|Perception and Memory - CNRS URA 2182|
|HEAD||Dr. LLEDO Pierre-Marie / email@example.com|
|MEMBERS||Alonso Mariana Post-doc / Gabellec Marie Madeleine Engineer / Gheusi Gilles Assistant Prof./ Grubb Matthew Post-doc / Guesdon Sylviane Secretary of Direction / Katagiri Hiroyuki Post-doc
Lledo Pierre-Marie DR1 CNRS / Mejia Sheyla Post-doc / Murray Kerren Technician / Mouret Aurélie PhD student / Nissant Antoine Post-doc / Ortega Inmaculada Post-doc / Wagner Sébastien Master degree
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.
Keywords: Adult-neurogenesis — Olfactory bulb — GABA interneurons — Neural stem cells
Activity Reports 2007 - Institut Pasteur
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