Spinal pathways involved in the control of forelimb motor function in rats

There is increasing interest in developing rodent models for cervical spinal cord injury (SCI) and techniques to assess forelimb motor function. Previously, we demonstrated that in rats, complete unilateral hemisection at cervical level five (C5) permanently eliminated the ability to grip and caused severe impairments in food retrieval by the forepaw ipsilateral to the lesion [Anderson, K.D., Gunawan, A., Steward, O., 2005. Quantitative behavioral analysis of forepaw function after cervical spinal cord injury in rats: Relationship to the corticospinal tract. Exp. Neurol. 194, 161-174]. Here, we analyzed the functional consequences of partial lesions that damaged tracts/cells located in the medial vs. lateral portion of the spinal cord. Female Sprague-Dawley rats were trained on the Grip Strength Meter (GSM) and the food pellet reaching task. Rats then received either a "medial lesion" that destroyed an approximately 0.5 mm wide zone from the midline laterally (which included the dorsal column) or "lateral lesion" that destroyed the lateral column at C5 and were tested for 8 weeks. Rats with histologically-verified medial lesions exhibited a complete loss of gripping ability for 7 weeks post-injury; only 1 of 4 animals exhibited any recovery of grip strength, and this occurred at 54 days. In contrast, rats with lateral lesions exhibited deficits, but the majority (7/10) recovered the ability to grip by 43 days post-injury. Interestingly, when tested on the food retrieval task, rats with medial lesions exhibited deficits that recovered; rats with lateral lesions exhibited more permanent deficits. These results suggest that different spinal circuits are involved in recovery of grip strength vs. recovery of skilled reaching.     

Quantitative assessment of deficits and recovery of forelimb motor function after cervical spinal cord injury in mice

A large proportion of spinal cord injuries (SCIs) in humans are at the cervical (C) level, but there are few tests to quantitatively assess forelimb motor function after cervical spinal cord injury in rodents. Here, we describe a simple and reliable technique for assessing forelimb grip strength over time. Female C57Bl/6 mice were trained on the Grip Strength Meter (GSM, TSE-Systems), then received a lateral hemisection of the spinal cord at level C5, C6, C7, or T1. Gripping ability by each forepaw was then tested for 4 weeks postinjury. Before injury, there was no significant difference in the force exerted by either forepaw. After hemisections at C5, C6, or C7, the forepaw ipsilateral to the injury was initially completely unable to grip (day 2 postinjury), and there was a slight transient decrease in the strength of the contralateral paw compared to presurgical levels. The ipsilateral forepaw exhibited no ability to grip until about 10-14 days postlesion, at which time grip reappeared and strength then recovered over a period of a few days to a level that was about 50% of preinjury levels. Grip strength was minimally and transiently affected by hemisection at T1. The grip strength analysis provides a convenient, quantitative measure of the loss and recovery of forelimb function after cervical injury.     

An investigation of the cortical control of forepaw gripping after cervical hemisection injuries in rats

Previous studies in mice have demonstrated that forepaw gripping ability, as measured by a grip strength meter (GSM), is dependent on the contralateral sensorimotor cortex, but this dependency changes after hemisection injury at cervical level 4 (C4). Initially, the mouse fails to grip with the forepaw ipsilateral to the hemisection but gripping recovers. Additionally, a mouse's gripping by the contralateral paw becomes independent of the sensorimotor cortex, indicating a reorganization of cortical control of gripping function (Blanco, J.E., Anderson, K.D., Steward, O. 2007. Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice. Exp. Neurol. 203, 333-348.). Here we explore whether a similar reorganization occurs after cervical hemisection injuries in rats. We show that as in mice, unilateral lesions of the sensorimotor cortex impair rats' griping by the contralateral paw. We also confirm from previous studies that cervical hemisections impair rats' griping by the ipsilateral paw. In contrast to mice, however there is minimal recovery of gripping after complete lateral hemisections and secondary lesions of the sensorimotor cortex continue to impair rats' gripping by the contralateral paw. Thus, forelimb gripping ability as measured by the GSM is dependent on the contralateral sensorimotor cortex in rats even after a cervical hemisection.     

