities. These results provide the first direct empirical

evidence in support of the essential social nature of human self-awareness.

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Session 3 Poster 18

Yet Another ADNI Machine Learning Paper? Paving The Way Towards

Fully-reproducible Research on Classification of Alzheimer’s Disease

Jorge Samper-Gonzáleza,b, Ninon Burgosa,b, Simona Bottania,b, Sabrina Fontanellaa,b, Pascal

Lua,b, Arnaud Marcouxa,b, Alexandre Routiera,b, Jérémy Guillona,b, Michael Baccia,b, Junhao

Wena,b, Anne Bertranda,b,c, Hugo Bertind, Marie-Odile Habertd,e, Stanley Durrlemana,b,

Theodoros Evgeniouf, Olivier Colliota,b,c,g, for the Alzheimer’s Disease Neuroimaging

Initiative and the Australian Imaging Biomarkers and Lifestyle flagship study of ageing a INRIA Paris, ARAMIS project-team, 75013 Paris, France. b Sorbonne Universités, UPMC Univ Paris 06,

Inserm, CNRS, Institut du cerveau et la moelle (ICM), AP-HP - Hôpital Pitié-Salpêtrière, 75013 Paris, France. c

AP-HP, Department of Neuroradiology, Pitié-Salpêtrière Hospital, Paris, France. d Sorbonne Universités,

UPMC Univ Paris 06, Inserm, CNRS, LIB, AP-HP, 75013 Paris, France. e AP-HP, Department of Nuclear

Medicine, Pitié-Salpêtrière Hospital, Paris, France. f INSEAD, Bd de Constance, 77305 Fontainebleau, France. g

AP-HP, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France

In recent years, the number of papers on Alzheimer’s disease classification has increased

dramatically, generating interesting methodological ideas on the use of machine learning and

feature extraction methods. However, practical impact is much more limited and, eventually,

one could not tell which of these approaches are the most efficient. While over 90% of these

works make use of ADNI an objective comparison between approaches is impossible due to

variations in the subjects included, image pre-processing, performance metrics and cross-

validation procedures. In this paper, we propose a framework for reproducible classification

experiments using multimodal MRI and PET data from ADNI. The core components are: 1)

code to automatically convert the full ADNI database into BIDS format; 2) a modular

architecture based on Nipype in order to easily plug-in different classification and feature

extraction tools; 3) feature extraction pipelines for MRI and PET data; 4) baseline

classification approaches for unimodal and multimodal features. This provides a flexible

framework for benchmarking different feature extraction and classification tools in a

reproducible manner. Data management tools for obtaining the lists of subjects in AD, MCI

converter, MCI non-converters, CN classes are also provided. We demonstrate its use on all

(1519) baseline T1 MR images and all (1102) baseline FDG PET images from ADNI 1,

ADNI GO and ADNI 2 with SPM-based feature extraction pipelines and three different

classification techniques (linear SVM, anatomically regularized SVM and multiple kernel

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learning SVM). The highest accuracies achieved were: 91% for AD vs CN, 83% for MCIc vs

CN, 75% for MCIc vs MCInc, 94% for AD-Aβ+ vs CN-Aβ- and 72% for MCIc-Aβ+ vs

MCInc-Aβ+. The code has been made publicly available at https://gitlab.icm-

institute.org/aramislab/AD-ML

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Session 3 Poster 19

Exponential random graph model for brain networks

Catalina Obando1 ;2 and Fabrizio De Vico Fallani1 ;2

1 Inria Paris, Aramis project-team, Paris, Francen, 2 CNRS UMR-7225, Sorbonne Universites, UPMC Univ

Paris 06, Inserm, Institut du cerveauet de la moelle (ICM) - Hopital Pitie-Salpetriere, Paris, France

Network science has been extensively developed to characterize structural properties of

complex systems. As a result of the inference process, networks estimated from

experimentally obtained biological data, represent one instance of a larger number of

realizations with similar intrinsic topology [1]. A modeling approach is therefore needed to

support statistical inference. In this work we adopted a statistical model based on exponential

random graphs (ERGM) to reproduce electroencephalographic (EEG) brain networks [2].

ERGMs are composed by different local graph metrics whereas the parameters weight the

respective contribution in explaining the observed network. Wevalidated this approach in a

dataset of N = 108 healthy subjects during eyes-open (EO)and eyes-closed (EC) resting-state

conditions.

