Task-dependent Presynaptic Inhibition

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Mar, 2003  |  Pubmed ID: 12629193

This study compares the level of presynaptic inhibition during two rhythmic movements in the cat: locomotion and scratch. Dorsal rootlets from L6, L7, or S1 segments were cut, and their proximal stumps were recorded during fictive locomotion occurring spontaneously in decerebrate cats and during fictive scratch induced by d-tubocurarine applied on the C1 and C2 segments. Compared with rest, the number of antidromic spikes was increased (by 12%) during locomotion, whereas it was greatly decreased (31%) during scratch, and the amplitude of dorsal root potentials (DRPs), evoked by stimulating a muscle nerve, was slightly decreased (7%) during locomotion but much more so during scratch (53%). When compared with locomotion, the decrease in the number of antidromic spikes (45%) and the decrease in DRP amplitude (43%) during scratch were of similar magnitude. Also, the amplitude of primary afferent depolarization (PAD), recorded with micropipettes in axons (n = 13) of two cats, was found to be significantly reduced (60%) during scratch compared with rest. During both rhythms, there were cyclic oscillations in dorsal root potential the timing of which was linearly related to the timing of rhythmic activity in tibialis anterior. The amplitude of these oscillations was significantly smaller (34%) during locomotion compared with scratch. These results suggest that the reduction in antidromic activity during scratch was attributable to a task-dependent decrease in transmission in PAD pathways and not to underlying potential oscillations related to the central pattern generator. It is concluded that presynaptic inhibition and antidromic discharge may have a more important role in the control of locomotion than scratch.

Spinal Cats on the Treadmill: Changes in Load Pathways

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Apr, 2003  |  Pubmed ID: 12684465

Treadmill training and clonidine, an alpha-2 noradrenergic agonist, have been shown to improve locomotion after spinal cord injury. We speculate that transmission in load pathways, which are involved in body support during stance, is specifically modified by training. This was evaluated by comparing two groups of spinal cats; one group (n = 11) was trained to walk until full-weight-bearing (3-4 weeks), and the other (shams; n = 7) was not. During an acute experiment, changes in group I pathways, monosynaptic excitation, disynaptic inhibition, and polysynaptic excitation were investigated by measuring the response amplitude in extensor motoneurons before and after clonidine injection. Monosynaptic excitation was not modified by clonidine but was decreased significantly by training. Disynaptic inhibition was significantly decreased by clonidine in both groups, but more significantly in trained cats, and significantly reduced by training after clonidine. Also, clonidine could reverse group IB inhibition into polysynaptic excitation in both groups but more frequently in trained cats. We also investigated whether fictive stepping revealed additional changes. In trained cats, the phase-dependent modulation of all three responses was similar to patterns reported previously, but in shams, modulation of monosynaptic and polysynaptic responses was not. Overall, training appears to decrease monosynaptic excitation and enhance the effects of clonidine in the reduction of disynaptic inhibition and reversal to polysynaptic excitation. Because it is believed that polysynaptic excitatory group I pathways transmit locomotor drive to extensor motoneurons, we suggest that the latter changes would facilitate the recruitment of extensor muscles for recovering weight-bearing during stepping.

Step Training-dependent Plasticity in Spinal Cutaneous Pathways

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2004  |  Pubmed ID: 15601938

