PhD program Neuroscience and Cognition PhD proposal ... · PhD program Neuroscience and Cognition...

PhD program Neuroscience and Cognition

PhD proposal starting autumn 2012

Host laboratory (Name, code, director):

Centre de neuroscience cognitive UMR 5229 CNRS-Université Claude Bernard Lyon I 67 Bd Pinel 69675 Bron Cedex Director, Jean-René Duhamel, [email protected]

Host research team : ( Name and director):

Neurobiology of cognitive processes Jean-René Duhamel Tèl : 04 37 91 12 18 Mèl : [email protected]

Thesis director (with habilitation, HDR): Suliann Ben Hamed Tèl : 04 37 91 12 40 Mèl : [email protected] 5 keywords : attention, perception, computational neuroscience, non-human primate, electrophysiology 3 year scholarship already available : NO Local candidate : NO

:

TITLE : Neurocomputational modelling of the parieto-frontal attentional and perceptual

network and of its dysfunctions. Our day to day survival is conditioned to an appropriate analysis of our environment. In healthy subjects, this operation takes place fluidly and is adapted to the behavioral requirements of the moment. This operation is carried out by a major brain function, namely the attentional function. The importance of this function becomes obvious when it is altered following vascular brain accidents or developmental and neurodegenerative brain deficits. Several cortical regions have been associated with attentional processes and their functions have been characterized. A parito-frontal network involved in spatial attention and perception has been particularly highlighted. Recent studies suggests that the functional deficits observed following local cortical damage is not only due to the absence of a part of the network but also to the profound alteration of the function of the whole network. The objective of the present PhD project is to propose a realistic neurocomputational model of fronto-parietal attentional and perceptual network accounting for three of its key characteristics (1) the directional information flow that can be observed within this network, (2) the high information redundancy between its different subregions and (2) the relatively mild deficits observed following focal lesions in this network. This model will serve as a predictor of the long range consequences of its dysfunctions and will be carried in tight interaction with non-human primate multi-electrode recording experiments targeting key locations in the functional network of interest. This approach will help understand how attentional deficits arise following vascular cortical accidents and developmental or neurodegenerative conditions. 3 publications : Ibos, G., Duhamel, J.-R. & Ben Hamed, S. The spatial and temporal deployment of voluntary attention across the visual field. PLoS ONE 4, e6716 (2009).

Farbod Kia, S., Strand, E., Ibos, G. & Ben Hamed, S. Readout of the intrinsic and extrinsic properties of a stimulus from un-experienced neuronal activities: Towards cognitive neuroprostheses. J. Physiol. Paris 105, 115–122 (2011).

Wardak, C., Denève, S. & Ben Hamed, S. Focused visual attention distorts distance perception away from the attentional locus. Neuropsychologia 49, 535–545 (2011).



Host laboratory (Name, code, director): Centre de Recherche en neurosciences de Lyon, INSERM U1028 Director: Olivier Bertrand


Brain Dynamics and Cognition Director: Olivier Bertrand

Thesis director (with habilitation, HDR): Olivier Bertrand

Co-director: Aurélie Bidet-Caulet 5 keywords: human, attention, audition, EEG 3 year scholarship already available: NO Local candidate : YES

:

Competition between bottom-up and top-down mechanisms of auditory attention

Attention is the brain function by which we, voluntarily or not, improve the processing of specific information in our

environment while other information is disregarded. In principle, the entry of information to the limited-capacity

system is controlled by two types of processes: top-down (TD) and bottom-up (BU) processes. TD attention enables the

good performance of an on-going task by selecting the relevant information. One’s attention can also be involuntarily

captured by an unexpected salient stimulus and thus diverted from the previously on-going task. This BU form of

attention is necessary to be aware of potentially important events that are nonetheless irrelevant to the on-going task

(e.g. fire alarm), and is commonly referred as distractibility. A good balance between BU and TD mechanisms is thus

crucial to be task-efficient while being aware of our surrounding environment. To our knowledge, really few paradigms

enable the assessment of the balance between BU and TD mechanisms. Therefore, this project aims at proposing a

new paradigm to assess both BU and TD mechanisms of auditory attention, at the same time, and to understand how

these mechanisms cooperate and compete in the healthy brain.

The neurophysiological responses reflecting TD attention will be dissociated from those to distracting sounds

corresponding to BU attentional capture, using scalp electroencephalography (EEG) data in healthy subjects (Study 1)

and intracortical data in patients with epilepsy implanted with depth electrodes in the auditory cortex (Study 2). Since,

the lateral prefrontal cortex (lPFC) plays a crucial role in the control of attention, the role of the lateral PFC in the

dynamic interaction of TD attention and BU attentional capture will be investigated using scalp EEG data in patients

with lPFC lesion (Study 3). These electrophysiological studies will require analyses of event-related potentials as well as

oscillatory activities.

3 publications :

Bidet-Caulet A, Mikyska C, Knight RT. Load effects in auditory selective attention: evidence for distinct facilitation and

inhibition mechanisms. (2010) Neuroimage, 50(1), 277-284.

Bidet-Caulet A, Fischer C, Besle J, Aguera PE, Giard MH & Bertrand O. Effects of selective attention on the

electrophysiological representation of concurrent sounds in the human auditory cortex. (2007) J Neurosci, 27(35),

9252-9261.

Voisin J, Bidet-Caulet A, Bertrand O, & Fonlupt P. Listening in silence activates auditory areas: a functional magnetic

resonance imaging study. (2006) J Neurosci, 26(1), 273-278.





Host laboratory: Centre de Neuroscience Cognitive, UMR CNRS 5229, Université Claude Bernard Lyon 1 &

CAMH-PET imaging center, University of Toronto.

Host research team : Approche Neurocognitive des Psychoses (C. Demily) & Research Imaging Centre

CAMH & Toronto Western Research Institute, Division of Brain Imaging & Behaviour Systems (A. Strafella).

Thesis director: Philippe Boulinguez, PhD, HDR

Co-director: Antonio Strafella, MD, PhD, FRCPC 5 keywords : Proactive Inhibitory Control - Catecholamines – fMRI – PET 3 year scholarship already available : NO Local candidate : YES Grant already available : YES (ANR MNP 039-01, FFGP)

:

TITLE : The role of catecholamines in response inhibition

The role of the main inhibitory neurotransmitter, GABA, in response inhibition has been extensively

studied. GABAergic inhibitory circuits in the motor cortex have been clearly identified. However, converging

clues from pharmacology and cognitive neuroscience suggest that response inhibition is instantiated within

frontostriatal circuits of the brain with patterns of activity that may be modulated by the catecholamines

dopamine (DA) and noradrenaline (NA). Much less is known about these circuits. In this project, we propose

to assess the role of catecholamines in response inhibition by:

1) using a new theoretical framework to model inhibitory control processes, i.e., investigating not only

reactive but also proactive brain activity,

2) conducting pharmacological fMRI studies in healthy subjects manipulating DA and NA transmission in

the brain (clonidine and pramipexole, respectively),

3) conducting PET studies in healthy subjects allowing an accurate assessment of dopaminergic

function within and outside the striatum (using respectively 11C-PHNO and 11C-FLB),

The project requires a close collaboration between the University of Lyon (points 1 and 2) and the

University of Toronto (point 3). The fMRI studies will be performed in Lyon while the PET studies will take

place in Toronto (the radiotracers are not available in Lyon). The PhD will be delivered by the University

Claude Bernard Lyon 1, with a “joint placement with the UoT” mention on the diploma. Incidentally, the

candidate will be allowed, at his own cost, to apply for entering the independent PhD program from the UoT in

order to get the UoT diploma as well.