Bilateral cervical contusion spinal cord injury in rats

There is increasing motivation to develop clinically relevant experimental models for cervical SCI in rodents and techniques to assess deficits in forelimb function. Here we describe a bilateral cervical contusion model in rats. Female Sprague–Dawley rats received mild or moderate cervical contusion injuries (using the Infinite Horizons device) at C5, C6, or C7/8. Forelimb motor function was assessed using a grip strength meter (GSM); sensory function was assessed by the von Frey hair test; the integrity of the corticospinal tract (CST) was assessed by biotinylated dextran amine (BDA) tract tracing. Mild contusions caused primarily dorsal column (DC) and gray matter (GM) damage while moderate contusions produced additional damage to lateral and ventral tissue. Forelimb and hindlimb function was severely impaired immediately post-injury, but all rats regained the ability to use their hindlimbs for locomotion. Gripping ability was abolished immediately after injury but recovered partially, depending upon the spinal level and severity of the injury. Rats exhibited a loss of sensation in both fore- and hindlimbs that partially recovered, and did not exhibit allodynia. Tract tracing revealed that the main contingent of CST axons in the DC was completely interrupted in all but one animal whereas the dorsolateral CST (dlCST) was partially spared, and dlCST axons gave rise to axons that arborized in the GM caudal to the injury. Our data demonstrate that rats can survive significant bilateral cervical contusion injuries at or below C5 and that forepaw gripping function recovers after mild injuries even when the main component of CST axons in the dorsal column is completely interrupted.     

Sensorimotor training promotes functional recovery and somatosensory cortical map reactivation following cervical spinal cord injury

Sensorimotor activity has been shown to play a key role in functional recovery after partial spinal cord injury (SCI). Most studies in rodents have focused on the rehabilitation of hindlimb locomotor functions after thoracic or lumbar SCI, whereas forelimb motor and somatosensory abilities after cervical SCI remain largely uninvestigated, despite the high incidence of such injuries in humans. Moreover, little is known about the neurophysiological substrates of training‐induced recovery in supraspinal structures. This study was aimed at evaluating the effects of a training procedure combining both motor and sensory stimulation on behavioral performance and somatosensory cortical map remodeling after cervical (C4–C5) spinal hemisection in rats. This SCI severely impaired both sensory and motor capacities in the ipsilateral limbs. Without training, post‐lesion motor capacities gradually improved, whereas forepaw tactile abilities remained impaired. Consistently, no stimulus‐evoked responses were recorded within the forepaw representational zone in the primary somatosensory (S1) cortex at 2 months after the SCI. However, our data reveal that with training started from the 7th day post‐lesion, a nearly complete recovery (characterized by an early and rapid improvement of motor functions) was associated with a gradual compensation of tactile deficits. Furthermore, the recovery of tactile abilities was correlated with the areal extent of reactivation of S1 cortex forepaw representations. Rehabilitative training promoted post‐lesion adaptive plasticity, probably by enhancing endogenous activity within spared spinal and supraspinal circuits and pathways sustaining sensory and motor functions. This study highlights the beneficial effect of sensorimotor training in motor improvement and its critical influence on tactile recovery after SCI.     

Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice

Previous studies using a grip strength meter (GSM) revealed a loss of gripping ability following cervical hemisection injuries in mice, followed by partial recovery. Here, we assess whether normal gripping ability and the recovered gripping ability after cervical hemisection depend on the cerebral cortex. First, we assessed grip strength of both forepaws of 18-week-old C57Bl/6 mice before and after a left sensorimotor cortex lesion or right lateral hemisection at C5. Both lesions led to a complete loss of gripping ability by the right forepaw and caused only minor deficits in the left. After cortical lesions, gripping ability re-appeared at about 17 days post-injury, and grip strength recovered to near-normal levels by 24 days post-injury. After C5 hemisections, gripping ability re-appeared after 31 days post-injury in 50% of the mice. Follow-up experiments were then carried out in which 10-week-old mice received C4 hemisection injuries and were tested for 28 days; then mice received secondary lesions of the sensorimotor cortex ipsi- or contralateral to the hemisection. Younger mice with cervical hemisections recovered gripping ability between 12 and 28 days post-hemisection. Cortical lesions on the side contralateral to the hemisection led to a complete loss of recovered gripping ability in all mice; cortical lesions on the side ipsilateral to the hemisection also disrupted recovered gripping ability in some animals. Surprisingly, lesions of the cortex ipsilateral to the hemisection did not impair gripping ability of the contralateral (left) forepaw. Finally, we assessed the effects of a third lesion of whichever side of the sensorimotor cortex remained, so that the sensorimotor cortex was ablated bilaterally. Remarkably, gripping function by the forepaw contralateral to the original hemisection was completely unaffected, and the recovered gripping function by the forepaw ipsilateral to the hemisection was disrupted in only some of the animals. These results indicate a substantial reorganization of motor control of gripping function after cervical injuries in mice so that gripping ability by both forepaws becomes largely independent of cortical control.     

