Dorsal Column Lesion Research Articles

AI-assisted 3D analysis of grasping and reaching behavior of squirrel monkeys during recovery from cervical spinal cord injury

We have previously demonstrated that machine learning-based video analysis, conducted via DeepLabCut, is more sensitive for detecting subtle deficits in hand grasping behavior than traditional end-point performance assessments. This superiority was observed in a nonhuman primate (NHP) model of cervical spinal cord injury, specifically a dorsal column lesion (DCL). The current study aims to further characterize the kinematic aspects of the deficits in hand reaching, grasping, and retrieving behavior from a 3D perspective following a DCL. Squirrel monkeys were trained to retrieve sugar pellets from eight wells, which were located either on a flat plate or a raised tube with varying well depths. This setup was designed to require coordinated finger movements during the task. Immediately after the DCL, the animals exhibited measurable behavioral deficits. These were characterized by significant increases in grasping speed squared and trial completion time, markedly widened movement trajectories of individual fingers, and abnormalities in inter-finger distance and orientation. Increased task difficulty was associated with more pronounced behavioral deficits. By three months post-DCL, video-based measurements indicated no significant recovery, even though global end-point performance had returned to baseline levels. Our findings demonstrate that deprivation of tactile information results in impaired dexterous hand behavior involving coordinated finger movements, and the impairment is sustained for 20 weeks. This spinal cord injury (SCI) model, along with DeepLapCut analysis, provides a valuable platform for separately evaluating sensory and motor functions and their contributions to dexterous hand behavior and may be used for evaluating therapeutic interventions using more sensitive behavioral outcome readouts.

The effect of dorsal column lesions in the primary somatosensory cortex and medulla of adult rats

Spinal cord injury is a devastating condition that haunts human lives. Typically, patients experience referred phantom sensations on the hand when they are touched on the face. In adult monkeys, massive deafferentations such as chronic dorsal column lesions at higher cervical levels result in the large-scale expansion of face inputs into the deafferented hand cortex of area 3b. However, adult rats with thoracic dorsal column lesions do not demonstrate such large-scale reorganization. The large-scale face expansion in area 3b of monkeys is driven by the reorganization of the cuneate nucleus in the medulla. The sprouting of afferents from the trigeminal nucleus to the adjacent deafferented cuneate nucleus is facilitated by close proximity and compactness of the medulla in primates. Previously, in adult rats with thoracic lesions, the cuneate nucleus was not deafferented and its functional organization was not explored. The extent of the deafferentation and the duration of the recovery period are two major factors that determine the extent of reorganization. Hence, higher cervical (C3-C4) dorsal column lesions were performed, which cause massive deafferentations, and physiological maps were obtained after prolonged recovery periods (3 weeks -18 months). In spite of the above, the expansion of the intact face inputs was not observed in the deafferented zones of the primary somatosensory cortex (SI) and medulla of adult rats. The deafferented forelimb and hindlimb representations in SI were unresponsive to cutaneous stimulation of any part of the body. The cuneate and gracile nuclei in rats with complete dorsal column lesions remained mostly inactive except for a few sites which responded to stimulation of the spared upper arm. Hence, dorsal column lesions have different effects on the adult primate and rodent somatosensory systems. Appreciating this inter-species difference can aid in identifying the underlying neural substrates and restrict maladaptive reorganizations to cure phantom sensations.

Inhibition of miR-221-3p promotes axonal regeneration and repair of primary sensory neurons via regulating p27 expression.

This study aimed to explore the key microRNA (miRNA) playing a vital role in axonal regeneration with a hostile microenvironment after spinal cord injury. Based on the theory that sciatic nerve conditioning injury (SNCI) could promote the repair of the injured dorsal column. Differentially expressed miRNAs were screened according to the microarray, revealing that 47 known miRNAs were differentially expressed after injury and perhaps involved in nerve regeneration. Among the 47 miRNAs, the expression of miR-221-3p decreased sharply in the SNCI group compared with the simple dorsal column lesion (SDCL) group. Subsequently, it was confirmed that p27 was the target gene of miR-221-3p from luciferase reporter assay. Further, we found that inhibition of miR-221-3p expression could specifically target p27 to upregulate the expression of growth-associated protein 43 (GAP-43), α-tubulin acetyltransferase (α-TAT1) together with α-tubulin, and advance the regeneration of dorsal root ganglion (DRG) neuronal axons. Chondroitin sulfate proteoglycans (CSPGs) are the main components of glial scar, which can hinder the extension and growth of damaged neuronal axons. After CSPGs were used in this study, the results demonstrated that restrained miR-221-3p expression also via p27 promoted the upregulation of GAP-43, α-TAT1, and α-tubulin and enhanced the axonal growth of DRG neurons. Hence, miR-221-3p could contribute significantly to the regeneration of DRG neurons by specifically regulating p27 in the p27/CDK2/GAP-43 and p27/α-TAT1/α-tubulin pathways even in the inhibitory environment with CSPGs.