5 publications: Ballanger, B, van Eimeren, T., Moro, E., Lozano, A. M., Hamani, C., Boulinguez, P., Pellecchia, G., Lang, A, & Strafella,

A. (2009). Stimulation of the subthalamic nucleus and impulsivity: release your horses. Annals of Neurology, 66(6), 817–824. doi:10.1002/ana.21795

Criaud, M., Wardak, C., Ben Hamed, S., Ballanger, B., & Boulinguez, P. (2012). Proactive inhibitory control of response as the default state of executive control. Frontiers in Psychology, 3, 59. doi:10.3389/fpsyg.2012.00059

Jaffard, Magali, Longcamp, M., Velay, J.-L., Anton, J.-L., Roth, M., Nazarian, B., & Boulinguez, P. (2008). Proactive inhibitory control of movement assessed by event-related fMRI. NeuroImage, 42(3), 1196–1206.

doi:10.1016/j.neuroimage.2008.05.041 Ko JH, Antonelli F, Monchi O, Ray N, Rusjan P, Houle S, Lang AE, Christopher L, Strafella AP. (2012). Prefrontal

dopaminergic receptor abnormalities and executive functions in Parkinson's disease. Human Brain Mapping. doi: 10.1002/hbm.22006.

Leh, S. E., Petrides, M., & Strafella, A. P. (2009). The Neural Circuitry of Executive Functions in Healthy Subjects and




INSERM U846, Stem Cell and Brain Research Institut, 18 avenue du Doyen Lépine, 69500, Bron http://www.sbri.fr/ Directors: C. Dehay and H. Kennedy


Department of Chronobiology, Team “Neurobiology of circadian rhythms” Team leader: H.M. Cooper

Thesis director (with habilitation, HDR):

Ouria DKHISSI-BENYAHYA ; ouria.benyahya@inserm. 5 keywords : retina, clock genes, circadian rhythm, melanopsin, light 3 year scholarship already available : YES NO Local candidate : YES NO

: TITLE : Light entrainment of the mammalian retinal clock: photoreceptors and molecular mechanisms involved

The detection of light by the retina is used for two different tasks: the visual perception of pictures, colours and

movement and non-visual photoreception. Non-visual photoreception integrates light information from our

environment through classical photoreceptors (rods and cones) and melanopsin ganglion cells. The integration of the

light signal provides synchronization of the central biological clock located in the suprachiasmatic nucleus (SCN). In

addition to the synchronizing role of the SCN, the retina also contains an autonomous circadian oscillator that controls

many physiological and functional circadian rhythms including rod outer segment disc shedding, expression of

immediate early genes and opsin genes in photoreceptors, dopamine/melatonin synthesis. The retinal clock in

mammals nevertheless remains poorly understood. The cellular localization of the retinal clock is still controversial and

the endogenous molecular mechanisms underlying regulatory processes and it control by light are not clearly defined.

The absence of one or several photoreceptors leads to behavioural deficits, suggesting alterations at retinal and/or

central levels of functioning of the circadian timing system. In humans, several retinal pathologies (such as retinitis

pigmentosa, macular degeneration, glaucoma) are characterized by degeneration of photoreceptors that receive and

integrate light signals from the environment. These ocular pathologies represent major causes of blindness that impact

on vision but also lead to a decrease or loss of the photic input to the circadian system, impairing proper

synchronization to the environmental 24h cycle and thus adding to vision loss another strong handicap.

In this project, we aim to explore the molecular mechanisms at the origin of light entrainment of retinal clocks and

to determine whether the absence of specific photoreceptors contributes to the retinal clock dysfunction. The

functional and physiological disorders of retinal clocks will be explored by coupling complementary approaches ex vivo,

in vivo and in vitro in several critical mouse models, deficient for a specific photoreceptor and carrying a luciferase

reporter gene.

Because circadian organization is a ubiquitous feature of the retina and controls fundamental processes,

disruption of retinal clock organization or its response to light can potentially have a major impact on visual and

circadian functions.

3 publications :




Centre de Neurosciences Cognitives, CNRS UMR5229, Duhamel


Dr Jean-Claude Dreher, DR2 CNRS, CNRS UMR 5229 Reward and decision making team Centre de Neurosciences Cognitives 67 Bd Pinel, 69675 Bron, France tel: 00 33 (0)4 37 91 12 38 fax: 00 33 (0)4 37 91 12 10

http://www.isc.cnrs.fr/dre/

Thesis director (with habilitation, HDR): Dr Jean-Claude Dreher

5 keywords : Prefrontal cortex, decision making, fMRI, neuroeconomics 3 year scholarship already available : NO Local candidate : NO

TITLE : Functional neuroimaging studies of Group and individual decision-making in humans A large body of behavioral evidence indicates that groups behave differently from individuals with regard to cooperation and competition, risk and uncertainty, trust and trustworthiness. Most studies conclude that people in groups act more selfishly and may be more risk seeking than when they make decisions individually. Yet, little is known about the neural mechanisms underlying the differences between choices made as an individual or in groups. There is also no direct neural evidence for the existence of specific group-decision making processes. The goal of this PhD proposal is to investigate the cerebral networks engaged when making decisions as individual and in groups. We will also investigate the neural coding of psychological processes that may underlie differences between individual and group decision-making, such as envy, compassion and the motivation to avoid guilt and blame when making decisions that affect others’ welfare, and the social pressure to conform to certain norms when one is in a group setting. Three different experiments will allow us to better understand the neural mechanisms involved in individual and group decision making: (a) the first concerns intergroup interactions in a non-stochastic environment, which leads to more cooperative outcomes in group settings than inter-individual interactions, (b) the second concerns intergroup interactions in a stochastic environment, which generally lead to less cooperative outcomes in group settings than interindividual interactions, (c) the third study concerns the effect of risk in groups. We will test whether the average group is more risk averse than the average individual in high-risk situations, but groups tend to be less risk averse in low-risk situations. Together, our findings should clarify the relationships between brain activation and decision-making in individuals and groups.

3 publications : - E Météreau and J-C Dreher. Cerebral correlates of salient prediction error for different rewards and punishments, Cerebral Cortex, /doi:10.1093/cercor/bhs037, 2012 - G. Sescousse, J. Redoute, J-C Dreher. The architecture of reward value coding in the orbitofrontal cortex, J Neurosci, 30(39):13095-104, 2010 - C. Prevost, M. Pessiglione, E. Metereau, M-L. Clery-Melin, J-C Dreher. Separate valuation subsystems for delay and effort decision costs, J Neurosci., 30(42):14080-90, 2010



Host laboratory (Name, code, director): Centre de Neurosciences Cognitives, CNRS UMR5229, Duhamel


Dr Jean-Claude Dreher, DR2 CNRS, CNRS UMR 5229 Reward and decision making team Centre de Neurosciences Cognitives 67 Bd Pinel, 69675 Bron, France http://www.isc.cnrs.fr/dre/

Thesis director (with habilitation, HDR): Dr Jean-Claude Dreher 5 keywords : Prefrontal cortex, decision making, fMRI, neuroeconomics 3 year scholarship already available : YES Local candidate : NO

:

TITLE : How Emotions Influence Decision-making: an Interdisciplinary perspective The neural mechanisms underlying the influences of emotional and motivational processes on decision making

remain poorly understood. The current project seeks a better understanding of the psychological and neurobiological bases of the influences of emotions on decision-making to inform models and theories of decision-making in behavioural economics. It adopts a combination of interdisciplinary perspective, combining neuroeconomics and multimodal neuroimaging (intracranial recordings in humans and model-based fMRI) to investigate the neural mechanisms underlying the interplay of emotion and cognition during decision making.

