Spatio-temporal contribution of dopamine in the execution of goal-directed movement in ratsdécembre 2022 Directeur(s) de thèse : Nicolas Mallet Résumé de thèse
The ability to produce movements adapted to our environment is crucial in our daily lives. Years of research to understand this function, which is crucial to our survival, have placed dopamine (DA) as key in motor selection and execution processes. Indeed, beyond its role in the reward circuit, this neuromodulator is known to be central in motor control. This capital function is well-illustrated in Parkinson’s disease (PD), where the death of dopaminergic neurons induces severe motor symptoms, such as difficulty in initiating movements (akinesia), and their slowness (bradykinesia). Importantly, the neurophysiological mechanisms underlying motor execution are not fully elucidated. This PhD aimed at determining the spatio-temporal contribution of DA in these processes. In the first part of my PhD project, we developed a “reach-and-grasp” motor task. Then, we characterized its neurophysiology. Our results show that optimal movements relied on the integrity of the motor cortex and basal ganglia outputs. In addition, we highlighted the necessity of the DLS for goal-directed movements and questioned the standard description of the DMS function in goal-directed actions. In the second part of my PhD, we studied the effect of a lack of DA on dexterous movement execution. We mimicked neuronal death observed in PD via the injection of 6-OHDA in the STR. This aimed at characterizing the spatio-temporal dynamic of motor symptoms development. These results demonstrate the necessity of DA in short time scale (in range of minutes) and question the necessity of fast-scale DA dynamics to control online motor execution. In contrast, DA transmission at a slower time scale seems to be important for the reinforcement and the maintenance of the striatal neuronal activity that is necessary for optimal motor execution. Additionally, our results illustrate the resilience capacity of the DLS to the lack of DA. Understanding the compensatory mechanisms will require further investigations, but its characterization could bring innovative ideas to develop new therapeutic strategies for PD.