Plasticity after spinal cord injury can be initiated by specific patterns of sensory feedback, leading to a reorganization of spinal networks. For example, proprioceptive feedback from limb loading during the stance phase is crucial for the recovery of stepping in spinal-injured animals and humans. Our recent results showed that step training modified transmission from group I afferents of extensors in spinal cats. However, cutaneous afferents are also activated during locomotion and are necessary for proper foot placement in spinal cats. We therefore hypothesized that step training would also modify transmission in cutaneous pathways to facilitate recovery of stepping. We tested transmission in cutaneous pathways by comparing intracellular responses in lumbar motoneurons (n = 136) in trained (n = 11) and untrained (n = 7) cats spinalized 3-5 weeks before the acute electrophysiological experiment. Three cutaneous nerves were stimulated, and each evoked up to three motoneuronal responses mediated by at least three different pathways. Overall, of 71 cutaneous pathways tested, 10 were modified by step training: transmission was reduced in 7 and facilitated in 3. Remarkably, 6 of 10 involved the medial plantar nerve innervating the plantar surface of the foot, including two of the facilitated pathways. Because the cutaneous reflexes are exaggerated after spinalization, we interpret the decrease in most pathways as a normalization of cutaneous transmission necessary to recover locomotor movements. Overall, the results showed a high degree of specificity in plasticity among cutaneous pathways and indicate that transmission of skin inputs signaling ground contact, in particular, is modified by step training.

Peripheral Nerve Grafts After Cervical Spinal Cord Injury in Adult Cats

Experimental Neurology. Sep, 2010  |  Pubmed ID: 20599980

Peripheral nerve grafts (PNG) into the rat spinal cord support axon regeneration after acute or chronic injury, with synaptic reconnection across the lesion site and some level of behavioral recovery. Here, we grafted a peripheral nerve into the injured spinal cord of cats as a preclinical treatment approach to promote regeneration for eventual translational use. Adult female cats received a partial hemisection lesion at the cervical level (C7) and immediate apposition of an autologous tibial nerve segment to the lesion site. Five weeks later, a dorsal quadrant lesion was performed caudally (T1), the lesion site treated with chondroitinase ABC 2 days later to digest growth inhibiting extracellular matrix molecules, and the distal end of the PNG apposed to the injury site. After 4-20 weeks, the grafts survived in 10/12 animals with several thousand myelinated axons present in each graft. The distal end of 9/10 grafts was well apposed to the spinal cord and numerous axons extended beyond the lesion site. Intraspinal stimulation evoked compound action potentials in the graft with an appropriate latency illustrating normal axonal conduction of the regenerated axons. Although stimulation of the PNG failed to elicit responses in the spinal cord distal to the lesion site, the presence of c-Fos immunoreactive neurons close to the distal apposition site indicates that regenerated axons formed functional synapses with host neurons. This study demonstrates the successful application of a nerve grafting approach to promote regeneration after spinal cord injury in a non-rodent, large animal model.

Activity-dependent Increase in Neurotrophic Factors is Associated with an Enhanced Modulation of Spinal Reflexes After Spinal Cord Injury

Journal of Neurotrauma. Feb, 2011  |  Pubmed ID: 21083432

Activity-based therapies such as passive bicycling and step-training on a treadmill contribute to motor recovery after spinal cord injury (SCI), leading to a greater number of steps performed, improved gait kinematics, recovery of phase-dependent modulation of spinal reflexes, and prevention of decrease in muscle mass. Both tasks consist of alternating movements that rhythmically stretch and shorten hindlimb muscles. However, the paralyzed hindlimbs are passively moved by a motorized apparatus during bike-training, whereas locomotor movements during step-training are generated by spinal networks triggered by afferent feedback. Our objective was to compare the task-dependent effect of bike- and step-training after SCI on physiological measures of spinal cord plasticity in relation to changes in levels of neurotrophic factors. Thirty adult female Sprague-Dawley rats underwent complete spinal transection at a low thoracic level (T12). The rats were assigned to one of three groups: bike-training, step-training, or no training. The exercise regimen consisted of 15 min/d, 5 days/week, for 4 weeks, beginning 5 days after SCI. During a terminal experiment, H-reflexes were recorded from interosseus foot muscles following stimulation of the tibial nerve at 0.3, 5, or 10 Hz. The animals were sacrificed and the spinal cords were harvested for Western blot analysis of the expression of neurotrophic factors in the lumbar spinal cord. We provide evidence that bike- and step-training significantly increase the levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4 in the lumbar enlargement of SCI rats, whereas only step-training increased glial cell-derived neurotrophic factor (GDNF) levels. An increase in neurotrophic factor protein levels that positively correlated with the recovery of H-reflex frequency-dependent depression suggests a role for neurotrophic factors in reflex normalization.