The specific aims of this project are to characterize: 1) basic neural coding of positive and negative emotions induced by different rewards and punishments and investigation of how different probability and uncertainty of these reinforcers influence brain activity; 2) the influences of positive/negative emotions induced by rewards/punishment on learning to associate neutral cues with rewarding/aversive outcomes; 3) the neural mechanisms by which emotion and cognitive control interact. To address these questions, we will combine three complementary approaches: 1) computational modeling using concepts from neuroeconomics, which is important to specify the relationships between the neural mechanisms, behaviour and the patterns of brain activation observed with model-based neuroimaging; 2) human intra-cranial recordings and fMRI, which is key for a comprehensive understanding of different descriptions levels (local field potentials and BOLD signal); 3) investigation of the interactions between emotions and decision making using a computational model-based fMRI approach. This combination of approaches will contribute to a fundamental understanding of the neural mechanisms underlying the influences of emotions on decision making in humans. The ground-breaking nature and potential impact of this research is to establish a neurobiological foundation for understanding disorders affecting motivational and decision making processes and for better understanding how the influences of emotions may explain deviations in actual decision-making from equilibrium predictions in economic models. 3 publications : - E Météreau and J-C Dreher. Cerebral correlates of salient prediction error for different rewards and punishments, Cerebral Cortex, /doi:10.1093/cercor/bhs037, 2012 - G. Sescousse, J. Redoute, J-C Dreher. The architecture of reward value coding in the orbitofrontal cortex, J Neurosci, 30(39):13095-104, 2010 - C. Prevost, M. Pessiglione, E. Metereau, M-L. Clery-Melin, J-C Dreher. Separate valuation subsystems for delay and effort decision costs, J Neurosci., 30(42):14080-90, 2010



Host laboratory (Name, code, director): CRNL, UMR5292, U1028, Lyon 1, Olivier Bertrand


BioRaN (Radiopharmaceutical & Neurochemical Biomarkers), Luc Zimmer

Thesis director (with habilitation, HDR): Dr. Luc DENOROY

Co-director: Dr. Thierry BILLARD (ICBMS) 5 keywords : Protein neurochemistry, alpha-synuclein, bioanalytical chemistry, neurodegenerative diseases 3 year scholarship already available : NO Local candidate : YES

:

TITLE : Toward specific ligands of aggregated alpha-synuclein The aggregation of alpha-synuclein (α-syn) into Lewy’s bodies is one of the hallmarks of Parkinson’s disease and of some dementias. However, there are presently no imaging or analytical techniques able to discriminate between monomeric (i.e. physiological) and aggregated (i.e. pathological) α-syn, which could be a tool for a specific and reliable diagnosis and/or monitoring of the progression of α-synucleopathies. Our project aims to screen potential ligands of aggregated or monomeric α-syn using mainly separation techniques such as capillary electrophoresis. The most selective ligands will be used as probes in the development of original analytical techniques for the selective determination of α-syn in biofluids (cerebrospinal fluid and plasma) from animal models of synucleinopathies and from patients. Furthermore, they will be also used as radiopharmaceuticals for the in vivo imaging of α-syn. This thesis will be centered on separation techniques for the analysis of brain proteins, including slab gel electrophoresis and western blotting, capillary electrophoresis and mass spectrometry. It will aim to providing new highly selective and sensitive approaches for the pre-clinical and clinical studies of synucleinopathies.

3 publications : - Zimmer L, Luxen A. PET radiotracers for molecular imaging in the brain: past, present and future. NeuroImage, in

press. - Denoroy L, Renaud B, Parrot S. Capillary Electrophoresis Analysis in Neuroscience. In “Capillary Electrophoresis: Fundamentals, Techniques and Applications”, Z. He Eds, Nova Science Publisher, in press - Zapata A, Chefer VI, Shippenberg TS, Denoroy L. Detection and quantification of neurotransmitters in dialysates. Curr Protoc Neurosci. 2009 ;Chapter 7:Unit 7.4.1-30.



Host laboratory (Name, code, director): CRNL , INSERM U1028 CNRS-UMR5292, O Bertrand Dir.


ONCOFLAM, J Honnorat Dir

Thesis director (with habilitation, HDR): JF Ghersi-Egea, HDR

Co-director: N Strazielle, HDR 5 keywords : Blood-brain barriers, choroid plexus, development, neuroprotection, perinatal disease 3 year scholarship already available : NO Local candidate : YES

:

TITLE : (text Calibri 11 interval 15, bold characters) Neuroprotective functions of the blood-brain interfaces in the developing brain: regulation of efflux transport and detoxification processes (text Calibri 10 interval 14) Blood-brain interfaces comprise the blood-brain barrier located at the endothelium of the microvessels and the blood-CSF barrier located at the epithelium of the choroid plexuses. They fulfill crucial neuroprotective functions owing to the presence of tight junctions, efflux transporters, and detoxification enzymes such as glutathione-S-transferases that tightly control blood-brain exchanges across these cellular interfaces. During brain development, the blood-brain barriers have often been considered as immature. Recent data from our and other laboratories however indicate that tight junctions are present and efficient early during development at both the blood-brain and blood-CSF barrier, and that detoxification processes are active in the choroid plexuses during the perinatal period. The aim of the thesis is to establish whether a failure in the neuroprotective functions of the blood-brain interfaces is involved in the pathophysiology of perinatal diseases, to assess in the developing brain the inducibility of transport and detoxification processes via the activation of specific metabolic pathways involving different nuclear receptors, and to design pharmacological strategies to activate these neuroprotective mechanisms in view to reduce the dramatic neurological deficits that often result from perinatal injury. A combination of in vivo and in vitro approaches will be used to study these different aspects. 3 publications :

Ghersi-Egea JF, Strazielle N, Murat A, Jouvet A, Buenerd A, Belin MF. Brain protection at the blood–cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism. J Cereb Blood Flow Metab, 2006, 26:1165–1175 Gazzin S, Strazielle N, Schmitt C, Fevre-Montange M, Ostrow JD, Tiribelli C, Ghersi-Egea JF. Differential Expression of the Multidrug Resistance-Related Proteins ABCb1 and ABCc1 Between Blood-Brain Interfaces. J Comp Neurol, 2008, 510:497–507 Ginguené C, Champier J, Maallem S, Strazielle N, Jouvet A, Fèvre-Montange M, Ghersi-Egea JF. P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Localize in the Microvessels Forming the Blood-Tumor Barrier in Ependymomas. Brain Pathol, 2010, 20:926-35.



Host laboratory : CRNL, INSERM U1028 - CNRS UMR 5292, director Olivier Bertrand

Host research team : Neurooncology and Neuroinflammation, director J. Honnorat

Thesis director/codirector (with HDR): Claire Meissirel, [email protected],

04 78 78 57 04 and Nicole Thomasset, [email protected] 5 keywords : brain tumor, glutamate receptor, VEGF, invasion/migration 3 year scholarship already available : NO Local candidate : NO

:

TITLE : (VEGF/glutamate: a new interaction underlying glioblastoma invasive capacities SCIENTIFIC CONTEXT: VEGF inhibitors are now the focus of anticancer therapy because VEGF is a critical

regulator of tumor angiogenesis and high levels of VEGF expression are of a bad prognosis. However, brain

tumors such as glioblastoma have been shown to eventually escape anti-VEGF treatments raising the question of

an alternative therapeutic target. Recent data demonstrated that glutamate is also released by glioblastoma cells

and tumor cells with high glutamate release have a distinct growth advantage in the host brain. Glioblastoma-

derived glutamate activates a subset of glutamate receptors on tumor cells, promoting their migratory behavior

and malignant phenotype, thereby contributing to the invasive properties of glioblastoma. Recently, the

promoting effect of VEGF on the behavior of migrating cells has been extended to developing neurons and was

shown by our research group to involve a cross-talk between VEGF and glutamate receptors. Therefore, we

hypothesized that VEGF receptors might interact with glutamate receptors and regulate their function in

glioblastoma cells. The invasive capacity of glioblastoma cells highly depends on their ability to reorganize the

actin cytoskeleton. Interestingly, the actin-binding proteins filamins, which control cytoskleton dynamics, have

been identified as a plasmatic marker of glioblastoma and are key partners of VEGF receptors during cell

migration.

