Introduction
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?
Pierre-Marie Lledo’s goal is to determine how acquisition and retention of odor information can be accomplished within a neuronal network characterized by a high level of neuronal replacement in the adult brain. He is aiming with his team at understanding the neural and cellular basis of sensory perception, learning, and memory.
They 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.
Projects
Pierre-Marie Lledo chose the mouse as a model system because it learns fast and effectively in spontaneous conditions and under constraint, in laboratory conditions. More specifically, the main olfactory bulb is a brain structure which is 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 a powerful model system to investigate odor information coding as well as to elucidate the cellular basis of odor memory.
Pierre-Marie Lledo and his team thus use the mouse olfactory bulb to address a series of fundamental questions concerning the role(s) that neurogenesis plays in the normal functioning of neuronal circuits:
1/ Why does neurogenesis persist in some part of the adult brain but not in other ones?
2/ Is it a recapitulation of embryogenesis or rather a unique feature of the adult forebrain?
3/ Why is it restricted, apparently, to only two specific regions in normal conditions?
4/ How do these regions balance the need for plasticity with the need to maintain already-functional information processing networks?
5/ 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?
6/ 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?
In addition to the previous questions that they ask at the behavioral, neural, cellular, and molecular level, Pierre-Marie Lledo and his laboratory intend to investigate neurogenesis in the mammalian olfactory bulb, using a combination of computational modeling and electrophysiology. They 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 they 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 them 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.
Together, their 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.
