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2021 winners of the "Innovative and Collaborative Research" calls: ICR, ICR Plus, and Technical Boost

Find in this article the details of the winning projects of the ICR, OCR Plus and Technicals Boost (TB) calls of 2021.

Estimated reading time : 15 min

Within the framework of the promotion of scientific exchanges, NeuroMarseille aims to encourage the emergence of new collaborative projects within the neuroscience community of Marseille and to support technical platforms.

In this context, the institute has opened three calls for projects in order to promote new collaborations between researchers, post-docs or engineers for the emergence of innovative projects, sometimes in collaboration with a technical platform. Find the details of these calls and the winning projects in this article.

Projects funded for the "ICR" category

Call details

For innovative and collaborative research projects

Nicolas MAURICE (IBDM) & Christelle BAUNEZ (INT) Functional characterization of the amygdala inputs onto the dorsal striatum

The basal ganglia (BG) are a collection of subcortical nuclei involved in motor control, sensorimotor learning and value-based decision making, contributing to the continuous specification of movements that endows voluntary actions (Park et al., 2020). To elaborate successful goal-directed behaviour, the BG and particularly the striatum and the subthalamic nucleus (STN), its main input structures, integrate a wide variety of information, including emotional states. However, the source of this emotional information is largely unknown. The amygdala is considered as a key player in the processing of emotional states. Despite anatomical evidence for projections from the amygdala to the dorsal striatum, its functional impact on the BG network is poorly understood.

This proposal aims at filling this gap in mice by characterizing

  1. the behavioral impact of the amygdala on BG-related behaviors by manipulating the amygdalo-striatal pathway with chemogenetics;
  2. the functional impact of this pathway onto the striatal neurons using ex vivo electrophysiology and optogenetics.

This project will provide novel insights onto the integration, by the dorsal striatum, of information with emotional content, by addressing for the first time the functional role of the amygdalar input in a relevant behavioural task. The electrophysiological experiments at the striatal level will further allow to specify the physiological properties of amygdala synapses in the dorsal striatum and to highlight possible differences according to the targeted postsynaptic neurons. The overall work will give a comprehensive view on whether and how information with emotional value coming from the amygdala is processed in the main input structure of the BG network to impact motor control and learning.

Christine ASSAIANTE (LNC), Jean-Philippe RANJEVA (CRMBM), Serge PINTO (LPL) et Pascale COLE (LPC) Understanding the role of sensorimotor representation in dyslexia: neural basis and impact of comorbidity

To determine the impact of the comorbidity with sensorimotor syndrome in the dyslexia deficits, our project aims to test the two phonological and sensorimotor hypotheses in a unique study. The question is whether an impairment of phonemic representations is associated with an impairment of articulatory and bodily actions. On the basis of behavioural studies, we have already characterized two groups of 15 young dyslexic adults with or without sensorimotor deficit, compared to two groups of 15 young control adults with or without sensorimotor deficit.

For the first time, on the basis of this unique cohort, behavioural results will be supported, by neuroimaging evidence on the basis of using  7T MRI  focusing on unique high contrast,  high spatial resolution and high temporal resolution for  MRI  data. We will assess whether these behavioural features are supported by cerebral features of networks devoted to the internal representation of action and learning process such as frontoparietal, cingulo-opercular, somatomotor and cerebellar-cortical networks. This step is crucial to consider new forms of remediation of dyslexia. Indeed, better targeting the sensorimotor contours of dyslexia should allow more holistic remediation to support the dyslexic subject throughout life and thus limiting collateral disorders such as decreased self-esteem and stress of learning situations.

