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Spinal cord injury (SCI) is a debilitating disease resulting in an estimated 18,000 new cases in the United States on an annual basis. Significant behavioral research on animal models has led to a large amount of data, some of which has been catalogued in the Open Data Commons for Spinal Cord Injury (ODC-SCI). More recently, high throughput sequencing experiments have been utilized to understand molecular mechanisms associated with SCI, with nearly 6,000 samples from over 90 studies available in the Sequence Read Archive. However, to date, no resource is available for efficiently mining high throughput sequencing data from SCI experiments. Therefore, we have developed a protocol for processing RNA-Seq samples from high-throughput sequencing experiments related to SCI resulting in both raw and normalized data that can be efficiently mined for comparisons across studies as well as homologous discovery across species. We have processed 1,196 publicly available RNA-seq samples from 50 bulk RNA-Seq studies across nine different species, resulting in an SQLite database that can be used by the SCI research community for further discovery. We provide both the database as well as a web-based front-end that can be used to query the database for genes of interest, differential gene expression, genes with high variance, and gene set enrichments.

Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. In uninjured animals, conditionally silencing LAPNs resulted in disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping in the adult rat. Given their ventrolateral location in the spinal cord white matter, many LAPN axons likely remain intact following thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would result in diminished hindlimb locomotor function. We found instead that silencing of spared LAPNs post-SCI restored the left-right hindlimb coordination associated with alternating gaits that was lost as a result of SCI. Several other fundamental characteristics of hindlimb stepping were also improved and the number of abnormal steps were reduced. However, hindlimb-forelimb coordination was not restored. These data suggest that the temporal information carried between the enlargements by the LAPNs after SCI may be detrimental to hindlimb locomotor function. These observations have implications for our understanding of the relationship between injury severity and functional outcome, for the efforts to develop neuro- and axo-protective therapeutic strategies, and also for the clinical study/implementation of spinal stimulation and neuromodulation.

Hemodynamic instability and cardiovascular (CV) dysfunction are hallmarks of patients living with cervical and high thoracic spinal cord injuries (SCI). Individuals experience bouts of autonomic dysreflexia (AD) and persistent hypotension which hamper the activities of daily living. Despite the widespread use of exercise training to improve health and CV function after SCI, little is known about how different training modalities impact hemodynamic stability and severity of AD in a model of incomplete SCI. In this study, we used implantable telemetry devices to assess animals with T2 contusions following 3.5 weeks of exercise training initiated 8 days post‐injury: passive hindlimb cycling (T2‐CYC, n = 5) or active forelimb swimming (T2‐SW, n = 6). Uninjured and non‐exercised SCI control groups were also included (CON, n = 6; T2‐CON, n = 7; T10‐CON, n = 6). Five weeks post‐injury, both T2‐CON and T2‐CYC presented with resting hypotension compared to uninjured CON and T10‐CON groups; no differences were noted in resting blood pressure in T2‐SW versus CON and T10‐CON. Furthermore, pressor responses to colorectal distention (AD) were larger in all T2‐injured groups compared to T10‐CON, and were not attenuated by either form of exercise training. Interestingly, when T2‐injured animals were re‐stratified based on terminal BBB scores (regardless of training group), animals with limited hindlimb recovery (T2‐LOW, n = 7) had more severe AD responses. Our results suggest that the spontaneous recovery of locomotor and autonomic function after severe but incomplete T2 SCI also influences the severity of AD, and that short periods (3.5 weeks) of passive hindlimb cycling or active forelimb swimming are ineffective in this model., Using a high‐thoracic, severe but incomplete model of spinal cord injury we found that passive cycling and swimming, initiated early post‐injury, do not significantly alter the severity of induced autonomic dysreflexia. We discovered that animals with the greatest recovery of hindlimb locomotor function had the smallest pressor responses during induced autonomic dysreflexia.

Multi-organ dysfunction is a major complication after spinal cord injury (SCI). In addition to local injury within the spinal cord, SCI causes major disruption to the peripheral organ innervation and regulation. The liver contains sympathetic, parasympathetic, and small sensory axons. The bi-directional signaling of sensory dorsal root ganglion (DRG) neurons that provide both efferent and afferent information is of key importance as it allows sensory neurons and peripheral organs to affect each other. SCI-induced liver inflammation precedes and may exacerbate intraspinal inflammation and pathology after SCI, which may be modulated by activity and exercise. In this study, we collected comprehensive gene expression data through RNA sequencing of liver tissue from rats with chronic SCI to determine the effects of activity and exercise on those expression patterns. The sequenced data are of high quality and show a high alignment rate to the Rn6 genome. Gene expression is demonstrated for genes associated with known liver pathologies. UCSC Genome Browser expression tracks are provided with the data to facilitate exploration of the samples., Design Type(s)gene expression analysis objective • stimulus or stress design • transcription profiling designMeasurement Type(s)gene expressionTechnology Type(s)RNA sequencingFactor Type(s)Spinal Cord Injury • Exercise • EnvironmentalVariable • biological replicateSample Characteristic(s)Rattus norvegicus • liver Machine-accessible metadata file describing the reported data (ISA-Tab format)