Differential tactile and motor recovery and cortical map alteration after C4-C5 spinal hemisection

After incomplete spinal cord injury (SCI), the adult central nervous system is spontaneously capable of substantial reorganizations that can underlie functional recovery. Most studies have focused on intraspinal reorganizations after SCI and not on the correlative cortical remodeling. Yet, differential studies of neural correlates of the recovery of sensory and motor abilities may be conducted by segregating motor and somatosensory representations in distinct and topologically organized primary cortical areas. This study was aimed at evaluating the effects of a cervical (C4-C5) spinal cord hemisection on sensorimotor performances and electrophysiological maps in primary somatosensory (S1) and motor (M1) cortices in adult rats. After SCI, an enduring loss of the affected forepaw tactile sensitivity was paralleled by the abolishment of somatosensory evoked responses in the deprived forepaw area within the S1 cortex. In contrast, severe motor deficits in unilateral forelimb were partially restored over the first postoperative month, despite remnant deficits in distal movement. The overall M1 map size was drastically reduced in SCI rats relative to intact rats. In the remaining M1 map, the shoulder and elbow movements were over-represented, consistent with the behavioral recovery of proximal joint movements in almost all rats. By contrast, residual wrist representations were observed in M1 maps of half of the rats that did not systematically correlate with a behavioral recovery of these joint movements. This study highlights the differential potential of ascending and descending pathways to reorganize after SCI.     

One day of motor training with amphetamine impairs motor recovery following spinal cord injury

It has previously been reported that a single dose of amphetamine paired with training on a beam walking task can enhance locomotor recovery following brain injury (Feeney et al., 1982). Here, we investigated whether this same drug/training regimen could enhance functional recovery following either thoracic (T9) or cervical (C5) spinal cord injury. Different groups of female Sprague-Dawley rats were trained on a beam walking task, and in a straight alley for assessment of hindlimb locomotor recovery using the BBB locomotor scale. For rats that received C5 hemisections, forelimb grip strength was assessed using a grip strength meter. Three separate experiments assessed the consequences of training rats on the beam walking task 24 h following a thoracic lateral hemisection with administration of either amphetamine or saline. Beginning 1 h following drug administration, rats either received additional testing/retraining on the beam hourly for 6 h, or they were returned to their home cages without further testing/retraining. Rats with thoracic spinal cord injuries that received amphetamine in conjunction with testing/retraining on the beam at 1 day post injury (DPI) exhibited significantly impaired recovery on the beam walking task and BBB. Rats with cervical spinal cord injuries that received training with amphetamine also exhibited significant impairments in beam walking and locomotion, as well as impairments in gripping and reaching abilities. Even when administered at 14 DPI, the drug/training regimen significantly impaired reaching ability in cervical spinal cord injured rats. Impairments were not seen in rats that received amphetamine without training. Histological analyses revealed that rats that received training with amphetamine had significantly larger lesions than saline controls. These data indicate that an amphetamine/training regimen that improves recovery after cortical injury has the opposite effect of impairing recovery following spinal cord injury because early training with amphetamine increases lesion severity.     

