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Neuromodulatory therapies for spinal cord injury (SCI) such as electrical epidural stimulation (EES) are increasingly effective at improving patient outcomes. These improvements are thought to be due, at least in part, to plasticity in neuronal circuits. Precisely which circuits are influenced and which afferent classes are most effective in stimulating change remain important open questions. Genetic tools, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), support targeted and reversible neuromodulation as well as histological characterization of manipulated neurons. We therefore transduced and activated lumbar large diameter peripheral afferents with excitatory (hM3Dq) DREADDs, in a manner analogous to EES, in a rat hemisection model, to begin to trace plasticity and observe concomitant locomotor changes. Chronic DREADDs activation, coupled with thrice weekly treadmill training, was observed to increase afferent fluorescent labeling within motor pools and Clarke's column when compared to control animals. This plasticity may underlie kinematic differences that we observed across stages of recovery, including an increased and less variable hindquarters height in DREADDs animals, shorter step durations, a more flexed ankle joint early in recovery, a less variable ankle joint angle in swing phase, but a more variable hip joint angle. Withdrawal of DREADDs agonist, clozapine-N-oxide (CNO) left these kinematic differences largely unaffected; suggesting that DREADDs activation is not necessary for them later in recovery. However, we observed an intermittent “buckling” phenomenon in DREADDs animals without CNO activation, that did not occur with CNO re-administration. Future studies could use more refined genetic targeted of specific afferent classes, and utilize muscle recordings to find where afferent modulation is most influential in altering motor output.

Spinal interneurons play a critical role in motor output. A given interneuron may receive convergent input from several different sensory modalities and descending centers and relay this information to just as many targets. Therefore, there is a critical need to quantify populations of spinal interneurons simultaneously. Here, we quantify the functional connectivity of spinal neurons through the concurrent recording of populations of lumbar interneurons and hindlimb motor units in the in vivo cat model during activation of either the ipsilateral sural nerve or contralateral tibial nerve. Two microelectrode arrays were placed into lamina VII, one at L3 and a second at L6/7, while an electrode array was placed on the surface of the exposed muscle. Stimulation of tibial and sural nerves elicited similar changes in the discharge rate of both interneurons and motor units. However, these same neurons showed highly significant differences in prevalence and magnitude of correlated activity underlying these two forms of afferent drive. Activation of the ipsilateral sural nerve resulted in highly correlated activity, particularly at the caudal array. In contrast, the contralateral tibial nerve resulted in less, but more widespread correlated activity at both arrays. These data suggest that the ipsilateral sural nerve has dense projections onto caudal lumbar spinal neurons, while contralateral tibial nerve has a sparse pattern of projections.

Spinal cord injury (SCI) often results in life-long sensorimotor impairment. Spontaneous recovery from SCI is limited, as supraspinal fibers cannot spontaneously regenerate to form functional networks below the level of injury. Despite this, animal models and humans exhibit many motor behaviors indicative of recovery when electrical stimulation is applied epidurally to the dorsal aspect of the lumbar spinal cord. In 1976, epidural stimulation was introduced to alleviate spasticity in Multiple Sclerosis. Since then, epidural electrical stimulation (EES) has been demonstrated to improve voluntary mobility across the knee and/or ankle in several SCI patients, highlighting its utility in enhancing motor activation. The mechanisms that EES induces to drive these improvements in sensorimotor function remain largely unknown. In this review, we discuss several sensorimotor plasticity mechanisms that we hypothesize may enable epidural stimulation to promote recovery, including changes in local lumbar circuitry, propriospinal interneurons, and the internal model. Finally, we discuss genetic tools for afferent modulation as an emerging method to facilitate the search for the mechanisms of action.

The high clinical relevance of models of incomplete cervical spinal cord injury (SCI) creates a need to address the spontaneous neuroplasticity that underlies changes in functional activity that occur over time after SCI. There is accumulating evidence supporting long projecting propriospinal neurons as suitable targets for therapeutic intervention after SCI, but focus has remained primarily oriented toward study of descending pathways. Long ascending axons from propriospinal neurons at lower thoracic and lumbar levels that form inter enlargement pathways are involved in forelimb-hindlimb coordination during locomotion and are capable of modulating cervical motor output. Magnetic stimulation was used as a non-invasive investigational tool to assess transmission in long ascending propriospinal pathways to investigate how a unilateral cervical spinal contusion that does not directly damage this pathway might influence spinal cord plasticity. Our results show that transmission is facilitated in this pathway on the ipsilesional side as early as 1 week post-SCI. We also probed for descending magnetic motor evoked potentials and found them absent or greatly reduced on the ipsilesional side as expected. H-reflex recorded from the forelimb triceps brachii was bilaterally impaired although Hmax/Mmax was increased only on the ipsilesional side. Behaviorally, stepping recovered, but there were deficits in forelimb-hindlimb coordination as detected by BBB and CatWalk measures. In summary, results suggest that uninjured, initially latent pathways mediate recovery pointing towards functional reorganization of spinal pathways rather than axonal sprouting as a mechanism for spontaneous recovery after SCI.