RESEARCH PROJECT: The aim of the current proposal is to investigate how VEGF and glutamate receptors

cross-talk to exacerbate glioblastoma tumor growth and to characterize the role of VEGF in the trafficking and

activation of glutamate receptors in cooperation with filamin. To resolve these issues, we will investigate i) the

expression of the VEGFRs, glutamate receptors and filamin in glioblastoma cells and their ability to form

signaling complexes. ii) the contribution of filamin in VEGFRs and glutamate receptor trafficking in

glioblastoma cells iii) the physiological significance of VEGFR/glutamate receptor/filamin cross-talk in the

invasive capacities of glioblastoma in vitro and in vivo.

For this purpose we will design experimental approaches based on cellular and molecular biology as well

as on in vivo imaging to develop new fluorescent models of glioblastoma and analyze their invasive capacities in

vitro and in vivo. Moreover, we will use biochemical tools to characterize the dynamic of these signaling

complexes and their contribution to the initial steps of glioblastoma invasion.

Our project will provide precise mechanisms of the VEGF and filamin action in glutamate receptor

recruitment and activation in glioblastoma cells and help determining whether VEGF crosstalk with glutamate

receptors can be responsible for tumor progression and invasion. In the future, this project may provide rationale

for combining anti-VEGF and specific anti-glutamate receptor targeted therapies in these brain tumors. 3 publications :

Mikasova et al. Disrupted surface cross-talk between NMDA and EphrinB2 receptors in anti-NMDA

encephalitis. Brain 2012; in press

Meissirel C et al. VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-

family kinases before synapse formation. Proc Natl Acad Sci (USA) 2011; 108(33):13782-7

Ruiz de Almodovar C et al. Matrix-binding VEGF isoforms guide granule cell migration in the

cerebellum via VEGF receptor Flk1. J Neurosci. 2010; 30(45):15052-66.



Host laboratory (Name, code, director): Centre de Recherche en Neurosciences de Lyon INSERM U1028 - CNRS UMR5292 (Olivier Bertrand)

Host research team : ( Name and director): Equipe ImpAct (Denis Pélisson)

Thesis director (with habilitation, HDR): Martine Meunier Co-director: Fadila Hadj-Bouziane 5 keywords : attention, neglect, extinction, fMRI, monkey 3 year scholarship already available : YES NO Local candidate : YES NO

:

TITLE : Exploring sensory competition using fMRI in monkey Neglect is a pathological condition characterized by a failure to attend and appropriately react to even the most conspicuous and relevant visual stimuli, such as persons or obstacles, on the contralesional side. Neglect is often accompanied by extinction, a paradigmatic example of how stimuli can compete for conscious awareness, whereby patients lose awareness of contralesional stimuli when ipsilesional stimuli are presented concurrently. Even the normal brain has a limited ability to process sensory information, frequently “extinguishing” one of two simultaneously presented stimuli. A comprehensive understanding of the physiological and pathological mechanisms of sensory competition is still lacking and this limitation has strong implication in the development of rehabilitation interventions to treat neglect/extinction patients. The present project aims at elucidating where and when sensory competition takes place in the brain in order to better understand and treat neglect/extinction. The very same task will be used in healthy humans and in trained monkeys to identify the network of competitive sensory perception using fMRI. The animal model will also be used to test novel pharmacological treatments for pathological extinction and neglect.

3 publications : Bell, A. H., Malecek, N. J., Morin, E. L., Hadj-Bouziane, F., Tootell, R. B., & Ungerleider, L. G. (2011). Relationship

between functional magnetic resonance imaging-identified regions and neuronal category selectivity. J Neurosci, 31(34), 12229-12240

Hadj-Bouziane, F., Bell, A. H., Knusten, T. A., Ungerleider, L. G., & Tootell, R. B. (2008). Perception of emotional expressions is independent of face selectivity in monkey inferior temporal cortex. Proc Natl Acad Sci U S A, 105(14), 5591-5596.

Jacobs, S., Brozzoli, C., Hadj-Bouziane, F., Meunier, M., A., Farnè (2011) Studying multisensory processing and its role in the representation of space through pathological and physiological crossmodal extinction. Frontiers in Perception Science, 2: 1-9.

To be sent to: Evelyne Robin ––[email protected] Deadline : 13 April 2012



Host laboratory (Name, code, director): Cognitive Neuroscience Center, CNR S UMR 5229, headed by Jean-René Duhamel

Host research team: (Name and director):

Physiopathology of basal ganglia, headed by Léon Tremblay

Thesis director (with habilitation, HDR): Véronique Sgambato-Faure

Co-director: 5 keywords: serotonin, basal ganglia, behavior, TEP imaging, immunohistochemistry 3 year scholarship already available: NO Local candidate: YES

:

TITLE: Role of a serotonergic lesion on behavioral troubles in the monkey: from cellular mechanisms to

potential therapeutic treatment.

Parkinsonian patients suffer from both motor and non-motor symptoms. Recent studies evidenced that an alteration

of the serotonergic system correlates with fatigue and depression in PD patients. Non-motor symptoms (apathetic and

anxious-like) can also be induced pharmacologically in the normal monkey, and some of them can be reduced following

selective serotonin reuptake inhibitors administration. In this project, based on the use of multiple approaches, our

objectives are double: 1) determine in the normal monkey the impact of a serotonergic lesion on non-motor symptoms

appearance and associated expression of dopaminergic and serotonergic markers; 2) determine if administration of a

selective serotonin reuptake inhibitor improves the trouble generated and modifies its cellular correlates.

The project will involve three parts: a first one will identify the impact of the serotonergic lesion, induced by MDMA

and monitored by PET imaging, on behavior studied through preference task (using stimuli of different nature,

positively or negatively reinforced) or Go NoGo, Stop Go tasks, but also in response to pharmacological micro-

injections in the striatum. A second part will assess the effects of the administration of selective serotonin reuptake

inhibitor on behavioral states and performances, as well as on DA and 5-HT markers by PET imaging. A last one will

characterize on post-mortem tissues the effects of MDMA lesion by looking at DA and 5-HT markers in the brain.

Results from this project will have a large impact on the understanding of physiopathology of behavioral disorders as

well as for their remediation in different pathologies such as Parkinson’s disease, depression or anxiety.

3 publications:

-Neumane S, Mounayar S, Jan C, Ballanger B, Epinat J, Coste N, Féger J, Thobois S, François C, Sgambato-Faure V and

Tremblay L. Effects of local injections of dopamine and serotonin antagonists in Basal Ganglia on the symptomatic

recovery of MPTP-treated monkeys. In revision for Neurobiology of Disease.

-Sgambato-Faure V, Cenci MA. (2012) Glutamatergic mechanisms in the dyskinesias induced by pharmacological

dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease. Progress in Neurobiology.

96(1):69-86.

-El Atifi-Borel M, Buggia-Prevot V, Platet N, Benabid AL, Berger F, Sgambato-Faure V. (2009) De novo and long-term l-

Dopa induce both common and distinct striatal gene profiles in the hemiparkinsonian rat. Neurobiology of Disease

34(2):340-50.

