Developmental changes in mouse motor skill learning and cortical circuitry

Learning motor skills requires plasticity in the primary motor cortex (M1), including changes in inhibitory circuitry. But how inhibitory synaptic connections change during skill acquisition and whether this varies over development is not fully understood. This study assesses the normal developmental trajectory of motor learning and then addresses inhibitory connectivity changes after motor learning. We trained mice of both sexes to run on a custom accelerating rotarod at ages from postnatal day (P) 20 to P120, tracking paw position and quantifying time to fall and changes in gait pattern. Performance improved most rapidly between P30-60, while paw position and gait patterns change with learning, though differently between age groups. To address circuit changes, we labeled task-active and task-inactive pyramidal cells with CaMPARI2, a genetically encoded activity marker. We then evoked inhibitory responses (IPSCs) from two major interneuron types: parvalbumin-expressing (PV+) interneurons and somatostatin-expressing (SOM+) interneurons. After one training day, PV-mediated inhibition is greater in task-active cells, while SOM-mediated inhibition is not different. These results suggest early changes in PV-mediated inhibition may support motor skill acquisition in mice. Whether PV-mediated inhibitory changes persist or changes in SOM+ interneuron connections arise later in training remains to be tested.

Highlights

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Motor learning aptitude is developmentally regulated, peaking at P30-P45 for the cortically-dependent accelerating rotarod task

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Mice learn by shifting from hopping to walking gait, with the gait shift in forelimbs preceding the shift in hindlimbs

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Inhibitory responses in task-active neurons are stronger than task-inactive neurons from parvalbumin-expressing fast-spiking neurons on the first training day

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Other interneuron connections from somatostatin-expressing interneurons are unchanged

Significance Statement

Plasticity in sensory cortex is restricted to a limited developmental window. Learning motor skills requires motor cortex plasticity, but it is unknown whether there are changes in learning aptitude over development and whether the synaptic mechanisms of plasticity vary across cortical areas. Here, we define the developmental trajectory of motor learning aptitude for the accelerating rotarod task in mice. We find that learning peaks at P30-P45, with mice learning to shift from hopping to walking gait to stay on the rotarod longer. Further, the gait shift in forelimbs precedes hindlimbs. We then find, using recordings targeted to task-active neurons, that inhibitory responses from specific subtypes of interneurons (parvalbumin-expressing) are stronger in active cells, while other interneuron connections (somatostatin-expressing) are unchanged. These results suggest early changes in PV-mediated inhibition support motor skill acquisition.