Understanding mechanisms underlying normal complex behaviours 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, electrophysiological, behavioural and imaging techniques that provide new insights into cellular organisation 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, and causes addiction. Our strength lies in the association of different kinds of complementary expertise allowing to address this problem from an integrative point of view. Addiction to nicotine is typically an ‘integrated’ pathology including short-term receptor modification, and long term modification of circuit equilibrium and behaviours. 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 centres on the detailed analysis of genetically modified mice (GMMs) and transgenic rats, 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 behaviour 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 at the interface between the prefrontal cortex (PFC), the ventral tegmental area (VTA), and the amygdala. Therefore, these receptors are major players controlling decision making and motivational processes. Within this hypothesis we focus on the role of endogeneous ACh and nicotine in the modulation of the dopaminergic (DA), glutamatergic and GABAergic system.