Reduced muscle mass and increased fatiguability are major complications after spinal cord injury (SCI), and often hinder the rehabilitation efforts of patients. Such detriments to the musculoskeletal system, and the concomitant reduction in level of activity, contribute to secondary complications such as cardiovascular disease, diabetes, bladder dysfunction and liver damage. As a result of decreased weight-bearing capacity after SCI, muscles undergo morphological, metabolic, and contractile changes. Recent studies have shown that exercise after SCI decreases muscle wasting and reduces the burden of secondary complications. Here, we describe RNA sequencing data for detecting chronic transcriptomic changes in the rat soleus after SCI at two levels of injury severity, under conditions of restricted in-cage activity and two methods of applied exercise, swimming or shallow water walking. We demonstrate that the sequenced data are of good quality and show a high alignment rate to the Rattus norvegicus reference assembly (Rn6). The raw data, along with UCSC Genome Browser tracks created to facilitate exploration of gene expression, are available in the NCBI Gene Expression Omnibus (GEO; GSE129694).

Spinal cord injury (SCI) is a devastating clinical condition resulting in significant disabilities. Apart from local injury within the spinal cord, SCI patients develop a myriad of complications including multi-organ dysfunction. Some of the dysfunctions may be directly or indirectly related to the sensory neurons of the dorsal root ganglia (DRG), which signal to both the spinal cord and the peripheral organs. After SCI, some classes of DRG neurons exhibit sensitization and undergo axonal sprouting both peripherally and centrally. Such physiological and anatomical re-organization after SCI contributes to both adaptive and maladaptive plasticity processes, which may be modulated by activity and exercise. In this study, we collected comprehensive gene expression data in whole DRG below the levels of the injury to compare the effects of SCI with and without two different forms of exercise in rats., Design Type(s)gene expression analysis objective • stimulus or stress design • transcription profiling designMeasurement Type(s)gene expressionTechnology Type(s)RNA sequencingFactor Type(s)Spinal Cord Injury • Exercise • biological replicateSample Characteristic(s)Rattus norvegicus • dorsal root ganglion Machine-accessible metadata file describing the reported data (ISA-Tab format)

Spinal cord injury (SCI) is a devastating condition that results in whole‐body dysfunction, notably cardiovascular (CV) disruption and disease. Injury‐induced destruction of autonomic pathways in conjunction with a progressive decline in physical fitness contribute to the poor CV status of SCI individuals. Despite the wide use of exercise training as a therapeutic option to reduce CV dysfunction, little is known about the acute hemodynamic responses to the exercise itself. We investigated CV responses to an exercise challenge (swimming) following both high and low thoracic contusion to determine if the CV system is able to respond appropriately to the challenge of swimming. Blood pressure (BP) telemetry and echocardiography were used to track the progression of dysfunction in rodents with T3 and T10 SCI (n = 8 each) for 10 weeks postcontusion. At 1 week postinjury, all animals displayed a drastic decline in heart rate (HR) during the exercise challenge, likely a consequence of neurogenic shock. Furthermore, over time, all groups developed a progressive inability to maintain BP within a narrow range during the exercise challenge despite displaying normal hemodynamic parameters at rest. Echocardiography of T10 animals revealed no persistent signs of cardiac dysfunction; T3 animals exhibited a transient decline in systolic function that returned to preinjury levels by 10 weeks postinjury. Novel evidence provided here illustrates that incomplete injuries produce hemodynamic instability that only becomes apparent during an exercise challenge. Further, this dysfunction lasts into the chronic phase of disease progression despite significant recovery of hindlimb locomotion and cardiac function.

