During locomotion, the spinal cord integrates sensory feedback with central commands to generate appropriate motor behavior. The spinal cord must determine which sensory inputs are important and which to ignore and then use these inputs to regulate motor output. Exactly how the spinal cord achieves this daunting task remains a major question in motor control and sensorimotor rehabilitation.

The broad purpose of this dissertation was to gain new insight into spinal sensory regulation during locomotion. To this end, I developed a novel in vitro spinal cord-hindlimb preparation (SCHP) composed of the isolated in vitro neonatal rat spinal cord oriented dorsal-up with intact hindlimbs allowed to locomote on a custom-built treadmill or instrumented force platforms. The SCHP combines the neural and pharmacological accessibility of classic in vitro spinal cord preparations with intact sensory feedback from physiological hindlimb movements. In this way, the SCHP expands our ability to study spinal sensory function and regulation. Following development, I validated the efficacy of the SCHP for studying behaviorally-relevant, sensory-modulated locomotion by showing the impact of sensory feedback on in vitro locomotion. When locomotion was activated by serotonin (5HT) and N-methyl D-aspartate (NMDA), the SCHP was capable of producing kinematics and muscle activation patterns similar to the intact adult rat. Even when activated by the same neurochemicals, the mechanosensory environment could significantly alter SCHP kinematics and muscle activitation patterns, showing that sensory feedback regulates in vitro spinal function. I further demonstrated that sensory feedback could reinforce or even initiate SCHP locomotion. In addition to validating the SCHP, these findings also provided the first biomechanical characterization of in vitro locomotion.

Using the SCHP and a custom-designed force platform system, I then investigated how presynaptic inhibition dynamically regulates sensory feedback during locomotion and how hindlimb mechanics influences this regulation. I hypothesized that contralateral limb mechanics would modulate presynaptic inhibition, and thus sensory regulation, on the ipsilateral limb. My results indicate that the contralateral limb, specifically stance-phase limb loading, plays a pivotal role in regulating ipsilateral swing-phase sensory inflow. As contralateral stance-phase force increases, contralateral afferents act via a GABAergic pathway to increase ipsilateral presynaptic inhibition, thereby inhibiting sensory feedback entering the spinal cord during ipsilateral swing. Such force-sensitive contralateral presynaptic inhibition likely serves to preserve swing by reducing or redirecting counterproductive sensory feedback. It may also help coordinate the limbs during locomotion, reduce sensory feedback at higher speeds, and adjust the sensorimotor strategy for task-specific demands.

This work has important implications for sensorimotor rehabilitation. After spinal cord injury, sensory feedback is one of the few remaining inputs available for accessing spinal locomotor circuitry. Thus, understanding how sensory feedback regulates and reinforces spinally-generated locomotion is vital for designing effective rehabilitation strategies. Further, sensory regulation is degraded by many neural injuries and diseases, including spinal cord injury, Parkinson's disease, and stroke, resulting in spasticity and impaired locomotor function. This work suggests that contralateral limb loading may be an important and readily manipulated variable for restoring appropriate sensory regulation during locomotion.