To be sent to: Evelyne Robin ––[email protected] Deadline : 13 April 2012



Host laboratory (Name, code, director): Lyon Neuroscience Research Center, CNRS-UMR5292, INSERM-U1028, Université Lyon 1, Olivier Bertrand

Host research team: (Name and director): Auditory Cognition & Psychoacoustics, Barbara Tillmann

Thesis director (with habilitation, HDR): Fabien Perrin

Co-director: Barbara Tillmann 5 keywords: coma, EEG, consciousness, music, auditory perception 3 year scholarship already available: NO Local candidate: YES

: TITLE: Influence of familiar sounds on cognition in patients with altered states of consciousness

One of the most important clinical challenges in patients with altered states of consciousness (comatose, vegetative

and minimally conscious patients) is to estimate their residual brain functions, in particular their actual conscious

perception of the environment. While various sophisticated experimental procedures have been built to specifically

assess consciousness, the interpretation of the acquired data was often limited to a group-level. This could be

explained by the fact that most of the previous studies used simple artificial stimuli without relevance for the patients.

Indeed, some studies have shown that emotionally charged and/or personally relevant stimuli, like the patient's own

first name, induce robust and reliable cerebral responses at an individual level.

The general objective of the project is to develop new approaches that could contribute to promote clinical evaluation

of patients with altered states of consciousness. In particular, we will test whether familiar autobiographical sounds

enhance cognition and self-awareness. We will focus our investigation on the beneficial effect of musical material as

previous research has provided evidence that music can improve cognitive recovery (memory, language, etc.) in

patients, probably because its emotional content increases arousal. The general effect of familiarity on cognition will

be also tested using familiar (emotionally charged and relevant) and unfamiliar sounds of various nature (language,

music, environmental sounds). High-density EEG will be used to assess the functional and effective connectivity within

cerebral networks implicated in the perception of familiar auditory stimuli as a function of the state of consciousness.

3 publications :



Host laboratory (Name, code, director): CRNL, (CNRS UMR5292, INSERM U1028, Université Claude Bernard-Lyon1), Dr Olivier Bertrand

Host research team : ( Name and director): SLEEP team, Director: Pierre-Hervé LUPPI

Thesis director (with habilitation, HDR): Christelle PEYRON

Co-director: 5 keywords : hypocretin/orexin, REM sleep, motor control, emotion, optogentics 3 year scholarship already available : NO Local candidate : YES NO

:

TITLE : (text Calibri 11 interval 15, bold characters) Mecanisms of induction and inhibition of cataplexy in a murin model of Narcolepsy, a sleep rare neurological disorder. Narcolepsy is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations (Dauvilliers et al, 2007). These include cataplexy (sudden loss of muscle tone during active wakefulness), sleep paralysis, hypnagogic hallucinations, and sleep-onset REM periods (SOREMP). Recent pathophysiological insights have demonstrated that narcolepsy with cataplexy is caused by the loss of hypothalamic neurons producing hypocretin/orexin (Peyron et al, 2000). However, when hypocretin signaling, a wake promoting system, is intact cataplexy is never observed. Further, cataplexy is triggered by strong emotions. The amygdala, a component of the limbic system involved in the expression of emotions seems to play a key role in triggering cataplexy. Notably, a hyperactivation of the amygdala to positive emotions has been reported in narcoleptic patients (Schwartz et al, 2008). A lesion of the amygdala in a murin model of narcolepsy, seems to be sufficient to suppress cataplexy (unpublished data). The aim of the proposed projet is to determine how the neuronal network of cataplexy is modulated by emotions, in particular by the amygdala and is inhibited by the hypocretin/orexin system. The similarity of cataplexy to muscle atonia observed during REM sleep indicates that cataplexy uses the same output network as REM sleep muscle atonia. In the past 20 years, we have combined in vivo electrophysiology, polysomnography, sleep deprivation, pharmacology and functional neuroanatomy and accumulated data identifying the neuronal network of REM sleep muscle atonia that is located in the brainstem (Luppi et al, 2011). We propose thus to study the interaction of the amygdala and the hypocretins with the neuronal groups of the brainstem we have identified. To do so, we will use a combination of techniques such as optogenetics, pharmacology and functional neuroanatomy in orexin knock-out mice, a well-recognized model of human narcolepsy.

3 publications :

Peyron C et al (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 6(9): 991-99

Dauvilliers Y, Arnulf I, Mignot E. (2007) Narcolepsy with cataplexy. Lancet 369: 499-511.

Luppi PH, Clement O, Sapin E, Gervasoni D, Peyron C, et al. (2011) The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev 15: 153-163.



Host laboratory (Name, code, director): Centre de Recherche en Neuroscience de Lyon CNRS-Université Lyon1 UMR5292- INSERM U1028, Dir : O. Bertrand (http://crnl.univ-lyon1.fr/index.php/fr)


Equipe « Du codage à la mémoire olfactive », Dir : R. Gervais

Thesis director (with habilitation, HDR): Nadine Ravel CR1 CNRS, HDR

Co-director: 5 keywords : Episodic Memory – Consolidation – olfaction –neural assembly- brain oscillation 3 year scholarship already available : NO Local candidate : NO

:

TITLE : Hippocampo-cortical interactions and long term episodic memory: Brain oscillatory dynamic study in behaving rats

One of the major questions in neuroscience is how the dynamic activity of specific neurons in the brain gives rise to the

lasting traces of experience that underlies memory. The general context of the PhD proposal is understanding how, in

selected regions and circuits in the mammalian brain, information is encoded in specific activity patterns and structural

configurations at the circuit, cellular, and molecular levels, thereby enabling the process of memory.

There is now a general agreement that long term memory storage is a process supported by hippocampo-cortical

dialog. Therefore, the specific objective of the project will be to describe how the hippocampus and parahippocampal

regions interact with different cortical areas to support the storage of episodic-like memory. This particular form of

memory, is characterized by the combination of different types of information ‘what-where-in which context’ linked to

a precise episode the animal has been experienced. This situation will allow us to probe recall of specific information as

well as combined associations in both recent and remote memory. This will give us the opportunity to study how, with

time, memories are dynamically reorganized during systems consolidation and to precise when cortical regions gain

growing control over recall.

We recently designed a novel behavioural task to study specific features of episodic memory in rats. This paradigm is

based on the ability to remember that the precise location of an odour in a particular enriched experimental context

will prevent the animal to experience a negative reinforcement and ensure it will get a positive one.

Regarding the experimental strategy, using intracerebral pharmacology, we will first test the specific involvement of

hippocampus and several cortical areas in the recall process according to the type of information to be remembered

and the age of memory. Then, using, multiple-sites network oscillations recordings combined to experimental

manipulation of specific cell types and gene targeting, we will try to describe the different phases of the hippocampo-

cortical dialog leading to system consolidation. This project is supported by a 2011-2014 ANR grant .

Publications: Martin C, Gervais R, Hugues E, Messaoudi B, Ravel N. (2004) Journal of Neuroscience, 24: 389-397. Martin C, Gervais R, Messaoudi B, Ravel N. (2006) European Journal of Neuroscience, 23: 1801-1810. Chapuis J, Garcia S, Messaoudi B, Thevenet M, Ferreira G, Gervais R, Ravel N. (2009) Journal of Neuroscience,

29:10287–10298.



