Perception and Memory - CNRS URA 2182  


  HEADLLEDO Pierre-Marie / pierre-marie.lledo@pasteur.fr
  MEMBERSDr. Alonso Mariana / Dr. Bardy Cedric / Dr. Belvindra Richard / Dr. Fireistein Claudia Gabellec Marie-Madeleine / Dr. Gheusi Gilles / Gras Julien / Dr. Grubb Matthew / Guesdon Sylviane / Dr. Katagiri Hiroyuki / Dr. Lazarini Françoise / Dr. Lledo Pierre-Marie / Dr. Mejia Sheyla / Murray Kerren / Mouret Aurélie / Dr. Nissant Antoine / Dr. Ortega Inmaculada / Wagner Sébastien / Dr. Harroch Sheila / Barbara Maison / Eva Pauper


  Annual Report

Adult Neurogenesis in the Mammalian Forebrain

In the olfactory bulb (OB), neurons are renewed during the whole life. The genetic and epigenetic determination of this permanent neuronal production, and its regulation, are still unclear. We are exploring the molecular mechanisms of this neurogenesis to define the key factors involved in cell production and characterize the maturation steps by which a stem cell becomes a functional neuron. Complementary models and experimental procedures integrate several approaches, including molecular and cellular biology, functional imaging, electrophysiology and behavioral analysis. All these methods aim at investigating the functional impact of adding new neurons to pre-existing circuits.

Stability versus flexibility

With the adult mouse OB as a model, we are addressing a series of fundamental questions concerning the role(s) that neurogenesis plays in the normal functioning of neuronal circuits: Why does neurogenesis persist in some part of the adult brain but not in other ones? Is it a recapitulation of embryogenesis or rather a unique feature of the adult forebrain? Why is it restricted, apparently, to only two specific regions in normal conditions? How do these regions balance the need for plasticity with the need to maintain already–functional information processing networks? Is neurogenesis in the adult brain a constant, restorative process, or is it flexible, producing different numbers of neurons to certain regions according to an animal’s environmental experience? And are new neurons in the adult brain born to perform a particular task not possible for mature neurons, or are they generated as flexible units to undertake whichever role their target structure is in need of most?

We have previously demonstrated that adult-born neurons integrate functionally into the adult bulbar circuit according to a unique maturation stage: neuroblasts first express GABAA receptors before receiving glutamatergic inputs, at the time they enter the OB. Only much later new cells fire action potential. The goal of our next studies consists in exploring the relation between the sequence of functional appearance of neurotransmitter receptors and normal targeting and survival of newborn neurons. As a first step, we have developed a forebrain organotypic ex vivo approach to follow the adult-generated neurons using time-lapse video imaging. Dynamic parameters of their morphological maturation (cell migration, dendritogenesis, synaptogenesis) will be studied using a two-photon laser scanning microscopy. This will allow a high-resolution visualization of dendritic spines, their motility, and the monitoring of intracellular Ca2+ transients.

This work should provide new insights about the steps by which an adult-generated neuron can silently insert into a functional network, without disturbing its functioning. Elucidating the chain of events involved in the proliferation, the tangential or radial migration of neuroblasts, as well as their maturation will help us to understand the fundamental processes employed by the adult brain. In addition, we believe that additional neurogenic niche might exist in the forebrain. We are characterizing a novel niche in which newborn neurons are produced from astrocyte. Additional experiments are required to precise if this area produces a precise subset of newborn neurons. Finally, our current researches may provide an important advance in the cell replacement technologies by revealing new neurogenic potential of the adult forebrain. Discovery of intrinsic and extrinsic factors controlling this new zone may extend the possibilities of using endogenous stem cell capabilities for brain repair.

Group Signaling in neural physiopathology - Sheila HARROCH

Protein Tyrosine Phosphatases in myelination and demyelinating diseases

In the laboratory of signaling of physiopathology neural directed by Dr. Sheila Harroch, we focus our research in molecules involved in the development of myelinating cells and in repair of non-inflammatory demyelinating disease. We aim to develop animal model of neurodegenerative disease to research potential therapies.

As a part of this, we dissect the role of receptor protein tyrosine phosphataseζ (RPTPζ-zeta) in the developing nervous system in physiological and pathological contexts. We have made use of cell culture systems, the yeast two hybrid system, and knockout animals to dissect the role of ζ and RPTPγ(Lamprianou et al, 2006) in neural development. We have demonstrated that ζ plays a critical role in recovery from demyelinating illness, highlighting its potentially important role in multiple sclerosis (Harroch et al, 2002). We also provided evidence that the oligodendrocytes in the ζ-deficient animals were more susceptible to apoptosis in the demyelinating/remyelinating process.We have identified a novel player in remyelination, ζ, which constitutes a non-immune pathway that drives oligodendrocyte proliferation and remyelination. We expect that understanding the molecular mechanisms behind these physiological changes will uncover novel signaling pathways that can be targeted for the therapy of demyelinating diseases.

Christine Stadelmann, Stefan Nessler, Sheila Harroch. Animal models for multiple sclerosis research. In press 2009

Keywords: Adult-neurogenesis — Olfactory bulb — GABA interneurons — Neural stem cells

Percmem.jpg

Figure 1: Learning and survival of new neurons: when time matters! A) One-week olfactory training with two odorants (linalool, Damascenone, Amyl Acetate) has effect on cell survival-death decision. B ) Regardless of the odorants used, olfactory learning increases the survival of 30-day-old neuronsand eliminates the 38-day-old neurons. C-D) These changes in the number of new neurons are observed along the entire rostrocaudal axis of the olfactory bulb (OB). Thus, in adult mice, newborn neurons throughout the OB are sensitive to learning, even if sensory inputs arrive at precise location. The spatial and temporal coincidence of sensory entry ( i.e., the ascending pathway) and centrifugal afferents ( i.e., the descending pathway) to the OB may be the conditions needed for triggering modulation of the death and life decision.



  Publications

  1. Mouret A, Gheusi G, Gabellec MM, de Chaumont F, Olivo-Marin JC & Lledo P-M (2008). Learning and survival of newly generated neurons: when time matters. J. Neurosci. 28, 11511-11516.

  2. Alonso M, Ortega-Perez I, Grubb M, Bourgeois JP, Charneau P & Lledo P-M (2008). A novel neurogenic niche for the adult olfactory bulb. J. Neurosci. 28, 11089-11102.

  3. Lagier S, Panzanelli P, Russo R, Sassoè-Pognetto M, Fritschy J-M & Lledo P-M (2007). GABAergic inhibition at dendro-dendritic synapses tunes gamma oscillations in the olfactory bulb.PNAS 104, 7259-7264.

  4. Hack M, Saghatelyan A, de Chevigny A, Lledo P-M & Götz M (2005). Neuronal fate determinants of adult olfactory bulb neurogenesis.Nat. Neurosci. 7, 865-872.

  5. Saghatelyan A, Roux P, Migliore M, Rochefort C, Charneau P, Shepherd G & Lledo P-M (2005). Activity-dependent adjustments of the inhibitory network in the adult olfactory bulb following early postnatal deprivation. Neuron 46, 103-116.



  Web Site

More informations on our web site




Activity Reports 2009 - Institut Pasteur
If you have problems with this Web page, please write to rescom@pasteur.fr