Emmanuel NIVET (INP) et Rosanna DONO (IBDM) Targeting neuroinflammation in human and mouse astrocytes by inhibition of a candidate Heparan sulfate proteoglycan

Neuroinflammatory events are increasingly considered as possible triggers of neurodegenerative diseases (NDs). Accordingly, the search for yet unknown factors involved in the regulatory control of inflammation in the brain may lead to identification of efficient and specific molecules enabling modulation of pathogenic neuroinflammatory processes. Heparan sulfate proteoglycans (HSPG) are interesting molecules involved in the control of numerous events that occur during inflammation. We and others have recently found that, in astrocytes, alterations affecting one of the members of the HSPG family associate with the ND genetic risk factor APOE4. We also recently showed that APOE4 predisposes toward a pro-inflammatory phenotype in astrocytes. In this context, our project will explore the unmet issue of HSPG implication in the control of neuroinflammation in astrocytes. To that end, we have defined two main objectives:

  1. Evaluating the potential of HSPG-specific blocking nanobodies on human astrocytes to control inflammation
  2. The generation of astrocyte-specific conditional KO mice for our HSPG candidate

To reach our objectives, we will take advantage of validated experimental paradigms and powerful human induced Pluripotent Stem Cell-based models; unique and patented products (blocking nanobodies); and a novel transgenic mouse model. Leveraging these new models/tools, combined with cellular and molecular analyses, this project will aim at demonstrating that inhibiting our HSPG candidate in astrocytes could modulate astrocyte reactivity in vitro an in vivo. Altogether, our research proposal will increase our understanding on the role of this HSPG molecule in astrocyte reactivity but also provide a rationale for targeting it in the clinic to reduce the consequence of neuroinflammatory events. This proposal aims at making the proof-of-concept that this yet poorly studied HSPG is a new target of interest for further therapeutic developments to prevent and/or treat NDs.

Projects for the "ICR Plus" category

Détails de l'appel

For innovative and collaborative research projects and platform involvment in 2021

Antoine DE CHEVIGNY (INMED) et Christophe LETERRIER (INP) / NCIS platform of the INP Regulation of axon initial segment plasticity by the transcription factor NEUROD2: implications for neurodevelopmental disorders

This proposal aims to determine whether and how NEUROD2 cell-autonomously regulates AIS structure and plasticity. In particular, we suggest that NEUROD2 might be a key missing link between calcium entry and AIS plasticity in forebrain excitatory neurons.

In particular, we suggest that NEUROD2 may be a key missing link between calcium input and AIS plasticity in excitatory neurons of the forebrain. We will test the impact of the autonomous deletion of Neurod2 cells on the structure and plasticity of AIS in vitro and in vivo.

This project is innovative at scientific, technical and conceptual levels.

  • Scientifically, it aims to characterize new key molecular players of AIS structural integrity and plasticity.
  • Technically, we will use state-of-the-art approaches to address AIS structure and plasticity both in vitro and in vivo. For the first time, we will (i) combine the well-established in vitro system for cytological AIS plasticity analyses with super-resolution microcopy, and (ii) in-depth characterize neurons from a disease model in this reductionist paradigm.
  • Conceptually, this project shall pave the way to better understanding and possibly treating neurodevelopmental disorders beyond those involving NEUROD2. Indeed, integrative genomic analyses indicate that NEUROD2 is a hub gene linked with many other neurodevelopmental disorder genes, and recent evidence suggests that neurodevelopmental syndromes involving such other genes might also be causatively associated with AIS defects. Hence, our results might support the new hypothesis that AIS lies at an important crossroad in neurodevelopmental disorders.

Myriam CAYRE (IBDM) and Nathalie Lorenzo (LNC) / Rodent Bihavior platform of the LNC Investigating the link between demyelination, cognition and Alzheimer’s disease in mice

The global objective of this project is to examine if and how myelin maintenance and remodelling may contribute to the physiopathology of non-familial forms of Alzheimer’s disease (AD). The specific objective of this collaboration is to evaluate cognitive impairments in mouse models of demyelination and of AD and to examine whether an early episode of demyelination/remyelination increases the risk to develop an AD-like syndrome or exacerbates/advances the symptoms in a rodent model of AD. Most forms of AD are not genetic but rather sporadic forms. We will thus use a mouse model that do not carry the known genetic mutations involved in familial forms of AD. Instead, we will use a metabolic mouse model of AD induced by streptozotocin injections (STZ). Demyelination will be induced by cuprizone (CUP) feeding during 5 weeks.