Cervical spinal cord injury in the adult rat: assessment of forelimb dysfunction

Traumatic injury to the adult human spinal cord most frequently occurs at the mid-to-low cervical segments and produces tetraplegia. To investigate treatments for improving upper extremity function after cervical spinal cord injury (SCI), three behavioral tests were examined for their potential usefulness in evaluating forelimb function in an adult rat model that mimics human low cervical SCI. Testing was conducted pre- and up to 4 weeks post-operation in adult female rats subjected to either contusion injury at the C7 spinal cord segment or sham-surgery. Modified Forelimb Tarlov scales revealed significant proximal and distal forelimb extension dysfunction in lesion rats at l-to-4 weeks post-cervical SCI. The Forelimb Grip Strength Test showed a significant decrease in forelimb grip strength of lesion rats throughout the 4 weeks post-cervical SCI. Significant deficits in reach and pellet retrieval by lesion rats were measured at l-to-4 weeks post-cervical SCI with the conditioned pellet retrieval Staircase Test. The results demonstrate that these qualitative and quantitative forelimb behavioral tests can be used to evaluate forelimb function following low cervical SCI and may be useful to investigate treatments for improving forelimb function in these lesions.     

Adult rat forelimb dysfunction after dorsal cervical spinal cord injury

Repairing upper extremity function would significantly enhance the quality of life for persons with cervical spinal cord injury (SCI). Repair strategy development requires investigations of the deficits and the spontaneous recovery that occurs when cervical spinal cord axonal pathways are damaged. The present study revealed that both anatomically and electrophysiologically complete myelotomies of the C4 spinal cord dorsal columns significantly increased the adult rat's averaged times to first attend to adhesive stickers placed on the palms of their forepaws at 1 week. Complete bilateral myelotomies of the dorsal funiculi and dorsal hemisection, but not bilateral dorsolateral funiculi injuries, also similarly increased these times at 1 week. These data extend a previous finding by showing that a forepaw tactile sensory deficit that occurred in the adult rat after bilateral C4 spinal cord dorsal funiculi injury is due to damage of the dorsal columns. Averaged times to first attend to the stickers also decreased to those of sham-operated rats at 3 and 4 weeks post-dorsal hemisection with weekly testing. In contrast, a separate group of rats with dorsal hemisections had significantly increased times when tested only at 4 weeks. These data indicate that frequent assessment of this particular behavior in rats with dorsal hemisections extinguishes it and/or engenders a learned response in the absence of sensory axons in the dorsal columns and dorsolateral funiculi. This finding contrasted with weekly testing of grid walking where increased forelimb footfall numbers persisted for 4 weeks post-dorsal hemisection.     

Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice

Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact corticospinal tract (CST) following unilateral injury and restore function to the denervated forelimb. Adult C57BL/6 mice underwent unilateral pyramidotomy and treatment with either ChABC or a vehicle control. Significant impairments in forepaw symmetry were observed following pyramidotomy, with injured mice preferentially using their intact paw during spontaneous vertical exploration of a cylinder. No recovery on this task was observed in vehicle‐treated mice. However, ChABC‐treated mice showed a marked recovery of function, with forelimb symmetry fully restored by 5 weeks post‐injury. Functional recovery was associated with robust sprouting of the uninjured CST, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. CST fibres in the denervated side of the spinal cord following ChABC treatment were closely associated with the synaptic marker vGlut1. Immunohistochemical assessment of chondroitin‐4‐sulphate revealed that CSPGs were heavily digested around lamina X, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri‐neuronal net staining was observed. Thus, we demonstrate that CSPG degradation promotes midline crossing and reinnervation of denervated target regions by intact CST axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using ChABC provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke.     

Advantages of delaying the onset of rehabilitative reaching training in rats with incomplete spinal cord injury

We have previously reported that rehabilitative reaching training initiated 4 days following an incomplete cervical spinal cord injury (SCI) in adult rats promotes plasticity and task-specific recovery. This training, however, also resulted in impairments in an untrained task. Here we examined whether delaying the rehabilitative training following cervical SCI is still effective in promoting task-specific recovery, but circumvents impairments in an untrained task, comparable to what has been reported in stroke models. Therefore, reaching training for a period of 6 weeks was initiated at Day 12 following a cervical dorso-lateral quadrant lesion. Thereupon the rats' ability to reach and to walk on a horizontal ladder (i.e. the untrained task) was assessed, and 8 weeks post-injury cortical map changes were investigated through microstimulation. Further, we examined changes in phospho protein kinase A (pPKA) levels following an immediate and a delayed onset of reaching training in rats with cervical SCI. We found that delayed rehabilitative training was comparably effective as immediate training in promoting task-specific recovery and sprouting of injured axons. Importantly, delayed training did not impair the performance on horizontal ladder walking. Strikingly, only delayed reaching training restored cortical PKA levels that had dropped significantly over 2 weeks post-injury. Additionally, delayed training did not influence cortical map changes following injury, but decreased white matter damage. In conclusion, our results show that a short delay in the onset of training in a forelimb task significantly alters our outcome measures, which should be considered in future rehabilitative approaches.     