Chapter 2--the Spinal Generation of Phases and Cycle Duration

Progress in Brain Research. 2011  |  Pubmed ID: 21333800

During walking, an increase in speed is accompanied by a decrease in the stance phase duration while the swing phase remains relatively invariant. By definition, the rhythm generator in the lumbar spinal cord controls cycle period, phase durations, and phase transitions. Our first aim was to determine if this asymmetry in the control of locomotor cycles is an inherent property of the central pattern generator (CPG). We recorded episodes of fictive locomotion, that is, locomotor patterns in absence of reafference, in decerebrate cats with or without a complete spinal transection (acute or chronic). In fictive locomotion, stance and swing phases typically correspond to extension and flexion, respectively. In the vast majority of locomotor episodes, cycle period varied more with extensor phase duration. This could be observed without phasic sensory feedback or supraspinal structures or pharmacology. In a few experiments, we stimulated the mesencephalic locomotor region or selected peripheral nerves during fictive locomotion and both could alter the phase/cycle period relationship. We conclude that there is a built-in asymmetry within the spinal rhythm generator for locomotion, which can be modified by extraneous factors. Locomotor and scratching rhythms are characterized by alternation of flexion and extension phases within one hindlimb, which are mediated by rhythm-generating circuitry within the spinal cord. Our second aim was to determine if rhythm generators for locomotion and scratch have similar control mechanisms in adult decerebrate cats. The regulation of cycle period during fictive scratching was evaluated, as were the effects of specific sensory inputs on phase durations and transitions during pinna-evoked fictive scratching. Results show that cycle period during fictive scratching varied predominantly with flexion phase duration, contrary to spontaneous fictive locomotion. Ankle dorsiflexion greatly increased extension phase duration and cycle period during fictive locomotion but did not alter cycle period during scratching. These data indicate that cycle period, phase durations, and phase transitions are not regulated similarly during fictive locomotion and scratching, with or without sensory inputs, providing evidence for the existence of distinct interneuronal components of rhythm generation within the mammalian spinal cord.

Peripheral Nerve Grafts Support Regeneration After Spinal Cord Injury

Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics. Apr, 2011  |  Pubmed ID: 21360238

Traumatic insults to the spinal cord induce both immediate mechanical damage and subsequent tissue degeneration leading to a substantial physiological, biochemical, and functional reorganization of the spinal cord. Various spinal cord injury (SCI) models have shown the adaptive potential of the spinal cord and its limitations in the case of total or partial absence of supraspinal influence. Meaningful recovery of function after SCI will most likely result from a combination of therapeutic strategies, including neural tissue transplants, exogenous neurotrophic factors, elimination of inhibitory molecules, functional sensorimotor training, and/or electrical stimulation of paralyzed muscles or spinal circuits. Peripheral nerve grafts provide a growth-permissive substratum and local neurotrophic factors to enhance the regenerative effort of axotomized neurons when grafted into the site of injury. Regenerating axons can be directed via the peripheral nerve graft toward an appropriate target, but they fail to extend beyond the distal graft-host interface because of the deposition of growth inhibitors at the site of SCI. One method to facilitate the emergence of axons from a graft into the spinal cord is to digest the chondroitin sulfate proteoglycans that are associated with a glial scar. Importantly, regenerating axons that do exit the graft are capable of forming functional synaptic contacts. These results have been demonstrated in acute injury models in rats and cats and after a chronic injury in rats and have important implications for our continuing efforts to promote structural and functional repair after SCI.

Nerve Grafting for Spinal Cord Injury in Cats: Are We Close to Translational Research?

Neurosurgery. Apr, 2011  |  Pubmed ID: 21792096