Host laboratory (Name, code, director): CRNL, UMR5292, U1028, Lyon 1, Olivier Bertrand


BioRaN (Radiopharmaceutical & Neurochemical Biomarkers), Luc Zimmer

Thesis director (with habilitation, HDR): Prof. Luc ZIMMER

Co-director: Dr. Sophie LANCELOT 5 keywords : Brain molecular imaging, PET, alpha-synuclein 3 year scholarship already available : NO Local candidate : YES

:

TITLE : Toward PET molecular imaging of alpha-synuclein The identification of alpha-synuclein (α-syn) as a protein causing familial neurodegenerative syndromes and directly implicated in the pathogenesis of dementias is one of the most exciting discoveries of the past 15 years in the neuroscience field. α-syn aggregation is a neuropathological hallmark of many neurodegenerative diseases including Parkinson’s disease and other neurodegenerative diseases with dementia, collectively named as synucleinopathies. If substantial advances in clinical criteria have allowed to improve the detection and the differential diagnosis of these brain disorders, there is no clear diagnostic imaging biomarker that affords a reliable differential diagnosis between the different forms of dementias (to distinguish to Alzheimer dementia) or that could facilitate tracking of disease progression and future evaluation of therapeutics. Our project aims at proposing the first positron emission tomography (PET) radiotracer of α-syn as a novel biomarker. Our approach is translational, from the chemistry of candidate-molecules to their biochemical evaluation, 18F-radiolabelling and in vitro or in vivo studies by microPET in animal models of synucleinopathies and in patients by post-mortem autoradiography. This thesis will be centered on PET imaging (in vitro, ex vivo and in vivo) and will aim at providing a proof-of-concept of a suitable α-syn PET radiotracer before its translation to imaging studies in patients.

3 publications : - Lemoine L, Vacher B , Lancelot S, Billard T, Newman-Tancredi A, Zimmer L. Radiosynthesis and preclinical evaluation

of [18F]F13714 as a fluorinated 5-HT1A receptor agonist radioligand for PET neuroimaging. Journal of Nuclear Medicine, in press.

- Zimmer L, Luxen A. PET radiotracers for molecular imaging in the brain: past, present and future. NeuroImage, in press.

- Verdurand M, Bérod A, Le Bars D, Zimmer L. Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus. Neurobiology of Aging, 2011, 32, 103-114.



Host laboratory (Name, code, director): Stem-Cell and Brain Research Institute, INSERM U846, Dr. Colette Dehay & Dr. Henry Kennedy http://www.sbri.fr/

Host research team : ( Name and director): Neurobiology of executive functions, Dr. Emmanuel Procyk

http://www.sbri.fr/members/emmanuel-procyk.html

Thesis director (with habilitation, HDR): Dr. Emmanuel Procyk

Co-director: Dr. Céline Amiez 5 keywords : behavioral adaptation, anterior cingulate cortex, functional magnetic resonance imaging, monkey, human 3 year scholarship already available : NO Local candidate : NO

:

TITLE: Behavioral adaptation in primates The ability to react appropriately to positive or dangerous events is of critical importance in decision-making, problem-solving, and social processes. Two types of events may signify the need to update a behavioral strategy: events that are linked to one's actions (e.g. adapt the strategy after an erroneous choice) and events that are not directly linked to actions (e.g. adapt the strategy after the unexpected shift of an opponent's strategy). To optimize adaptation at the occurrence of these event types, it is necessary to learn the relationships between actions and their results, but also to learn the meaning of unexpected changes in the environment as well as to estimate the statistical properties of their occurrence. At the present time, the neuronal networks involved in the autonomous regulation of these critical functions remain unknown. The identification of these networks and the description of their functioning are of critical importance as it will explain how cognitive systems generate flexible behaviors and the implementation of artificial versions of these systems will then be possible. Our previous works suggest that it may exists a general system managing all types of events that signify the need to adapt the strategy (linked or not to action). In this system, the anterior cingulate cortex seems to have a key role. In addition to its strong interconnections to the dorsolateral prefrontal cortex that is involved in the spatio-temporal control of actions, it is also interconnected with the dopaminergic mesencephalic system that has been shown to be of critical importance in the organization and regulation of flexible behaviors. The goal of this PhD work is to assess the computational and neurobiological base of such general system in both human and awake rhesus monkey using functional magnetic resonance imaging (fMRI) techniques. Part of this project may involve to spend a couple of months in the laboratory of one of our main collaborator, i.e. in the laboratory of Dr Michael Petrides at McGill University in Montreal (Québec, Canada). 3 publications : Khamassi M et al. Front Neurorobot. 2011;5:1-14. Quilodran et al. Behavioral shifts and action valuation in the anterior cingulate cortex. Neuron, 2008, 57:314–325. Amiez et al. Reward Encoding in the Monkey Anterior Cingulate. Cereb Cortex. 2006, 16(7):1040-55.



Host laboratory (Name, code, director): Lyon Neuroscience Research Center (INSERM U1028 - CNRS UMR 5292 - UCBL1), dir: Olivier Bertrand

Host research team : ( Name and director): Integrated Physiology of Brain arousal systems (WAKING), dir:

Jian-Sheng LIN

Thesis director (with habilitation, HDR): Jian-Sheng LIN

Co-director: Laurent SEUGNET 5 keywords : Sleep/wake, molecular genetics, Drosophila, Histamine, Orexin 3 year scholarship already available : NO Local candidate : NO

:

TITLE : Uncovering molecular pathways of wakefulness Wakefulness is an essential brain state allowing vital activities and cognitive behaviors. Its maintenance requires convergent and divergent activities of complex brain arousal systems. We have previously shown that the posterior hypothalamus plays a central role in waking and that this function is mediated, in part, by histaminergic (HA) and orexinergic (Ox or hypocretinergic) neurons. We have further shown that HA and Ox act distinctly and synergistically in terms of wake control using knock out mice models (1). Importantly, double knock-out mice lacking both HA and Ox exhibit not only all of the phenotypes of both single knock out mice lacking HA or Ox, but also other important phenotypes including SOREM (sleep onset REM), somnolence, cataplexy and hypersomnia as well as a marked obesity, characteristics of narcolepsy, a neurological disease characterized by excessive somnolence and cataplexy in humans (manuscript in preparation). Thus, the HA and Ox systems constitute adequate starting points to investigate the integrative properties of wake regulation. However, the molecular targets of HA and Ox involved in cortical arousal are unknown. The identification of these molecular targets is an important element to decipher the function of HA and Ox. To achieve this goal, we have used whole genome profiling to compare gene activation between mice completely deficient for both HA and Ox, and their wild type littermates. The abundance of transcriptional changes seen in the cortex indicates that this ultimate target of the brain waking systems is significantly affected by HA and Ox removal. These genes potentially reflect unidentified mechanisms involved in waking, therefore, evaluating in vivo the sleep-wake regulatory function of a large number of these genes is required. Because such a screening is impracticable in mammalian systems, we will use the Drosophila model which is particularly well suited for this experimental approach. Virtually all genes can be rapidly evaluated in Drosophila thanks to the vast number of genetic stocks readily available from public collections. Sleep in Drosophila exhibits many key similarities with mammalian sleep, and can be monitored in thousands of individual animals by automated locomotion detection systems. Using the Gal4-UAS system and UAS-RNAi transgenes, a specific shRNA will be expressed either in neurons or in glial cells. A difference in the sleep/wake phenotype (total amount, bout duration, circadian modulation) of the shRNA expressing flies compared to the control groups will identify genes potentially involved in wake regulation. From this initial screen, we will select a gene for a detailed functional study, both in Drosophila and in the mouse, using available experimental approaches. The data obtained from this project may provide new concepts to help our understanding of wakefulness, and open new therapeutic avenues for attention and vigilance disorders. 3 publications :

1. Anaclet, C., et al., Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models. J Neurosci, 2009. 14423-38.

2. Seugnet, L., et al., Identifying sleep regulatory genes using a Drosophila model of insomnia. J Neurosci, 2009. 29(22): p. 7148-57.

3. Seugnet, L., et al., D1 receptor activation in the mushroom bodies rescues sleep-loss-induced learning impairments in Drosophila. Curr Biol, 2008. 18(15): p. 1110-7.