In this one-year collaborative project, our goal is to obtain the first set of data to test the hypothesis that myelin insults or dysfunction may contribute to the development of AD. We will have two precise aims.

  1. We will compare control mice to demyelinated (CUP) mice to establish if challenging myelin post lesional plasticity can induce AD-like symptom.
  2. We will test if an episode of demyelination/ remyelination can precipitate or aggravate AD symptoms in the non-genetic model of AD (STZ).

Since the discovery of mutated genes in familial forms of AD, the leading concept underlying research in AD field has been the “amyloid cascade”, stipulating that intracerebral deposition of Aß is causative for AD pathology and that other brain lesions follow. However, none of the 300 compounds found to be effective in murine transgenic models successfully translated into clinical therapy. Lack of understanding of the multiple interacting processes involved in the pathophysiology of AD is probably the cause of this failure. Our project questions AD pathogenesis from an original and new angle, paying particular attention to the white matter since higher brain functions also depend on myelin integrity.

Virginie CALLOT (CRMBM) et Franck VIDAL (LNC)/ CEMEREM platform of the CRMBM In vivo characterization of the Supplementary Motor area projections using brain and spinAl cord ulTra high field magnetic resonance imaging (SMART)

The ultimate goals of this exploratory and interdisciplinary project are :

  1. to determine where the CST projections from the SMA end to,
  2. to evaluate the ratio of laminae IX SMA-projections (if any) relative to laminae IX M1-projections, so as to understand which kind of motor functions the SMA can or cannot subserve.

Specific methodological developments will thus be performed in order to adapt our techniques and fulfil the underlying scientific questions. For the upcoming year, if granted, the preliminary objectives and tasks have thus been identified as follow:

  1. Feasibility study to tract fibers from the SMA to the spinal cord,
  2. Determination of the most adequate MR protocol to identify transverse projection within the spinal cord (spatial resolution and SNR vs. potentially confounding partial volume effect),
  3. Development of a post-processing pipeline to correctly manage diffusion analysis and projection identification,
  4. Identification, at the individual level, of the SMA projection onto the spinal cord.

The innovation and novelty of this project are two-fold: first, from the methodological point of view, such a combined MRI exploration is a real technological challenge. Second, little is known about the CST-endpoint projections from the SMA onto the human spinal cord and about the kind of motor functions, the SMA subserves. Knowledge about the fiber tracts topology within the spinal cord in human is also very scarce. Despite great challenges, and even if we don’t answer the question completely, this exploratory project should thus bring new fundamental and technological knowledge.

Corinne BEURRIER (IBDM) et Eduardo GASCON GONZALO (INT) / NeuroVir platform of the INT In vivo quantification of miR-124 levels in striatal cholinergic interneurons: physiological roles and implications for Parkinson disease

Although the role of specific miRNAs in neurodegenerative disorders is increasingly recognized, experimental evidence supporting this notion is still scarce. This is, at least in part, due to our rudimentary knowledge of the very basic biology of miRNA homeostasis in the brain. A major effort is therefore required to determine the precise expression patterns of brain miRNAs as well as the regulatory processes involved in their generation, maturation and turnover under both physiological and pathological conditions. Investigating such crucial issues has been largely precluded by experimental constraints intrinsic to miRNA detection in the brain.

