Valentin Plateau

Electrophysiological characterization and functional importance of midbrain dopaminergic neurons projecting to the primary motor cortex

février 2023 Directeur(s) de thèse : Morgane Le Bon-Jégo Résumé de thèse

The primary motor cortex (M1) plays a key role in motor learning processes. Learning sophisticated motor sequences, such as skill-reaching behavior, relies on dopamine (DA)-dependent structural and synaptic plasticity in M1. Although the architecture of the dopaminergic system within M1 has been well characterized anatomically, the electrophysiological characterization and functional importance of these midbrain dopaminergic neurons projecting to M1 remains poorly understood. Thus, the objectives of this thesis were, on the one hand, to identify and characterize the intrinsic properties of the dopaminergic neurons of the midbrain projecting to M1, and then to study their activity during motor learning; and on the other hand, to study the functional importance of this dopaminergic innervation at the level of M1 neurons. Firstly, retrograde tracing experiments demonstrated in mice a rostro-ventrolateral localization of midbrain dopaminergic neurons projecting to M1. Ex vivo electrophysiological recordings of the activity of these neurons showed that they have an electrophysiological signature similar to that of dopaminergic neurons of the nigrostriatal pathway. It has then been demonstrated that their excitability increases during the learning of a new fine motor task (single pellet reaching task), and that this increase in excitability was correlated with the greatest increase in learning in mice. Moreover, this increase in excitability was no longer observable when the motor task was learned. DA release in M1 was then demonstrated by ex vivo imaging using GRABDA1m, a genetically encoded dopaminergic sensor. Then, optogenetic activation of dopaminergic fibers from midbrain neurons revealed glutamate and/or GABA corelease in rare experiments in some M1 pyramidal cells. To measure the functional importance of these dopaminergic afferents on pyramidal neurons, a pharmacological approach was used. In order to study the role of the D1 receptor in M1, experiments were performed in young and adult mice to test if age-dependent differences are observed as it has been shown in the prefrontal cortex. First, a mapping of D1 receptors in M1 was performed, indicating no real age-dependent difference in D1 receptor localization. Ex vivo electrophysiological recordings then showed that D1 receptor activation induces an increase in the excitability of M1 pyramidal neurons in young and adult mice, whereas D1 receptor blockade induces a decrease in the excitability of these neurons in young mice, but an increase in adult mice. Thus, the modulation of M1 pyramidal neurons by D1 receptors is age dependent. This project has led to a better understanding and knowledge of the origins and implications at the cellular and behavioral levels of dopamine in M1.