Claude Bernard University, Lyon I

Neuroscience and Cognition Doctoral School (NSCo)

PhD proposal 2012-2013

Research Unit: CRNL, INSERM U1028 - CNRS UMR 5292, director Olivier Bertrand

Research Team: Neurooncology and Neuroinflammation (Head: J. Honnorat), Faculté Laennec, 7 rue

G. Paradin 69372 Lyon cedex 08

Research leaders (1HDR): Olivier Pascual, Jérome Honnorat

Research project proposed: Modality of gliotransmission in the perioncogenic area

SCIENTIFIC CONTEXT: The term “gliotransmission” is referring to the capacity of glial cells to release

transmitters in a calcium dependant manner. Gliotransmission has been particularly studied in astrocytes, a subtype of glial cell. It is now widely accepted that gliotransmission from astrocytes participate to synaptic transmission by modulating neuronal activity and synaptic plasticity. We have recently demonstrated that at onset of inflammation, microglia, another type of glia, can modulate neuronal activity by releasing small amounts of ATP and by using astrocytes as an intermediate. However, gliotransmission modalities in microglia are poorly understood. Microglia, the immune cells of the brain, are involved in most central nervous diseases by participating to inflammation. Inflammation associated to the pathological brain drastically changes glial phenotype, turning astrocytes into reactive astrocytes and microglia into activated microglia. Gliotransmission during inflammation has not yet been investigated; this is the purpose of this project.

RESEARCH PROJECT: To study gliotransmission during inflammation, we will use the perioncogenic area

associated to glioma in mice. Gliomas are a spectrum of tumors of varying differentiation and malignancy grades. Gliomas are often associated with epilepsy, cognitive and motor disorders that strongly hinder patient’s quality of life. The periphery of the tumor or of the tumoral cells in case of diffuse glioma is characterized by an inflammatory territory containing reactive astrocytes and activated microglia. Our hypothesis is that parts of the side effects associated to glioma are due to a change in gliotransmission in the periconcogenic area that affects synaptic transmission. More specifically, we will: - Study the modality of gliotransmitter release by microglia using optogenetic coupled to electrophysiological recording of neurons in acute slices. We will also test the capacity of microglial cells to detect neuronal activity by measuring calcium oscillation in microglial cells using genetically encoded calcium indicator specifically expressed in microglial cells. - Study gliotransmission in activated microglia and reactive astrocytes in acute slices. We will pay special attention to the capacity of the tissue to generate seizure activity and test the capacity of inflammed glial cells to participate to synaptic transmission. For this purpose, we will assess gliotransmission in the perioncogenic area and compare it to the gliotransmission in control area. We will monitor different known parameters of the gliotransmission; the susceptibility to trigger Slow Inward Currents (SIC) and to modulate the presynaptic terminals glutamate probability of release.

Altogether this project will allow us to assess the importance of gliotransmission in the healthy and

pathological brain.

Selected publications of the team:

- Pascual et al. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A. 2012; 109(4):E197-205.

- Roumier et al. Prenatal activation of microglia induces delayed impairment of glutamatergic synaptic function. PLoS One. 2008; 3(7):e2595.

- Pascual et al. Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005; 310(5745):113-6.

- Fellin et al Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 2004; 43(5):729-43.

Grant available: No

Local candidate: No



Host laboratory (Name, code, director): Lyon Neuroscience Research Center, INSERM UMR-S1028, CNRS UMR5292 Director: Dr. Olivier Bertrand

Host research team: ( Name and director):

Neuro-Oncology & Neuro-Inflammation (ONCOFLAM) Director: Professor Jérôme Honnorat

Thesis director (with habilitation, HDR): Mahaz Améli-Moradi Co-director: Jérôme Honnorat 5 keywords : CRMP5, Dynein, selective transport, neuronal development 3 year scholarship already available: YES NO Local candidate : YES NO

: TITLE : The role of CRMP5 in selective transport during neuronal development Collapsin response mediator proteins (CRMPs) are one of the major phosphoprotein in the developing nervous system. These multifunctional proteins consist of a family of five cytosolic proteins (CRMP1-5) acting as signaling molecules involved in the regulation of microtubule polymerization, actin bundling and endocytosis leading to neuronal differentiation The best-studied member of the family, CRMP2, is involved in different functions such as the regulation of neuronal polarity, axon elongation, vesicle trafficking and synaptic physiology. Fewer stsudies relate to CRMP5, which is highly expressed in developing brain, but decreases in adult brain where its expression is only restrained to the brain area, that retain neurogenesis. CRMP5 exhibits spatio-temporal expression in the cortex, hippocampus and cerebellum. We recently demonstrated that CRMP5 inhibits neurite outgrowth by forming a complex with tubulin and the Microtubule Associated Protein MAP-2. CRMP5 abrogates the CRMP2 promotional effect on dendrite outgrowth by reducing the CRMP2 interaction with tubulin. Intriguingly, CRMP5 is expressed preferentially in future dendrites inhibiting their outgrowth, while the dendrites begin to growth upon a decrease in its expression. This suggests that CRMP5, by antagonizing the growth-promoting effect of CRMP2, modulates the regulation of neuronal polarity. However, CRMP5, like other CRMPs, is a multifunctional adaptor protein, involved in other functions, which still remain obscure. In this research project, we try to gain insights into the functions of CRMP5 protein through identification of its interacting partners and its pattern of cellular distribution in the context of neuronal development. It is now admitted that CRMP2 binds to kinesin-1 light chain and selectively transport tubulin heterodimers to the distal end of nascent axon, playing a role in axon specification. Our preliminary data indicate that CRMP5 is able to interact with the molecular motor dynein, another key molecules for the transport of the cargo, which moves toward the minus-end of the microtubules. The aim of our study is to investigate the role of CRMP5 in selective transport. Tacking into account that the dendritic microtubules possess a mixed polarity, with either plus-end or minus-end directed toward the distal part of the neuron, one can assume that CRMP5 by binding to dynein may play a role in both retrograde and anterograde transport as cargo adaptor allowing the delivery of various organelles, membranous structure, and/or cytosolic proteins. In addition, our recent finding on the localization of CRMP5 in mitochondria argues in favor of a model in which CRMP5 may influence mitochondrial transport. Beside, the phosphorylation state of the molecule being an important step in the regulation of the loading and unloading of the cargo a complementary line of this research will focus on CRMP5 phosphorylation. 3 publications : - Rogemond R., Auger C., Giraudon P., Becchi M., Auvergnon N., Belin M.F., Honnorat J. & Moradi-Améli M. Processing and nuclear localization of CRMP2 during brain development induce neurite outgrowrh inhibition. J. Biol. Chem. (2008) 283, 14751-14761. - Brot S., Rogemond V., Perrot V., Choulnamountri N., Auger C., Honnorat J.& Moradi-Améli M.CRMP5 interacts with tubulin to inhibit neurite outgrowth, thereby modulating the function of CRMP2. J. Neurosci. (2010) 30, 10639-10654.



Host laboratory (Name, code, director): Centre de Recherche en Neuroscience de Lyon-Université Lyon1 UMR5292-INSERM U1028, Dir : O. Bertrand (http://crnl.univ-lyon1.fr/index.php/fr)

Host research team: ( Name and director):

Equipe ONCOFLAM « neuro-oncologie et neuro-inflammation», Dir : J. Honnorat

Thesis director (with habilitation, HDR): Nelly Noraz (CR1 Inserm, HDR)

Co-director: Véronique Pellier-Monnin (Maître de Conférence) 5 keywords: Syk kinases – Immunoreceptor - Cerebellar development – Granule cells –migration 3 year scholarship already available : No Local candidate : Yes

:

TITLE : Role of the Syk kinase family in cerebellar granule cells migration during development

The function of the protein tyrosine kinases of the Syk family (Syk and ZAP-70) has been well characterized in the hematopoietic system. They relay, with the coordinated action of the Src kinases, the signals emanating from the immunoreceptors, pillars of immune responses. Long regarded as restricted to hematopoietic cells, the function of Syk kinases has been extended to non-hematopoietic cells. Crosstalk between immunoreceptors and other membrane proteins explains in part such a multiplicity of function. These data indicate that the immunoreceptor-based signaling paradigm has much wider implication than previously anticipated.