Results showed that the model including k-triangles and k-stars statistically reproduced the

main properties of the EEG brain networks measured by global- and local efficiency. We

tested the goodness-of-fit of the model, cross-validate the results by means of other graph

metrics and performed a statistical group analysis. Furthermore, the fitted ERGM parameter

values provided complementary information showing that clustering connections are

significantly more represented from EC to EO. These findings support the current view of the

brain functional segregation and integration in terms of modules and hubs, and provide a

statistical approach to extract new information on the (re)organizational mechanisms in

brains.

1. De VicoFallani, F., Richiardi, J., Chavez, M., Achard, S.: Graph analysis of functional brain

networks: practical issues in translational neuroscie nce. Phil. Trans. R. Soc. B, 369(1653),

20130521 (2014) 2. Robins, G., Pattison, P., Kalish, Y., Lusher, D.: An introduction to exponential random graph

(p*) models for social networks. Social networks, 29(2), 173-191 (2007) 3. Vogelstein, J.T., Conroy, J.M., Lyzinski, V., Podrazik, L.J., Kratzer, S.G., Harley,

E.T.,

Fishkind, D.E., Vogelstein, R.J. and Priebe, C.E.: Fast approximate quadratic programming

for graph matching. PLOS one, 10(4), e0121002 (2015

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Session 3 Poster 20

Physiopathology of autoimmune encephalopathy linked to anti-LGI1 antibodies

Paul Baudin1, Sarah Lecas1, Mark Williams1, Delphine Roussel1, Maria Damiano2 , Stéphane

Charpier1, Jean-Yves Delattre1, Jérôme Honnorat3, Vincent Navarro1

1ICM ; Sorbonne Universités, UPMC Univ Paris 06; AP-HP, Hôpital Pitié Salpêtrière, Paris. 2AP-HP Groupe

Hospitalier Pitié Salpêtrière Charles Foix, Departement de neurologie. 3Centre de référence des syndromes

neurologiques paranéoplasiques et encéphalites auto-immunes, Hospices Civils de Lyon, Hôpital Neurologique,

F-69677 Bron.

Autoimmune encephalopathy is a severe neurological disorder responsible for subacute

cognitive impairment and various types of epileptic seizures. The discovery of autoantibodies

associated with these encephalopathies has revolutionized their classification, allowing a

better physiopathological and therapeutic approach. In 2010, Leucine Rich Glioma

Inactivated 1 (LGI1) protein was identified as one of the targets of these antibodies. It is part

of a trans-synaptic complex that regulates pre- and post-synaptic ion channels. The

encephalopathy linked to anti-LGI1 antibodies has a very specific clinical presentation,

associating short and repeated motor seizures, and hippocampal damages. In mice,

inactivation of the LGI1 gene leads to epileptic seizures, underlining the role of this protein in

controlling neuronal excitability.

During my thesis, I intend to study the pathophysiological consequences of the anti-LGI1

autoantibody leading to epileptic seizures, as well as the neuroimmunological abnormalities

at the origin of the anti-LGI1 autoimmune encephalopathy.

I will study the electrophysiological changes induced by the anti-LGI1 autoantibody. (i) On

one hand, I will do stereotactic injections in vivo, in different structures of anesthetized rat

brain, of purified solutions of anti-LGI1 antibodies from patients, while doing

electrocorticographics and extracellular recordings. The aim is to study the modifications of

local multi-unit activities before a seizure, as well as larger modifications on

electrocorticograms. (ii) On the other hand, in order to understand the pathophysiology at the

cellular scale, I will study in vitro, on rat brain slices, through multi-electrode recordings, the

modalities of neurons synchronization. Besides, through patch clamp recordings, we would

better describe changes in autoantibody-induced excitability and investigate the synaptic

signaling pathways using pharmacological agents. (iii) To describe the immune response in a

murine model and the changes on cerebral morphology induced in the pathology, I will

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achieve an active immunization against the LGI1 protein in mice, according to a protocol that

has proved its effectiveness. (iv) To better characterize the origin of the autoimmunity in this

disease, I will characterize lymphocyte phenotypes in patients, and will study their intestinal

flora.

The study at the neuronal scale should provide valuable information about the origin of the

neuronal and synaptic disorganization induced by this autoantibody. Immunological studies

would improve our understanding of the causes, symptoms and progression of the disease.

This would allow us later to develop new therapeutic targets in this very serious pathology.

IoN-ICM PhD & Post-Doc 2017 Workshop - Program · 2018-05-15 · IoN-ICM PhD & Post-Doc 2017...

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