Validation of Spinal Cord Injury Sensory Deficit Model with Head-Fixed Rat

Background/Objective: Numerous studies have reported restoring motor function through spinal cord stimulation in a rodent spinal cord injury model; however, replicating sensory information through spinal cord stimulation has not been thoroughly tested.We have previously trained rats to detect artificial sensations which lead to the question if this can be generated in a spinal cord injured rat. Our study begins to address this question by first validating a spinal cord injury model to test. Our hypothesis is if a decrease in the percent correct response compared to pre-procedure is observed, then this will verify sensory loss in this dorsal column lesion model of spinal cord injury.
 Methods: We use sensory detection in a head-fixed rat to verify a spinal cord injury sensory deficit model. We begin by placing a water-deprived rat into a custom-made head-fix set up where two water spouts are placed in front of the rat. Vibration stimuli is applied to the hind paw via a vibration motor set at 200 hz ± 50 hz. The rat is trained to associate stimulus with left spout and no stimulus with right spout. Correct percent response is recorded and once rat demonstrates detection, the rat undergoes a dorsal column hemi-section procedure. Post procedure, the rat will be placed back in the head-fix set up to repeat the behavioral experiment.
 Results: Thus far, only habituation training has been completed with the rat. The following steps include detection training, dorsal column hemi section, and re doing the detection training to measure a difference in correct response rate.
 Conclusion and Potential Impact:This is a crucial step for spinal cord injury research as this confirms sensory loss and will allow further testing to restore sensation. After validation, we can begin testing to restore sensation using stimulation of the spinal cord.

Anti-CV2-mediated sensory neuronopathy with lesions of posterior columns in spinal MRI

•CV2-antibodies cause radiculitis and secondary damage to the posterior fasciculi. •Paraneoplastic sensory neuronopathy should be considered in differential diagnosis of dorsal column lesions. •Paraneoplastic sensory neuronopathy causes delayed spinal cord lesions, initial MRI can show no imaging correlate.

Nicotinic acetylcholine signaling is required for motor learning but not for rehabilitation from spinal cord injury.

Therapeutic intervention for spinal cord injury is limited, with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training. As compared with learning novel compensatory strategies, rehabilitation focuses on restoring movements lost to injury. Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning, or if it engages previously trained motor circuits without requiring novel learning remains an open question. In this study, mice were randomly assigned to receive intraperitoneal injection with the pan-nicotinic, non-competitive antagonist mecamylamine and the nicotinic α7 subunit selective antagonist methyllycaconitine citrate salt or vehicle (normal saline) prior to motor learning assays, then randomly reassigned after motor learning for rehabilitation study post-injury. Cervical spinal cord dorsal column lesion was used as a model of incomplete injury. Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury. Our findings indicate that critical differences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.

Transplanting Neural Progenitor Cells into a Chronic Dorsal Column Lesion Model

Cell transplantation therapy is a promising strategy for spinal cord injury (SCI) repair. Despite advancements in the development of therapeutic strategies in acute and subacute SCI, much less is known about effective strategies for chronic SCI. In previous studies we demonstrated that transplants of neural progenitor cells (NPC) created a permissive environment for axon regeneration and formed a neuronal relay across the injury following an acute dorsal column injury. Here we explored the efficacy of such a strategy in a chronic injury. We tested two preparations of NPCs derived from rat spinal cord at embryonic day 13.5: one prepared using stocks of cultured cells and the other of dissociated cells transplanted without culturing. Transplantation was delayed for 4-, 6- and 12-weeks post injury for a chronic injury model. We found that the dissociated NPC transplants survived and proliferated for at least 5 weeks post transplantation, in contrast to the poor survival of transplants prepared from cultured NPC stocks. The dissociated NPC transplants differentiated into neurons expressing excitatory markers, promoted axon regeneration into the injury/transplant site and extended axons from graft-derived neurons into the host. These results support the potential of NPC transplants to form neuronal relays across a chronic SCI, but they also underscore the challenges of achieving efficient cell survival in the environment of a chronic injury.

Inhibition of central axon regeneration: perspective from chondroitin sulfate proteoglycans in lamprey spinal cord injury.

Inhibition of central axon regeneration: perspective from chondroitin sulfate proteoglycans in lamprey spinal cord injury.

Extracellular histones, a new class of inhibitory molecules of CNS axonal regeneration.

