Afferent input from load and joint receptors has been shown to reactivate the central pattern generators for locomotion (CPGs) in spinal cord injury patients and thereby improve their motor function and mobility. Elucidation of the pathways interposed between the afferents and CPGs is critical for the determination of the capacity of sensory input to activate the CPGs when the continuity of the white matter tracts is impaired following spinal cord injury. Using electrophysiological recordings, confocal imaging studies of spinal neurons and surgical manipulations of the white matter, we show that the capacity of sacrocaudal afferent (SCA) input to produce locomotor activity in isolated rat spinal cords depends not only on long ascending pathways, but also on recruitment of sacral proprioneurons interposed between the second order neurons and the hindlimb CPGs. We argue that large heterogeneous populations of second-order and proprioneurons whose crossed and uncrossed axons project rostrally through the ventral, ventrolateral/lateral and dorsolateral white matter funiculi contribute to the generation of the rhythm by the stimulated sacrocaudal input. The complex organization and multiple projection patterns of these populations enable the sacrocaudal afferent input to activate the CPGs even if the white matter pathways are severely damaged. Further studies are required to clarify the mechanisms involved in SCA-induced locomotor activity and assess its potential use for the rescue of lost motor functions after spinal cord injury.

Sacrocaudal afferent (SCA) stimulation is used in this work to study neural pathways involved in sensory-activation of central pattern generators (CPGs) in the isolated spinal cord of the neonatal rat. Surgical manipulations of the white matter funiculi and confocal imaging of back-labeled funicular pathways suggest that the CPGs are activated during SCA stimulation by crossed and uncrossed multifunicular projections of sacral neurons and that activation of short projecting proprioneurons is sufficient for the generation of the rhythm by SCA stimulation. The versatile organization of the pathways involved in the SCA-induced rhythm makes it a potent and durable activator of the CPGs in the absence of descending control from the brain. The significance of our findings and their potential clinical use are discussed.

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Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in the mouse models of peripheral nerve injury-and paclitaxel-induced neuropathic pain. Here, we used electrophysiology, immunohistochemistry, and electron microscopy to examine the extent to which MGE cells integrate into host circuitry and recapitulate endogenous inhibitory circuits. Whether the transplants were performed before or after nerve injury, the MGE cells developed into mature neurons and exhibited firing patterns characteristic of subpopulations of cortical and spinal cord inhibitory interneurons. Conversely, the transplanted cells preserved cortical morphological and neurochemical properties. We also observed a robust anatomical and functional synaptic integration of the transplanted cells into host circuitry in both injured and uninjured animals. The MGE cells were activated by primary afferents, including TRPV1-expressing nociceptors, and formed GABAergic, bicucullinesensitive, synapses onto host neurons. Unexpectedly, MGE cells transplanted before injury prevented the development of mechanical hypersensitivity. Together, our findings provide direct confirmation of an extensive, functional synaptic integration of MGE cells into host spinal cord circuits. This integration underlies normalization of the dorsal horn inhibitory tone after injury and may be responsible for the prophylactic effect of preinjury transplants.

Identification of neural networks and pathways involved in activation and modulation of spinal central pattern generators (CPGs) in the absence of the descending control from the brain is important for further understanding of neural control of movement and for developing innovative therapeutic approaches to improve the mobility of spinal cord injury patients. Activation of the hindlimb innervating segments by sacrocaudal (SC) afferent input and by specific application of neurochemicals to the sacral networks is feasible in the isolated spinal cord preparation of the newborn rat. Here we review our recent studies of sacral relay neurons with lumbar projections and evaluate their role in linking the sacral and thoracolumbar (TL) networks during different motor behaviors. Our major findings show that: (1) heterogeneous groups of dorsal, intermediate and ventral sacral-neurons with ventral and lateral ascending funicular projections mediate the activation of the locomotor CPGs through sacral sensory input; and (2) rhythmic excitation of lumbar flexor motoneurons, produced by bath application of alpha-1 adrenoceptor agonists to the sacral segments is mediated exclusively by ventral clusters of sacral-neurons with lumbar projections through the ventral funiculus.