Our research group applies a top-down approach with the aim of understanding the neural and cellular basis of sensory perception, learning, and memory in rodents. We chose the mouse because it learns fast and effectively in spontaneous conditions and under constraint, in laboratory conditions. We try to relate the various levels of analysis to each other by asking the same questions at the behavioral, neural, cellular, and molecular level.
We are also interested in the function and regulation of neural stem cells in the adult brain. Fundamental questions are addressed with a view to investigating the mechanisms of neuronal birth, migration, differentiation, and also how new neural cells are integrated into, and contribute to, the function of postnatal circuits involved in olfaction.
Our Major Goals
With the adult mouse olfactory bulb 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?
Together our recent descriptions of the properties of bulbar neuronal networks, and emerging principles concerning the function of local interneurons, indicate that the newborn cells play a much more complex role than that of simple gatekeepers inhibiting the olfactory bulb network.
Our experimental model
Our laboratory is focused on neuronal plasticity in the main olfactory bulb, the first central relay of the olfactory system where synaptic transmission between dendrites represents the major device for neuronal interaction. At this level, synaptic transmission includes both inhibitory and excitatory signals that coexist in a purposeful balance. This structure is involved not only in transmission of olfactory information but also in odor processing and memory. During learning, the olfactory bulb is subjected both to plastic synaptic changes and to neurogenesis related to mnesic storage.
For all these reasons and because of its relatively simple anatomical organization and easy accessibility, the olfactory bulb is our favored model system to investigate odor information coding as well as to elucidate the cellular basis of odor memory. Using a pluridisciplinary approach combining molecular, cellular and behavioral levels, our goal is to determine in adult brain, how acquisition and retention of odor information can be accomplished within a neuronal network characterized by a high level of neuronal replacement.
Modeling the functional effects of adult neurogenesis
The phenomenon of neurogenesis in adult animals, which has therapeutic potential in treating neurodegenerative diseases, leads to several questions: What controls the pattern of connections formed by new cells? How is the stability of memory and of information processing maintained when cells and synapses are constantly being lost and new ones produced?
To answer these questions we intend to investigate neurogenesis in the mammalian olfactory bulb, using a combination of computational modeling and electrophysiology. We propose to develop a detailed, biologically-realistic computational model of the olfactory bulb neuronal network, incorporating recent findings about neuronal membrane and synaptic properties, and obtaining new experimental data as necessary to constrain the model. Using this model we will investigate odor information processing, learning and memory in the olfactory bulb, and how these are affected by neurogenesis. Use of a computational model will allow us to quickly perform simulation experiments to investigate alternative hypotheses. The most promising simulation results will be tested by experimental methods: patch-clamp electrophysiology in mouse olfactory bulb slices, and possibly behavioral methods.
Members of the Lledo Lab (January 2011)
- Mejia-Gervacio S, Murray K, Lledo PM. NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain. (2011) Neural Dev. Feb 1;6(1):4.
- Lazarini F, Lledo PM. Is adult neurogenesis essential for olfaction? (2010) Trends Neurosci. Jan;34(1):20-30.
- Bardy C, Alonso M, Bouthour W, Lledo PM. How, when, and where new inhibitory neurons release neurotransmitters in the adult olfactory bulb. (2010) J Neurosci. Dec 15;30(50):17023-34.
- Feierstein CE, Lazarini F, Wagner S, Gabellec MM, de Chaumont F, Olivo-Marin JC, Boussin FD, Lledo PM, Gheusi G. Disruption of Adult Neurogenesis in the Olfactory Bulb Affects Social Interaction but not Maternal Behavior. (2010) Front Behav Neurosci. Dec 1;4:176.
- Panzanelli P, Bardy C, Nissant A, Pallotto M, Sassoè-Pognetto M, Lledo PM, Fritschy JM. Early synapse formation in developing interneurons of the adult olfactory bulb. (2009) J Neurosci. Dec 2;29(48):15039-52.
- Mouret A, Lepousez G, Gras J, Gabellec MM, Lledo PM. Turnover of newborn olfactory bulb neurons optimizes olfaction. (2009) J Neurosci. 29(39):12302-14.
- Lazarini F, Mouthon MA, Gheusi G, de Chaumont F, Olivo-Marin JC, Lamarque S, Abrous DN, Boussin FD, Lledo PM. Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice. (2009) PLoS One. 4(9):e7017.
- Nissant A, Bardy C, Murray K, Lledo PM. Adult neurogenesis promotes synaptic plasticity in the adult olfactory bulb. (2009) Nature Neurosci. 12, 728-730.
- Belvindrah R, Lazarini F, Lledo PM. Postnatal neurogenesis: from neuroblast migration to neuronal integration. (2009) Rev Neurosci.;20(5-6):331-46. Review.
- Gheusi G, Ortega-Perez I, Murray K, Lledo PM. A niche for adult neurogenesis in social behavior. (2009) Behav Brain Res. Jun 25;200(2):315-22. Review.
- Grubb M, Nissant A, Murray K, Lledo PM. Functional maturation of the first synapse in olfaction: Development and adult neurogenesis. (2008) J. Neurosci. 28, 2919-2932.
- Lagier S, Panzanelli P, Sassoè-Pognetto M, Fritschy JM, Lledo PM. GABAergic inhibition at dendro-dendritic synapses tunes gamma oscillations. (2007) Proc. Natl. Acad. Sci. (USA) 104, 7259-64.
- Lledo PM, Grubb M, Alonso M. Adult neurogenesis and functional plasticity in neuronal circuits. (2006) Nat. Neurosci. Rev. 7, 179-193.
- Hack M, Saghatelyan A, de Chevigny A, Lledo PM, Götz M. Neuronal fate determinants of adult olfactory bulb neurogenesis. (2005) Nat. Neurosci. 8, 865-871.
- Saghatelyan A, Roux P, Migliore M, Rochefort C, Charneau P, Shepherd G, Lledo PM. Activity-dependent adjustments of the inhibitory network in the adult olfactory bulb following early postnatal deprivation. (2005) Neuron 46, 103-116.
- Saghatelyan A, DeChevigny A, Schachner M, Lledo PM. Tenascin-R fosters radial migration of neuroblasts in the adult forebrain. (2004) Nat. Neurosci. 7, 347-356.
- Carleton A, Petreanu L, Lansford R, Alvarez-Buylla A, Lledo PM. Becoming a new neuron in the adult olfactory bulb. (2003) Nat. Neurosci. 6, 507-518.
- Gheusi G, Cremer H, McLean H, Vincent JD, Lledo PM. Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. (2000) Proc. Natl. Acad. Sci. 97, 1823-1828.
Please see our Institut Pasteur lab website for current information about the lab. And please contact our lab if interested in an undergraduate summer internship program. Post-doctoral positions are available to investigate the plasticity of olfactory bulb circuits.