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Cellular Integration of Neuromodulatory Processes |
Group leader Pierre VINCENT |
| Mesencephalic dopaminergic neurons project towards various brain regions, including the striatum and the prefrontal cortex. Dopamine is involved in the modulation of a number of functions in the central nervous system (reward, attention, motor programs), and dysfunctions in dopaminergic signaling are associated with severe neuropsychiatric diseases (Parkinson's disease, addiction, schizophrenia…) Using a novel biosensor imaging approach, our team has revealed the importance of neuronal architecture and enzymatic equipment in the integration of the dopamine signal via the cAMP/PKA signaling cascade. We revealed strong differences between the cortex and the striatum and we suggest that striatal neuron have a specific ability to respond to very brief dopaminergic stimulations such as those involved in learning and reward. This project continues by the analysis of cAMP/PKA signal propagation through the dendritic tree using two-photon imaging and uncaging of photoactivatable molecules. We will also analyze the negative controls exerted by phosphodiesterases and phosphatases on signal integration and spatial propagation within the cell. We will particularly focus on type 10 phosphodiesterase since blockers of this enzyme revealed a totally unexpected antipsychotic effects which is now tested in clinical trial. We will study the connection between PDE10 and D2 receptors since the blockade of D2 receptors is currently the only common point of all schizophrenia treatments. In parallel, we try to put these cellular data back into the context of the living animal, and we obtained for the first time images of PKA activation in deep brain regions. This project will continue with new biosensors and imaging in the freely moving animal. |  |
B2A UMR 8256 @Février 2014