Reorganization of Intact Descending Motor Circuits to Replace Lost Connections After Injury

Neurons have a limited capacity to regenerate in the adult central nervous system (CNS). The inability of damaged axons to re-establish original circuits results in permanent functional impairment after spinal cord injury (SCI). Despite abortive regeneration of axotomized CNS neurons, limited spontaneous recovery of motor function emerges after partial SCI in humans and experimental rodent models of SCI. It is hypothesized that this spontaneous functional recovery is the result of the reorganization of descending motor pathways spared by the injury, suggesting that plasticity of intact circuits is a potent alternative conduit to enhance functional recovery after SCI. In support of this hypothesis, several studies have shown that after unilateral corticospinal tract (CST) lesion (unilateral pyramidotomy), the intact CST functionally sprouts into the denervated side of the spinal cord. Furthermore, pharmacologic and genetic methods that enhance the intrinsic growth capacity of adult neurons or block extracellular growth inhibitors are effective at significantly enhancing intact CST reorganization and recovery of motor function. Owing to its importance in controlling fine motor behavior in primates, the CST is the most widely studied descending motor pathway; however, additional studies in rodents have shown that plasticity within other spared descending motor pathways, including the rubrospinal tract, raphespinal tract, and reticulospinal tract, can also result in restoration of function after incomplete SCI. Identifying the molecular mechanisms that drive plasticity within intact circuits is crucial in developing novel, potent, and specific therapeutics to restore function after SCI. In this review we discuss the evidence supporting a focus on exploring the capacity of intact motor circuits to functionally repair the damaged CNS after SCI.     

The vermicelli handling test: a simple quantitative measure of dexterous forepaw function in rats

Loss of function in the hands occurs with many brain disorders, but there are few measures of skillful forepaw use in rats available to model these impairments that are both sensitive and simple to administer. Whishaw and Coles previously described the dexterous manner in which rats manipulate food items with their paws, including thin pieces of pasta [Whishaw IQ, Coles BL. Varieties of paw and digit movement during spontaneous food handling in rats: postures, bimanual coordination, preferences, and the effect of forelimb cortex lesions. Behav Brain Res 1996;77:135–48]. We set out to develop a measure of this food handling behavior that would be quantitative, easy to administer, sensitive to the effects of damage to sensory and motor systems of the CNS and useful for identifying the side of lateralized impairments. When rats handle 7 cm lengths of vermicelli, they manipulate the pasta by repeatedly adjusting the forepaw hold on the pasta piece. As operationally defined, these adjustments can be easily identified and counted by an experimenter without specialized equipment. After unilateral sensorimotor cortex (SMC) lesions, transient middle cerebral artery occlusion (MCAO) and striatal dopamine depleting (6-hydroxydopamine, 6-OHDA) lesions in adult rats, there were enduring reductions in adjustments made with the contralateral forepaw. Additional pasta handling characteristics distinguished between the lesion types. MCAO and 6-OHDA lesions increased the frequency of several identified atypical handling patterns. Severe dopamine depletion increased eating time and adjustments made with the ipsilateral forepaw. However, contralateral forepaw adjustment number most sensitively detected enduring impairments across lesion types. Because of its ease of administration and sensitivity to lateralized impairments in skilled forepaw use, this measure may be useful in rat models of upper extremity impairment.     

