Romain William Sala

Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum primarily via the ventral and intralaminar thalamus, respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.

Voies de communications parallèles cerebello-cérébrales dans le cadre de l’apprentissage implicite: Le cervelet est principalement connu pour être un acteur de la régulation des actions motrices. Néanmoins, il possède un fort degré d’inter-connexion avec diverses structures corticales et sous-corticales, ce qui laisse supposer une implication du cervelet dans la régulation d’autres fonctions cérébrales, tels que les processus cognitifs. En particulier, les liens étroits entre le cervelet, les circuits moteurs et les circuits limbiques suggèrent qu’il pourrait jouer un rôle dans l’apprentissage moteur et l'apprentissage émotionnel. En utilisant des approches anatomiques, électrophysiologiques et comportementale, le but de cette thèse est de découvrir l’implication du cervelet dans la régulation de l’apprentissage d’extinction d’une mémoire de peur par le biais du contrôle d’oscillations thalamo-corticales liées à la peur. Par la suite, cette thèse fera l’étude des rôles des réseaux cerebello-corticaux et cerebello-striataux dans le contexte de l’acquisition et de la consolidation d’une tache motrice. Enfin, elle se focalisera sur l’étude de l’intégrité des voies cerebello-thalamiques dans un modèle murin de DYT25, une forme génétique de dystonie, ainsi que sur les conséquences de ces altérations dans le contexte de l’apprentissage moteur.

Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum primarily via the ventral and intralaminar thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.

Learning a motor skill requires exploring multiple possible solutions to find and retain an optimal strategy. The exploration and consolidation of the motor strategy are usually considered to be segregated respectively between task practice and rest periods. Here we show that two types of offline reactivations of neuronal representations of locomotor strategies in a brain-wide motor circuit are associated with exploration and retention. During short rests between trials, replays of these brainwide representations predict subsequent shifts in strategies indicating that distributed offline processes participate in strategy exploration. Shifts in strategy are consolidated, and their retention follows population reactivation in cerebellar sleep spindles and stabilization of cerebello-cerebral functional connectivity patterns, consistent with the role of spindles in brain plasticity. Overall, motor strategy optimization and consolidation are supported by two intertwined but distinct types of offline distributed reactivation events involving interregional interactions.

Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum primarily via the ventral and intralaminar thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABAARs in a manner dependent on microglial TNFα and P2RX7. We further show that microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunt memory consolidation in sleep-dependent learning tasks. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABAARs, sculpt sleep slow waves, and support memory consolidation.