Développement, réparation et vieillissement cérébral

DRVC étudie les mécanismes impliquées dans le développement, la réparation, et le vieillissement du cerveau, avec comme modèles l'hippocampe et le cervelet, in vivo et in vitro.

Nous cherchons à élucider les bases biologiques de ces mécanismes et d'explorer leurs applications cliniques.

Nous étudions des gènes et voies de signalisation sous-tendant la stabilisation sélective des synapses pendant le développement olivocérébelleux, et la réparation post lésion de cette voie. Nous étudions aussi la formation, le maintien, et l'éventuelle perturbation de la plasticité synaptique homéostatique, nécessaire pour la balance stabilité/flexibilité fonctionnelle des réseaux neuronaux. Un troisième projet concerne le rôle des protéines associées avec la maladie d'Alzheimer, dans le dysfonctionnement synaptique précoce observé.

Nos connaissances sur ces thématiques nous permettent de développer des approches translationnelles. Nos études sur les traitements non-invasifs, e.g. l'activation psychomotrice ou la stimulation cérébrale par rTMS, nous permettent d’optimiser la protection et réparation des réseaux synaptiques dans le cerveau âgé ou endommagé. De plus, nous utilisons un nouveau test très complet du dysfonctionnement cognitif, pour obtenir un diagnostic plus précoce chez les patients et donc des interventions thérapeutiques précoces.

Les approches multidisciplinaires de l'équipe-- des molécules aux comportements, de la paillasse à la clinique-- élargissent les domaines de recherche de l'UMR vers les possibilités de réparation des dysfonctionnements synaptiques croissants avec l’âge.

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BDRA studies mechanisms underlying the development, repair and ageing of the brain, using cerebellar and hippocampal models to address the biological bases of these phenomena and to explore clinical applications.

Our interest in synaptic maturation and function includes the genes and signalling paths permitting selective synapse stabilisation during olivocerebellar development and repair, mechanisms underlying the establishment and loss of homeostatic plasticity as well as causes of early hippocampal synaptic dysfunction in Alzheimer’s disease.

We are applying knowledge gained from these fundamental studies to develop translational approaches. First, we examine the potential for non-invasive psychomotor and magnetic brain stimulation to optimize maintenance, protection and repair of synaptic circuits in the damaged or ageing brain. Second, we are evaluating a new complete test of cognitive function for aged patients in order to provide earlier diagnosis of minimal cognitive decline and thus early therapeutic intervention.

The team’s multidisciplinary approach, from molecules to behaviour and bench to the clinic, expands the Unit’s research fields into the evolution of accumulating synaptic dysfunction with time and the potential for its repair.

Résultats importants

Key results within our domain of neuronal and synaptic function throughout life, include:

  • 1) Within the olivocerebellar projection, developmental synaptogenesis and selective stabilization permanently alters each synaptic partner to block their capacity to recapitulate development.
  • 2) BDNF-induced olivocerebellar repair in the maturing animal confers recovery of motor and navigation tasks; this repair is increased by psychomotor activity.
  • 3) Accumulating cognitive dysfunction with age, in the form of spatial learning deficit, directly correlates with deficits in maintaining hippocampal LTP.
  • 4) Over-expression or mutation of presenilin-1 (PS1) perturbs the establishment and maintenance of LTP in young adult mice; this impairment increases during aging, in association with dendritic spine abnormalities and learning impairment.
  • 5) ROR is a key transcription factor in the process of neuroageing. Haploinsufficiency of ROR is associated with premature PC death in the cerebellum due to early reduction of circulating sex steroids.
  • 6) In addition to neurons, ROR is expressed in astrocytes, through which it finely controls cytokine interleukin-6 expression and promotes neuronal survival following hypoxia.

Projets

  • 1)The team will build on its achievements in the field of neural circuit repair to further characterise important mechanisms.In addition to evaluating the role of several candidate genes in this process, we will undertake transcriptome analysis of reinnervating and target tissue to find novel molecules and make in silico searches to identify new targets regulated by these candidate genes.
  • 2)We will also examine the impact of non-invasive brain stimulation paradigms on synaptic homeostasis and dendritic integration of afferent data in order to understand effects on whole network function.
  • 3)To deepen the links between fundamental biology and clinical age-related neurological problems, we add to our mouse studies on synaptic dysfunction in Alzheimer’s disease the roles of 2 potentially treatable components: (a) the roles of different glia in neuroinflammation underlying Alzheimer’s pathology; and (b) the role of sleep dysfunction especially SOAS (Sleep Obstructive Apneas Syndrome) in disease progression in mice and in Human through the patients cohorts of DHU FAST.

Collaborations

  • Borsello, Tiziana, International, Institute M. Negri, Milano, Italy
  • Harvey, Alan, International; School of anatomy and Human Biology, University of Western Australia
  • Mattick, John S, International, University of Queensland, Australia
  • Mattson, Mark P, International, National Institute on Aging, Baltimore MD, USA
  • Rodger, Jenny, International, Experimental and Regenerative Neurosciences, Uni Western Australia.
  • Sugihara, Izumi, International, University of Tokyo, Japan
  • Vogel, Michael,International, University of Maryland, Baltimore, USA.
  • Bailly, Yannick, National ; CNRS & Université de Strasbourg
  • Gressens, Pierre, Local, Inserm Hopital R. Debré Paris
  • Tedgui, Alain, Local, INSERM & HEGP hospital Paris
  • Dusart, Isabelle, Local, UMR8246
  • Di Gregorio, David, Local, Institut Pasteur, Paris