Correlated activity of neurons can lead to long-term strengthening or weakening of the connections between them. In addition, the behavioral context, imparted by execution of physical movements or the presence of a reward, can modulate the plasticity induced by Hebbian mechanisms. In the present study, we have combined behavior and induced neuronal correlations to strengthen connections in the motor cortex of adult behaving monkeys. Correlated activity was induced using an electrical-conditioning protocol in which stimuli gated by voluntary movements were used to produce coactivation of neurons at motor-cortical sites involved in those movements. Delivery of movement-dependent stimulation resulted in small increases in the strength of associated cortical connections immediately after conditioning. Remarkably, when paired with further repetition of the movements that gated the conditioning stimuli, there were substantially larger gains in the strength of cortical connections, which occurred in a use-dependent manner, without delivery of additional conditioning stimulation. In the absence of such movements, little change was observed in the strength of motor-cortical connections. Performance of the motor behavior in the absence of conditioning also did not produce any changes in connectivity. Our results show that combining movement-gated stimulation with further natural use of the “conditioned” pathways after stimulation ends can produce use-dependent strengthening of connections in adult primates, highlighting an important role for behavior in cortical plasticity. Our data also provide strong support for combining movement-gated stimulation with use-dependent physical rehabilitation for strengthening connections weakened by a stroke or spinal cord injury.

Upper limb motor recovery is a priority for chronic SCI patients to improve functionality and quality of life. Treatment options available for acute SCI provide limited benefit to those with persistent motor symptoms years after injury, creating a need for interventions to target chronic motor damage. Our therapeutic approach utilizes quipazine, a serotonergic agonist, as a chemical neuromodulator to induce plasticity of spared motor pathways in a rat model of chronic SCI. Therapy consisted of quipazine delivery via microinfusion pump and physical training with a forelimb reach-and-grasp task. We found that quipazine administration produced a significant improvement in motor performance over rats receiving physical training alone. These therapeutic gains persisted beyond the period of quipazine administration during a four-week follow up period, producing a long-term improvement in motor performance. Notably, our intervention produced the greatest gains in rats with more severe injuries over those with moderate injuries. When analyzing reach vs. grasp as individual components of total motor performance, quipazine administration produced greater gains in both measures, compared with physical training alone. Our results provide evidence for quipazine administration as a therapeutic intervention to promote long-term motor benefits in chronic SCI. Our data offers support for the role of quipazine as a modulator of the dysregulated serotonergic system in SCI, promoting functional recovery. These findings have implications for the future use of neuromodulator therapy in improving motor performance to address the needs of chronic SCI patients.

Correlated activity of neurons can lead to long-term strengthening or weakening of the connections between them. In addition, the behavioral context, imparted by execution of physical movements or the presence of a reward, can modulate the plasticity induced by Hebbian mechanisms. In the present study, we have combined behavior and induced neuronal correlations to strengthen connections in the motor cortex of adult behaving monkeys. Correlated activity was induced using an electrical-conditioning protocol in which stimuli gated by voluntary movements were used to produce co-activation of neurons at motor-cortical sites involved in those movements. Delivery of movement-dependent stimulation resulted in small increases in the strength of associated cortical connections immediately after conditioning. Remarkably, when paired with further repetition of the movements that gated the conditioning stimuli, there were substantially larger gains in the strength of cortical connections, that occurred in a use-dependent manner, without delivery of additional conditioning stimulation. In the absence of such movements, little change was observed in the strength of motor-cortical connections. Performance of the motor behavior in the absence of conditioning also did not produce any changes in connectivity. Our results show that combining movement-gated stimulation with further natural use of the "conditioned" pathways after stimulation ends can produce use-dependent strengthening of connections in adult primates, highlighting an important role for behavior in cortical plasticity. Our data also provide strong support for combining movement-gated stimulation with use-dependent physical rehabilitation for strengthening connections weakened by a stroke or spinal-cord injury.