Integrative Neurobiology of Cholinergic Systems - CNRS URA2182  

  MEMBERSDr AVALE Elena / CUI Yihui / Dr CRESSANT Arnaud / EDDINE Raphael / Dr FAURE Philippe / Dr GRANON Sylvie / MARTI Fabio / MAUBOURGUET Nicolas / MEUNIER Yolande / PONS Stéphanie / SASO Anja / SERREAU Pierre / SOUDANT Martine / SURESH Nina / TOLU Stefania

  Annual Report

Understanding mechanisms underlying normal complex behaviors and the abnormalities that accompany most neuropathologies is a primary challenge in fundamental and biomedical research. However, optimal use of the large body of genetic, molecular, physiological, behavioral and imaging techniques that provide new insights into cellular organization at the microscopic level, and functional circuits at the macroscopic level, is hampered by the usual dissociation of these techniques. Today, the crucial challenge lies in the integration of these approaches in order to target a unified scientific question at multiple levels.

The subject of our entity is the functional analysis of brain circuits with a multi-level approach. Specifically, we aim to understand how nicotine acts on the brain, affects cognition, causes addiction, but also neuroprotetion in the case of Alzheimer's and Parkinson's Disease. Our strength lies in the association of different kinds of complementary expertise allowing to address these problems from an integrative point of view. Understanding such phenomena requires the development of new tools, like fibred fluorescence microscopy, see illustration. Nicotine addiction presents a serious social and public health problem, hence, the identification of the molecular mechanisms and circuits involved in nicotine reinforcement and cognition is urgent. Many aspects of the role of endogenous acetylcholine (ACh) can be targeted by administering nicotine to genetically modified animals (GMAs) and to study their response.

Our approach centers on the detailed analysis of genetically modified mice (GMMs) addressing the roles of nAChR subunits. The laboratory headed by Jean-Pierre Changeux has been the first to inactivate nAChR subunits in the mouse, and one among the very first worldwide to apply gene targeting to the brain. Members of his laboratory including ourselves have then been able to study the consequences of gene knock-outs at a variety of levels, from the molecular to behavior and cognitive. As many subunits are expressed ubiquitously in the brain, the initial analysis of KO mice has identified those subunits that are necessary for a specific function, for example the executive functions, or nicotine self-administration. However, the brain area(s) that are sufficient to mediate a given phenotype remain to be resolved and delineated. Our working hypothesis is that the nAChRs play a pivotal role in different brain areas. Within this hypothesis we currently focus on the role of endogenous ACh and nicotine in the modulation of the dopaminergic (DA) and GABAergic systems.

Our laboratory has developed over the last 6 years a novel fibre-optic in vivo imaging approach, with a Paris-based start-up company. It allows to access deep brain nuclei, like the dopaminergic system implicated in nicotine addiction and Parkinson’s disease, and to obtain real-time live images of the activity and morphology of the corresponding neurons.

Keywords: Acetylcholine, Alzheimer's disease, neurodegeneration, in vivo imaging, in vivo electrophysiology, Parkinson’s disease, nicotine addiction



• ME Avale, P Faure, S Pons, P Robledo, T Deltheil, DJ David, AM Gardier, R Maldonado, S Granon, J-P Changeux & U Maskos (2008) Interplay of β2* nicotinic receptors and dopamine pathways in the control of spontaneous locomotion.Proc. Natl. Acad. Sci. U S A 105, 15991-15996.

• M Besson*, S Granon*, M Mameli-Engvall, I Cloëz-Tayarani, N Maubourguet, A Cormier, P Cazala, V David, J-P Changeux & P Faure, (2007) Long-term effects of chronic nicotine exposure on brain nicotinic receptors, Proc. Natl. Acad. Sci. U S A 104, 8155-8160 (* co-first authors)

• P Vincent*, U Maskos*, I Charvet, L Bourgeais, L Stoppini, R Lambert, J-P Changeux, P Meda & D Tritsch (2006) Live imaging of neural structure and function by fibered confocal fluorescence microscopy. EMBO Reports 7, 1154-1161. (*equal contribution)

• M Mameli-Engvall, A Evrard, S Pons, U Maskos, T Svensson, J-P Changeux & P Faure (2006) Hierarchical Control of Dopamine Neuron-Firing Patterns by Nicotinic Receptors. Neuron 50, 911-921.

• U Maskos, BE Molles, S Pons, M Besson, BP Guiard, J-P Guilloux, A Evrard, P Cazala, A Cormier, M Mameli-Engvall, N Dufour, I Cloëz-Tayarani, A-P Bemelmans, J Mallet, AM Gardier, V David, P Faure, S Granon & J-P Changeux (2005) Recovery of nicotine reinforcement and cognitive functions by targeted expression of nicotinic receptors. Nature 436, 99-106.

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