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 neuroprotection 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 these microcircuits 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 and rats addressing the roles of nAChR subunits. 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. We currently focus on the role of endogenous ACh and nicotine in the modulation of the dopaminergic (DA) and GABAergic systems, and the cortex.

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

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