Neurophysiology and behavior

Dopamine (DA) projections from the midbrain (including ventral tegmental area and substantia nigra) to striatum and frontal cortex play a major role in behavioral actions controlled by reward and in the formation of habits. The dopaminergic system is also involved in drug addiction.

Using a combination of behavioral analysis, in vivo and in vitro electrophysiological recordings, genetic tools and optogenetics, we analyze

  • the role of the nicotinic modulation of DA cells activity and
  • the modifications of DA network dynamics in the different steps leading to nicotine addiction including genetic and environmental factors, and the consequences of these modifications on decision making.
  • The team created a tool called MouseTube, an online database stimulating the exchange and sharing of recordings of mouse ultrasonic vocalisations between all members of the community. MouseTube allows to sort vocalisation recordings by mouse strain, individuals or by a given context within a protocol to facilitate comparisons. This open data application is designed to boost knowledge on mouse ultrasonic communication. Follow the link (https://mousetube.pasteur.fr) and check the short video clip to get an overview of the organisation and challenges of mouseTube

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Nicotine addiction represents a serious social and public health problem. In the lab, we address a series of questions regarding the roles of nicotinic receptors (nAChRs) in the mechanisms underlying choice modification under drug exposure. Numerous theories have been developed to model addiction, but an important framework states that addictive drugs change the characteristics of dopaminergic (DA) system activity in reward signaling and in decision-making.

Using behavioral analysis, in- and ex- vivo electrophysiological recordings, genetic tools to modify nAChRs expression, optogenetics and optochemical genetics to specifically control neuronal subnetworks, we analyze the modifications of DA network dynamics in the different steps leading to nicotine addiction.

Highlights

We recently showed that the nAChR distribution between DA and GABA neurons of the VTA is critical to generate bursts of action potential (Tolu et al. Mol. Psy. 2013). By re-expressing high-affinity nAChRs in the VTA, exclusively on either DAergic or g-aminobutyric acid-releasing (GABAergic) neurons, or both, we showed that, contrarily to widely accepted models, activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity.

Our results demonstrate that both positive and negative motivational values are transmitted through DA neurons, but that concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons.

More recently, we analysed the role of a single-nucleotide polymorphism frequent in various human populations, the non-synonymous α5 variant rs16969968, on nicotine intake (Morel et al., Mol. Psy. 2014). This polymorphism exhibits a partial loss of function of the nAChR in vivo, which leads to increased nicotine consumption in a self-administration paradigm. We thus defined a critical link between a human marker of predisposition, its expression in DA neurons and nicotine intake.

Future directions

We will pursue our analysis of the networks underlying nicotine effect, by focusing on four main aspects:

  • First, we are aiming at dissecting nicotinic control over DA cells. For that purpose we are developing novel photochemical strategies for optically activating/inhibiting specific nAChR subtypes in targeted cells and within living animals (Kramer et al., Nat. Neurosc. 2013).
  • The second aspect refers to the existence of functional subnetworks within the ventral tegmental area (VTA) DA cell population and the effect of chronic nicotine exposure on these subnetworks.
  • The third one is related to the genetic and environmental factors increasing the risk of nicotine consumption. Stress and alcohol are two factors that will be particularly investigated. Genetic factor analysis will focus on the analysis of the role of specific nAChR subunits.
  • The last aspect concerns the role of DA subnetworks in reinforcement learning and exploration, the drug–induced alterations of their dynamics and the consequences on decision-making.

Collaborations

  • Integrative Neurobiology of Cholinergic Systems (Dr Uwe Maskos) - Institut Pasteur, CNRS UMR 3571
  • Génétique Humaine et Fonctions Cognitives (Dr Elodie Ey and Pr Thomas Bourgeron) - Institut Pasteur, CNRS UMR 3571
  • Interactions between emotions and memory systems: from normal to pathological ageing (Dr Vincent David) - Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Universités de Bordeaux 1 et 2, CNRS UMR 5287
  • Trauner lab (Pr Dirk Trauner) - LMU Munich
  • Kramer lab (Pr Richard Kramer) - UC Berkeley
  • Antoine Taly (IBPC Paris)

MouseTube

Introduction of the tool

MouseTube