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Rui M. Costa

Generating and shaping novel action repertoires

Actions are organized as sequences of particular movements. The organization of learned actions as sequences of movements typically encompasses precise timing and/or ordering of movements within a sequence to increase precision or accuracy, and appropriate initiation and termination of the sequence. We used a self-paced operant task in which mice were trained to perform a particular sequence of lever presses to obtain an outcome, and recorded the neural activity in nigrostiatal circuits during action sequence learning. We uncovered neural activity specifically signaling the initiation and termination of sequences of actions in putative striatal medium spiny neurons, and nigral dopaminergic and GABAergic neurons. This start/stop selective activity emerged during sequence learning, was specific for particular actions, and did not seem to reflect interval timing or differences in expected action value at the beginning and end of a sequence. We verified that a striatal-specific genetic deletion of NMDA receptors selectively impairs the development of this start/stop activity and sequence learning. Next, we developed a task where mice need to perform a specific action sequence very rapidly, close to the timescale of human speech and birdsong (a limited-time fixed-ratio differential reinforcement schedule). We recorded the activity in striatum and downstream target regions of direct pathway neurons (Substantia nigra pars reticulata -SNr) and indirect pathway neurons (Globus pallidus external GPe). We found that besides start/stop activity, activity related to the execution of the whole sequence developed during learning, and that this activity developed differentially in SNr and GPe. we used optogenetic tools to indentify and manipulate the activity of direct and indirect pathway striatal neurons during different moments of ultrafast sequence execution. These data have important implications for understanding the learning and execution of action sequences, and the impairments observed in basal ganglia disorders like Parkinson’s and Huntington’s disease.