An increasing number of data involve ITAM-bearing immunoreceptors in brain development, synaptic plasticity and behavior. However it has yet to be determined whether these proteins in fact transmit an immunoreceptor-like signal in non-hematopoietic neuronal cells. The recruitment and activation of the Syk family tyrosine kinases, being a critical step in this process, we conducted a thorough analysis of Syk/ZAP-70 expression pattern in brain tissues. Syk/ZAP-70 is present in neurons of different brain structures including the visual system, the olfactory system, the hippocampus and the cerebellum (Hatterer et al., Neuroscience Research, 2011). In the developing cerebellum, Syk is expressed in a subpopulation of neurons, the granular cells. Importantly, Syk is phosphorylated on tyrosine residues representative of an active form of the kinase in a restricted area corresponding to post-mitotic granule cells (GC) migrating tangentially through the external granular layer (EGL).

To establish the implication of Syk in this function, EGL micro-explants were cultured in the presence of a Syk pharmacological inhibitor. Strikingly, GC migration rates were markedly reduced in EGL micro-explants treated with the Syk inhibitor. Syk KO animals die soon after birth, therefore, the role of Syk in GC tangential migration will be further evaluated on EGL micro-explants and on cerebellar slices using Syk shRNA lentiviral vectors. A search for ligand(s)/receptor(s) responsible for Syk activation in this biological system will be undertaken. Two major candidates, sema6A/plexinA2 and the adhesion molecule TAG1 will be carefully examined. Indeed, they present the same developmental pattern of expression and crosstalk between an immunoreceptor and the sema6A receptor Plexin A2 have been described in immune cells. In this context, we will first look for the lost of Syk phosphorylation on P6 cerebellar sections of sema6A, plexin A2 and TAG-1 KO animals. Notably, in all of these KO mice, ectopic GC are observed in the molecular layer. As mentioned before, Syk KO animals die soon after birth and we don’t have access to Syk conditional mice at this time. However, we are breeding Syk+/- / ZAP-70-/- mice which are currently analyzed for the presence of ectopic granule cells in the molecular layer. The implication of Syk kinases downstream of these receptors will be further examined in vitro. The impact of Syk on TAG-1-induced neurite outgrowth will be assessed on purified GC and the role of Sema6A-mediated GC migration will be studied on EGL micro-explants. Finally, biochemical studies will be performed on either purified GC or in the Cos cells system. This work is conducted with the input of Alain Chédotal’s Lab (Institut de la vision, Paris) and Victor tybulewicz’s Lab (National Institute for Medical Research, London).



Host laboratory (Name, code, director): CRNL – Olivier Bertrand director

Host research team : ( Name and director): Dycog team – Olivier Bertrand director

Thesis director (with habilitation, HDR): Jean-Philippe Lachaux (HDR)

Co-director: 5 keywords : electrophysiology – attention – gamma band activity – electrocorticography – mind-wandering 3 year scholarship already available : NO candidate : YES

:

Neural and behavioural characterization of the ability to sustain executive attention Even in motivated individuals, performance in attention-demanding activities is often characterized by temporal fluctuations due to transient, involuntary shifts of attention away from the task at hand, with sometimes disastrous consequences. Those “Momentary Lapses of Attention” (MLA) have recently been the topic of several fMRI studies, which have associated MLA with hyperactivation of a specific frontal-parietal cortical network, called the default-network. The primary aim of this project is to understand in details how the default-network interferes with task-related processes to disrupt executive and selective attention during MLA. An attention-demanding paradigm, called LEST, has been designed that provides a behavioural measure of attention allocation on a second-to-second basis. Using both invasive, intracerebral EEG recordings in patients with millimetre/millisecond resolution, and non invasive EEG/fMRI recordings in healthy adults, the thesis will provide the most complete description of the neural origin of MLA so far, and the first direct investigation of its precise neural mechanisms. Further, the thesis will involve the acquisition of normative oculometric and behavioural measures during LEST performance in healthy adults and children populations that will available for comparison to diagnose quantitatively possible executive attention-deficits in any individual. LEST will be the first behavioural task with known neural correlates to measure MLA on the order of seconds to minutes.



Host laboratory (Name, code, director): CRNL - CNRS UMR5292 - INSERM U1028 - Lyon 1 ; Director: Olivier Bertrand


SLEEP (Physiopathologie des réseaux neuronaux du cycle veille-sommeil) ; Director : Pierre-Hervé Luppi

Thesis director (with habilitation, HDR): Dr Pierre-Hervé Luppi ([email protected])

Co-director: Dr Frédéric Brischoux ([email protected]) 5 keywords : obstructive sleep apnea, hypoglossal motor nucleus, glycine, brainstem, REM sleep 3 year scholarship already available : YES NO Local candidate : YES NO

:

TITLE : Brainstem mechanisms involved in the control of muscle activity in the upper airways during paradoxical sleep in the rat: a new experimental model for sleep apnea syndrome. Obstructive sleep apnea (OSA) is a common pathology in humans, characterized by repeated upper airway closure during sleep resulting in severe and deleterious consequences on patient’s health such as cardiovascular diseases or cognitive dysfunctions. However, no pharmaceutical treatment is available yet. The pathogenesis of OSA has been linked to the suppression of pharyngeal muscle activity during sleep, particularly during paradoxical sleep (PS), that leads to upper airway occlusion in individuals with a small airway. Pharyngeal muscle activity is under the control of the hypoglossal motor nucleus (12N), a nucleus located in the medio-dorsal part of the medulla. However, little is known about the mechanisms and the neuronal systems that suppress the activity of hypoglossal motoneurons during PS. The aim of the project will be to characterize the anatomical and functional organization of the neuronal networks critical for the suppression of pharyngeal dilator muscle activity during PS. In particular, it will be to verify the hypothesis that GABAergic/glycinergic neuron populations localized in the reticular formation of the medulla are responsible for the inhibition of hypoglossal motoneurons during PS. This project contains two main steps: i) the identification of the neurons responsible for the inactivation of hypoglossal motoneurons during PS. This step combines functional neuroanatomy (retrograde tract tracing from the 12N combined with Fos expression study and immunohistochemistry or in situ hybridization in rats after specific PS deprivation or PS rebound) and in vivo electrophysiology (extracellular recordings in naturally waking-sleeping, head-restrained rats), two complementary approaches to describe the anatomical organization and the electrophysiological properties of these neurons. ii) the control of the pharyngeal muscle activation using RNA-mediated interference methodology. RNA-mediated interference is a specific and efficient method to knock-down protein levels using small interfering RNAs (siRNAs). Local injections of specific adeno-associated viral vectors (AAVs) containing siRNAs targeting the vesicular GABA and glycine transporter (VGAT) gene in discrete regions of the brain will allow a selective suppression of GABA/glycine neurotransmission from these regions. This step will aim to demonstrate that the neurons active during PS and projecting to 12N play a major role in the inhibition of pharyngeal dilator muscles. 3 publications : - Sirieix C, Gervasoni D, Luppi PH, Léger L (2012) Role of the lateral paragigantocellular nucleus in the network of paradoxical (REM) sleep: an electrophysiological and anatomical study in the rat. PLoS ONE, 7, e28724. - Luppi PH, Clément O, Sapin E, Gervasoni D, Peyron C, Léger L, Salvert D, Fort P (2011) The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep Med Rev, 15, 153-156. - Sapin E, Lapray D, Bérod A, Goutagny R, Léger L, Ravassard P, Clément O, Hanriot L, Fort P, Luppi PH (2009) Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS One, 4, e4272.

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