Neural circuitry in the lumbar spinal cord governs two principal features of locomotion, rhythm and pattern, which reflect intra- and interlimb movement. These features are functionally organized into a hierarchy that precisely controls stepping in a stereotypic, speed-dependent fashion. Here, we show that a specific component of the locomotor pattern can be independently manipulated. Silencing spinal L2 interneurons that project to L5 selectively disrupts hindlimb alternation allowing a continuum of walking to hopping to emerge from the otherwise intact network. This perturbation, which is independent of speed and occurs spontaneously with each step, does not disrupt multi-joint movements or forelimb alternation, nor does it translate to a non-weight-bearing locomotor activity. Both the underlying rhythm and the usual relationship between speed and spatiotemporal characteristics of stepping persist. These data illustrate that hindlimb alternation can be manipulated independently from other core features of stepping, revealing a striking freedom in an otherwise precisely controlled system., Intra- and interlimb coordination during locomotion is governed by hierarchically organized lumbar spinal networks. Here, the authors show that reversible silencing of spinal L2–L5 interneurons specifically disrupts hindlimb alternation leading to a continuum of walking to hopping.

Efforts to understand spinal cord injury (SCI) and other complex neurotrauma disorders at the pre-clinical level have shown progress in recent years. However, successful translation of basic research into clinical practice has been slow, partly because of the large, heterogeneous data sets involved. In this sense, translational neurological research represents a "big data" problem. In an effort to expedite translation of pre-clinical knowledge into standards of patient care for SCI, we describe the development of a novel database for translational neurotrauma research known as Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI). We present demographics, descriptive statistics, and translational syndromic outcomes derived from our ongoing efforts to build a multi-center, multi-species pre-clinical database for SCI models. We leveraged archived surgical records, postoperative care logs, behavioral outcome measures, and histopathology from approximately 3000 mice, rats, and monkeys from pre-clinical SCI studies published between 1993 and 2013. The majority of animals in the database have measures collected for health monitoring, such as weight loss/gain, heart rate, blood pressure, postoperative monitoring of bladder function and drug/fluid administration, behavioral outcome measures of locomotion, and tissue sparing postmortem. Attempts to align these variables with currently accepted common data elements highlighted the need for more translational outcomes to be identified as clinical endpoints for therapeutic testing. Last, we use syndromic analysis to identify conserved biological mechanisms of recovery after cervical SCI between rats and monkeys that will allow for more-efficient testing of therapeutics that will need to be translated toward future clinical trials.

When exploring potential treatments for spinal cord injury (SCI), functional recovery is deemed the most relevant outcome measure when it comes to translational considerations. Yet, assessing such recovery and potential treatment effects is challenging and the pitfalls are frequently underestimated. The consequences are that in many cases positive results cannot be reliably replicated, and likely treatments that appear to lack effects have been dismissed prematurely. In this article we review the relationships between lesion location/severity and functional outcomes with specific consideration given to floor and ceiling effects. The roles of compensatory strategies, the challenges of distinguishing them from bona fide recovery, and of comparing function to pre-injury levels given the variability inherent in animal testing are discussed. Ultimately, we offer a series of considerations to enhance the power of functional analysis in animal models of SCI.

In adult rats, locomotor deficits following a contusive thoracic spinal cord injury (SCI) are caused primarily by white matter loss/dysfunction at the epicenter. This loss/dysfunction decreases descending input from the brain and cervical spinal cord, and decreases ascending signals in long propriospinal, spinocerebellar and somatosensory pathways, among many others. Predicting the long-term functional consequences of a contusive injury acutely, without knowledge of the injury severity is difficult due to the temporary flaccid paralysis and loss of reflexes that accompanies spinal shock. It is now well known that recovery of high quality hindlimb stepping requires only 12-15% spared white matter at the epicenter, but that forelimb-hindlimb coordination and precision stepping (grid or horizontal ladder) requires substantially more trans-contusion communication. In order to translate our understanding of the neural substrates for functional recovery in the rat to the clinical arena, common outcome measures and imaging modalities are required. In the current study we furthered the exploration of one of these approaches, diffusion tensor magnetic resonance imaging (DTI), a technique now used commonly to image the brain in clinical research but rarely used diagnostically or prognostically for spinal cord injury. In the adult rat model of SCI, we found that hyper-acute (