Limits on recovery in the corticospinal tract of the rat: partial lesions impair skilled reaching and the topographic representation of the forelimb in motor cortex

Although evidence suggests that there are impairments in skilled movements following very large lesions of the pyramidal component of the corticospinal tract, the behavioral and electrophysiological effects of partial lesion has not received equal attention. Here, rats with complete lesions or partial lesions (medial, central, or lateral third) of the pyramidal tract at the medullary pyramids were evaluated for their quantitative and qualitative postsurgical performance on a skilled reaching task, following which the topographic representation of their forelimb was mapped with intracortical microstimulation (ICMS). Complete lesions impaired reaching success, impaired the qualitative features of reaching movements, and abolished ICMS evoked movement from the forelimb region of motor cortex. Although partial lesions did not impair reaching success, they did impair qualitative aspects of limb movement including forepaw aiming, supination, and food pellet release. ICMS indicated a reduction in the size of the forelimb area, especially the distal area of the caudal forelimb area (CFA), of the motor map. The behavioral and electrophysiological impairments did not vary with lesion location within the pyramidal tract. The incomplete recovery, as measured both behaviorally and electrophysiologically, demonstrates that plasticity within the corticospinal system is limited even with lesions that permit substantial sparing of pyramidal tract fibers.     

Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury

Spinal injury disrupts connections between the brain and spinal cord, causing life-long paralysis. Most spinal injuries are incomplete, leaving spared neural pathways to motor neurons that initiate and coordinate movement. One therapeutic strategy to induce functional motor recovery is to harness plasticity in these spared neural pathways. Chronic intermittent hypoxia (CIH) (72 episodes per night, 7 nights) increases synaptic strength in crossed spinal synaptic pathways to phrenic motoneurons below a C2 spinal hemisection. However, CIH also causes morbidity (e.g., high blood pressure, hippocampal apoptosis), rendering it unsuitable as a therapeutic approach to chronic spinal injury. Less severe protocols of repetitive acute intermittent hypoxia may elicit plasticity without associated morbidity. Here we demonstrate that daily acute intermittent hypoxia (dAIH; 10 episodes per day, 7 d) induces motor plasticity in respiratory and nonrespiratory motor behaviors without evidence for associated morbidity. dAIH induces plasticity in spared, spinal pathways to respiratory and nonrespiratory motor neurons, improving respiratory and nonrespiratory (forelimb) motor function in rats with chronic cervical injuries. Functional improvements were persistent and were mirrored by neurochemical changes in proteins that contribute to respiratory motor plasticity after intermittent hypoxia (BDNF and TrkB) within both respiratory and nonrespiratory motor nuclei. Collectively, these studies demonstrate that repetitive acute intermittent hypoxia may be an effective and non-invasive means of improving function in multiple motor systems after chronic spinal injury.     

Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury

As most spinal cord injuries(SCIs) are incomplete,an important target for promoting neural repair and recovery of lost motor function is to promote the connections of spared descending spinal pathways with spinal motor circuits.Among the pathways,the corticospinal tract(CST) is most associated with skilled voluntary functions in humans and many animals.CST loss,whether at its origin in the motor cortex or in the white matter tracts subcortically and in the spinal cord,leads to movement impairments and paralysis.To restore motor function after injury will require repair of the damaged CST.In this review,I discuss how knowledge of activity-dependent development of the CST—which establishes connectional specificity through axon pruning,axon outgrowth,and synaptic competition among CST terminals—informed a novel activity-based therapy for promoting sprouting of spared CST axons after injur in mature animals.This therapy,which comprises motor cortex electrical stimulation with and without concurrent trans-spinal direct current stimulation,leads to an increase in the gray matter axon length of spared CST axons in the rat spinal cord and,after a pyramidal tract lesion,restoration of skilled locomotor movements.I discuss how this approach is now being applied to a C4 contusion rat model.     

Forelimb locomotor assessment scale (FLAS): Novel assessment of forelimb dysfunction after cervical spinal cord injury