Indeed, we still ignore whether particular miRNAs are restricted to specific neuronal subpopulations and/or whether their expression levels are cell-specifically affected during the course of neurodegenerative diseases. In this proposal, we seek to generate novel tools enabling addressing some of these basic aspects. Focusing on a highly brain-enriched miRNA, miR-124, potentially linked to Parkinson’s disease (PD), we expect to highlight its role in a neuronal population relevant to PD, the striatal cholinergic interneurons (CINs). Our working hypothesis is that miR-124 contribute to shaping the functional heterogeneity of CINs in both physiological and pathological conditions. We will address this hypothesis through 2 specific objectives:

  1. to validate, in vivo, a novel reporter strategy to accurately quantify miR-124 levels in CINs and
  2. to test, for the first time, whether the levels of miR-124 are correlated to CIN properties in physiological condition and in a well-established mouse model of PD.

This project will provide a rationale for investigating the potential use of miRNAs in clinical applications (e.g. biomarkers) and in a therapeutic perspective.

EUSEBIO Alexandre (APHM/INT) & TSVETKOV Philipp (INP) / NCIS platform of INP Identifying a plasma signature of parkinsonian syndromes

The main objective of this study is to confirm the existence and characterize a plasma denaturation signature for parkinsonian patients by Differential Scanning Calorimetry (DSC). To achieve this objective, we will collect:

  •  Plasma of 120 PD patients at different stages of the disease as well as that of 80 patients with atypical parkinsonism
  • The clinical data that will be collected for all patients is demographic data, disease duration, appropriate motor rating scales, standard cognitive assessments, medication.

The novelty of the project consists of the non-conventional application of thermal shift instruments to obtain plasma denaturation profiles, which could be useful for diagnostics. Identifying biomarkers for the early diagnosis of parkinsonian syndromes is of critical importance as these conditions may have different outcomes, treatments and prognosis. Developing a low invasive method to help diagnosis of Parkinsonian Syndromes that does not rely on the prior identification of molecular biomarkers would be a real conceptual breakthrough and would open up the path for other neurodegenerative diseases that are challenging to diagnose and for which traditional invasive diagnosis methods (such as lumbar puncture) are needed or sometimes irrelevant because of the lack of specific biomarkers. If such a plasma signature of PD is confirmed the next step would be to investigate it as a potential early sign of the disease.

Project funded for the "Technical Boost" category

Détails de l'appel

For collaborative projects with a platform

Béatrice MARQUEZE-POUEY (UNIS) et Claude VILLARD (INP) / PINT platform of INP Mass spectrometry-based- proteomic characterization of ion channel signalling complexes, a key to comprehension of activity-dependent plasticity mechanisms involved in amblyopia

Amblyopia is a visual deficit resulting from abnormal visual experience during postnatal development. An eye fails to achieve normal visual acuity even with prescription glasses despite no damage of the retina, due to little or no transmission of visual images to the brain.
The project aims to identify the mechanisms at the origin of the loss of visual responsiveness.

D. Debanne’s group at the “Ion channels and synaptic neurobiology” unit (INSERM U1072) is characterizing activity- sensitive intrinsic excitability in rat dLGN neurons, primary recipients of retinal information in the visual thalamus. In contrast to synaptic plasticity, intrinsic plasticity is not mediated by changes in neurotransmitter receptors but results from modifications of voltage- or calcium-dependent ion channels. Using monocular deprivation protocol in rat, ion channels involved in such plasticity are depicted, using different protocols and specific blockers.
Joining recently D. Debanne’s group, my project is to apprehend the molecular mechanisms elicited in activity-dependent ion channel regulations. I intend to characterize differences in channel interacting networks after visual deprivation from ipsilateral (open eye) and contralateral (deprived eye) dLGN areas by target channel immunoprecipitation and tandem mass spectroscopy proteomic analyses at the Interactome Timone Plateform (PINT).

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NeuroMarseille and NeuroSchool fund actions aimed at training new generations of scientists, increasing the visibility and attractiveness of Aix-Marseille University and asserting its potential with socio-economic partners.

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Ingrid Meucci Chargée de communication
Author

Après la validation d’un master en neuroscience et un master communication, je me suis spécialisée dans la communication neuroscientifique au service de l'institut NeuroMarseille.

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