Background. Locomotor training of rats with thoracic contusion spinal cord injuries can induce task-specific changes in stepping but rarely results in improved overground locomotion, possibly due to a ceiling effect. Thus, the authors hypothesize that incompletely injured rats maximally retrain themselves while moving about in their cages over the first few weeks postinjury. Objective. To test the hypothesis using hindlimb immobilization after mild thoracic contusion spinal cord injury in adult female rats. A passive stretch protocol was included as an independent treatment. Methods. Wheelchairs were used to hold the hindlimbs stationary in an extended position leaving the forelimbs free. The wheelchairs were used for 15 to 18 hours per day, 5 days per week for 8 weeks, beginning at 4 days postinjury. A 20-minute passive hindlimb stretch therapy was applied to half of the animals. Results. Hindlimb locomotor function of the wheelchair group was not different from controls at 1 week postinjury but declined significantly over the next 4 weeks. Passive stretch had no influence on wheelchair animals but limited functional recovery of normally housed animals, preventing them from regaining forelimb–hindlimb coordination. Following 8 weeks of wheelchair immobilization and stretch therapy, only the wheelchair group displayed an improvement in function when returned to normal housing but retained significant deficits in stepping and coordination out to 16 weeks. Conclusion. Hindlimb immobilization and passive stretch may hinder or conceal the normal course of functional recovery of spinal cord injured rats. These observations have implications for the management of acute clinical spinal cord injuries.

Activity-based rehabilitation is a promising strategy for improving functional recovery following spinal cord injury (SCI). While results from both clinical and animal studies have shown that a variety of approaches can be effective, debate still exists regarding the optimal post-injury period to apply rehabilitation. We recently demonstrated that rats with moderately severe thoracic contusive SCI can be re-trained to swim when training is initiated 2 weeks after injury and that swim training had no effect on the recovery of overground locomotion. We concluded that swim training is a task-specific model of post-SCI activity-based rehabilitation. In the present study, we ask if re-training initiated acutely is more or less effective than when initiated at 2 weeks post-injury. Using the Louisville Swim Scale, an 18-point swimming assessment, supplemented by kinematic assessment of hindlimb movement during swimming, we report that acute re-training is less effective than training initiated at 2 weeks. Using the bioluminescent protein luciferase as a blood-borne macromolecular marker, we also show a significant increase in extravasation in and around the site of SCI following only 8 min of swimming at 3 days post-injury. Taken together, these results suggest that acute re-training in a rat model of SCI may compromise rehabilitation efforts via mechanisms that may involve one or more secondary injury cascades, including acute spinal microvascular dysfunction.

Background. The authors have shown that rats can be retrained to swim after a moderately severe thoracic spinal cord contusion. They also found that improvements in body position and hindlimb activity occurred rapidly over the first 2 weeks of training, reaching a plateau by week 4. Overground walking was not influenced by swim training, suggesting that swimming may be a task-specific model of locomotor retraining. Objective. To provide a quantitative description of hindlimb movements of uninjured adult rats during swimming, and then after injury and retraining. Methods. The authors used a novel and streamlined kinematic assessment of swimming in which each limb is described in 2 dimensions, as 3 segments and 2 angles. Results. The kinematics of uninjured rats do not change over 4 weeks of daily swimming, suggesting that acclimatization does not involve refinements in hindlimb movement. After spinal cord injury, retraining involved increases in hindlimb excursion and improved limb position, but the velocity of the movements remained slow. Conclusion. These data suggest that the activity pattern of swimming is hardwired in the rat spinal cord. After spinal cord injury, repetition is sufficient to bring about significant improvements in the pattern of hindlimb movement but does not improve the forces generated, leaving the animals with persistent deficits. These data support the concept that force (load) and pattern generation (recruitment) are independent and may have to be managed together with respect to postinjury rehabilitation.

Identification of long tracts responsible for the initiation of spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. Pathways derived from the mesencephalic locomotor region and pontomedullary medial reticular formation responsible for fictive locomotion in decerebrate preparations project to the thoracolumbar levels of the spinal cord via reticulospinal axons in the ventrolateral funiculus (VLF). However, white matter regions critical for spontaneous over-ground locomotion remain unclear because cats, monkeys, and humans display varying degrees of locomotor recovery after ventral SCIs. We studied the contributions of myelinated tracts in the VLF and ventral columns (VC) to spontaneous over-ground locomotion in the adult rat using demyelinating lesions. Animals received ethidium bromide plus photon irradiation producing discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, VC, VLF–VC, or complete ventral white matter (CV). Behavior [open-field Basso, Beattie, and Bresnahan (BBB) scores and grid walking] and transcranial magnetic motor-evoked potentials (tcMMEP) were studied at 1, 2, and 4 weeks after lesion. VLF lesions resulted in complete loss or severe attenuation of tcMMEPs, with mean BBB scores of 18.0, and no grid walking deficits. VC lesions produced behavior similar to VLF-lesioned animals but did not significantly affect tcMMEPs. VC–VLF and CV lesions resulted in complete loss of tcMMEP signals with mean BBB scores of 12.7 and 6.5, respectively. Our data support a diffuse arrangement of axons within the ventral white matter that may comprise a system of multiple descending pathways subserving spontaneous over-ground locomotion in the intact animal.