We describe here a novel forelimb locomotor assessment scale (FLAS) that assesses forelimb use during locomotion in rats injured at the cervical level. A quantitative scale was developed that measures movements of shoulder, elbow, and wrist joints, forepaw position and digit placement, forelimb–hindlimb coordination, compensatory behaviors adopted while walking, and balance. Female Sprague-Dawley rats received graded cervical contusions ranging from 200 to 230 (“mild,” n = 11) and 250–290 kdyn (“moderate,” n = 13) between C5 and C8. Rats were videotaped post-injury as they walked along an alley to determine deficits and recovery of forelimb function. Recovery of shoulder and elbow joint movement occurred rapidly (within 1–7 days post-injury), whereas recovery of wrist joint movement was slower and more variable. Most rats in all groups displayed persistent deficits in forepaw and digit movement, but developed compensatory behaviors to allow functional forward locomotion within 1–2 weeks post-injury. Recovery of forelimb function as measured by the FLAS reached a plateau by 3 weeks post-injury in all groups. Rats with mild contusions displayed greater locomotor recovery than rats with moderate contusions, but exhibited persistent deficits compared to sham controls. Reliability was tested by having seven raters (three internal, four external) from different laboratories, independently and blindly score videos of all rats. The multivariate correlation between all raters, all animals, and all time points ranged from r² = 0.88–0.96 (p < 0.0001), indicating a high inter-rater reliability. Thus, the FLAS is a simple, inexpensive, sensitive, and reliable measure of forelimb function during locomotion following cervical SCI.     

Peripheral and central changes combine to induce motor behavioral deficits in a moderate repetition task

Repetitive motion disorders, such as carpal tunnel syndrome and focal hand dystonia, can be associated with tasks that require prolonged, repetitive behaviors. Previous studies using animal models of repetitive motion have correlated cortical neuroplastic changes or peripheral tissue inflammation with fine motor performance. However, the possibility that both peripheral and central mechanisms coexist with altered motor performance has not been studied. In this study, we investigated the relationship between motor behavior changes associated with repetitive behaviors and both peripheral tissue inflammation and cortical neuroplasticity. A rat model of reaching and grasping involving moderate repetitive reaching with negligible force (MRNF) was used. Rats performed the MRNF task for 2 h/day, 3 days/week for 8 weeks. Reach performance was monitored by measuring reach rate/success, daily exposure, reach movement reversals/patterns, reach/grasp phase times, grip strength and grooming function. With cumulative task exposure, reach performance, grip strength and agility declined while an inefficient food retrieval pattern increased. In S1 of MRNF rats, a dramatic disorganization of the topographic forepaw representation was observed, including the emergence of large receptive fields located on both the wrist/forearm and forepaw with alterations of neuronal properties. In M1, there was a drastic enlargement of the overall forepaw map area, and of the cortex devoted to digit, arm–digits and elbow–wrist responses. In addition, unusually low current amplitude evoked digit movements. IL-1β and TNF-α increased in forearm flexor muscles and tendons of MRNF animals. The increases in IL-1β and TNF-α negatively correlated with grip strength and amount of current needed to evoke forelimb movements. This study provides strong evidence that both peripheral inflammation and cortical neuroplasticity jointly contribute to the development of chronic repetitive motion disorders.     

Loss and spontaneous recovery of forelimb evoked potentials in both the adult rat cuneate nucleus and somatosensory cortex following contusive cervical spinal cord injury

Varying degrees of neurologic function spontaneously recovers in humans and animals during the days and months after spinal cord injury (SCI). For example, abolished upper limb somatosensory potentials (SSEPs) and cutaneous sensations can recover in persons post-contusive cervical SCI. To maximize recovery and the development/evaluation of repair strategies, a better understanding of the anatomical locations and physiological processes underlying spontaneous recovery after SCI is needed. As an initial step, the present study examined whether recovery of upper limb SSEPs after contusive cervical SCI was due to the integrity of some spared dorsal column primary afferents that terminate within the cuneate nucleus and not one of several alternate routes. C5-6 contusions were performed on male adult rats. Electrophysiological techniques were used in the same rat to determine forelimb evoked neuronal responses in both cortex (SSEPs) and the cuneate nucleus (terminal extracellular recordings). SSEPs were not evoked 2 days post-SCI but were found at 7 days and beyond, with an observed change in latencies between 7 and 14 days (suggestive of spared axon remyelination). Forelimb evoked activity in the cuneate nucleus at 15 but not 3 days post-injury occurred despite dorsal column damage throughout the cervical injury (as seen histologically). Neuroanatomical tracing (using 1% unconjugated cholera toxin B subunit) confirmed that upper limb primary afferent terminals remained within the cuneate nuclei. Taken together, these results indicate that neural transmission between dorsal column primary afferents and cuneate nuclei neurons is likely involved in the recovery of upper limb SSEPs after contusive cervical SCI.