Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation.
Motor skill learning relies on the plasticity of the primary motor cortex as task acquisition drives cortical motor network remodeling. Large-scale cortical remodeling of evoked motor outputs occurs during the learning of corticospinal-dependent prehension behavior, but not simple, non-dexterous tasks. Here we determine the response of corticospinal neurons to two distinct motor training paradigms and assess the role of corticospinal neurons in the execution of a task requiring precise modulation of forelimb movement and one that does not. In vivo calcium imaging in mice revealed temporal coding of corticospinal activity coincident with the development of precise prehension movements, but not more simplistic movement patterns. Transection of the corticospinal tract and optogenetic regulation of corticospinal activity show the necessity for patterned corticospinal network activity in the execution of precise movements but not simplistic ones. Our findings reveal a critical role for corticospinal network modulation in the learning and execution of precise motor movements.
The learning of motor skills relies on plasticity of the primary motor cortex as task acquisition drives the remodeling of cortical motor networks. Large scale cortical remodeling of evoked motor outputs occurs in response to the learning of skilled, corticospinal-dependent behavior, but not simple, unskilled tasks. Here we determine the response of corticospinal neurons to both skilled and unskilled motor training and assess the role of corticospinal neuron activity in the execution of the trained behaviors. Using in vivo calcium imaging, we found that refinement of corticospinal activity correlated with the development of skilled, but not unskilled, motor expertise. Animals that failed to learn our skilled task exhibited a limited repertoire of dynamic movements and a corresponding absence of network modulation. Transection of the corticospinal tract and aberrant activation of corticospinal neurons show the necessity for corticospinal network activity patterns in the execution of skilled, but not unskilled, movement. We reveal a critical role for corticospinal network modulation in the learning and execution of skilled motor movements. The integrity of the corticospinal tract is essential to the recovery of voluntary movement after central nervous system injuries and these findings should help to shape translational approaches to motor recovery.
Hand and arm manual dexterity is a hallmark of humans and non-human primates. While rodents are less dexterous than primates, they provide powerful models for testing neural circuit function in behavioral output, including dexterous behaviors. In rodents, the single pellet reach task has been used extensively to study both dexterous forelimb motor learning as well as recovery from injury; however, mice exhibit high variability in task acquisition in comparison to rats and a significant percentage fail to learn the task. We have created a recessed version of the task that requires greater dexterity. This subtle modification increases both task difficulty as well as the proportion of mice that show an improvement with training. Furthermore, motor cortex inactivation shows a greater effect on the execution of the recessed forelimb reach task, with distinct effects on reach targeting vs grasping components depending on the timing of inhibitory activation. Kinematic analysis revealed differences in reach targeting upon transient cortical inhibition prior to reach onset. In summary, the recessed single pellet reach task provides a robust assessment of forelimb dexterity in mice and a tool for studying skilled motor acquisition and execution.
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