Axonal regeneration in the mature CNS is limited by extracellular inhibitory factors. Triple knockout mice lacking the major myelin-associated inhibitors do not display spontaneous regeneration after injury, indicating the presence of other inhibitors. Searching for such inhibitors, we have detected elevated levels of histone H3 in human CSF 24 h after spinal cord injury. Following dorsal column lesions in mice and optic nerve crushes in rats, elevated levels of extracellular histone H3 were detected at the injury site. Similar to myelin-associated inhibitors, these extracellular histones induced growth cone collapse and inhibited neurite outgrowth. Histones mediate inhibition through the transcription factor Y-box-binding protein 1 and Toll-like receptor 2, and these effects are independent of the Nogo receptor. Histone-mediated inhibition can be reversed by the addition of activated protein C in vitro, and activated protein C treatment promotes axonal regeneration in the crushed optic nerve in vivo. These findings identify extracellular histones as a new class of nerve regeneration-inhibiting molecules within the injured CNS.

Thermosensitive collagen/fibrinogen gels loaded with decorin suppress lesion site cavitation and promote functional recovery after spinal cord injury

The treatment of spinal cord injury (SCI) is a complex challenge in regenerative medicine, complicated by the low intrinsic capacity of CNS neurons to regenerate their axons and the heterogeneity in size, shape and extent of human injuries. For example, some contusion injuries do not compromise the dura mater and in such cases implantation of preformed scaffolds or drug delivery systems may cause further damage. Injectable in situ thermosensitive scaffolds are therefore a less invasive alternative. In this study, we report the development of a novel, flowable, thermosensitive, injectable drug delivery system comprising bovine collagen (BC) and fibrinogen (FB) that forms a solid BC/FB gel (Gel) immediately upon exposure to physiological conditions and can be used to deliver reparative drugs, such as the naturally occurring anti-inflammatory, anti-scarring agent Decorin, into adult rat spinal cord lesion sites. In dorsal column lesions of adult rats treated with the Gel + Decorin, cavitation was completely suppressed and instead lesion sites became filled with injury-responsive cells and extracellular matrix materials, including collagen and laminin. Decorin increased the intrinsic potential of dorsal root ganglion neurons (DRGN) by increasing their expression of regeneration associated genes (RAGs), enhanced local axon regeneration/sprouting, as evidenced both histologically and by improved electrophysiological, locomotor and sensory function recovery. These results suggest that this drug formulated, injectable hydrogel has the potential to be further studied and translated into the clinic.

Behavioral recovery after a spinal deafferentation injury in monkeys does not correlate with extent of corticospinal sprouting

A long held view in the spinal cord injury field is that corticospinal terminal sprouting is needed for new connections to form, that then mediate behavioral recovery. This makes sense, but tells us little about the relationship between corticospinal sprouting extent and recovery potential. The inference has been that more extensive axonal sprouting predicts greater recovery, though there is little evidence to support this. Here we addressed this by comparing behavioral data from monkeys that had received one of two established deafferentation spinal injury models in monkeys (Darian-Smith et al., 2014, Fisher et al., 2019, 2020). Both injuries cut similar afferent pools supplying the thumb, index and middle fingers of one hand but each resulted in a very different corticospinal tract (CST) sprouting response. Following a cervical dorsal root lesion, the somatosensory CST retracted significantly, while the motor CST stayed largely intact. In contrast, when a dorsal column lesion was combined with the DRL, somatosensory and motor CSTs sprouted dramatically within the cervical cord. How these two responses relate to the behavioral outcome was not clear. Here we analyzed the behavioral outcome for the two lesions, and provide a clear example that sprouting extent does not track with behavioral recovery.

Axotomy Induces Drp1-Dependent Fragmentation of Axonal Mitochondria

It is well established that CNS axons fail to regenerate, undergo retrograde dieback, and form dystrophic growth cones due to both intrinsic and extrinsic factors. We sought to investigate the role of axonal mitochondria in the axonal response to injury. A viral vector (AAV) containing a mitochondrially targeted fluorescent protein (mitoDsRed) as well as fluorescently tagged LC3 (GFP-LC3), an autophagosomal marker, was injected into the primary motor cortex, to label the corticospinal tract (CST), of adult rats. The axons of the CST were then injured by dorsal column lesion at C4-C5. We found that mitochondria in injured CST axons near the injury site are fragmented and fragmentation of mitochondria persists for 2 weeks before returning to pre-injury lengths. Fragmented mitochondria have consistently been shown to be dysfunctional and detrimental to cellular health. Inhibition of Drp1, the GTPase responsible for mitochondrial fission, using a specific pharmacological inhibitor (mDivi-1) blocked fragmentation. Additionally, it was determined that there is increased mitophagy in CST axons following Spinal cord injury (SCI) based on increased colocalization of mitochondria and LC3. In vitro models revealed that mitochondrial divalent ion uptake is necessary for injury-induced mitochondrial fission, as inhibiting the mitochondrial calcium uniporter (MCU) using RU360 prevented injury-induced fission. This phenomenon was also observed in vivo. These studies indicate that following the injury, both in vivo and in vitro, axonal mitochondria undergo increased fission, which may contribute to the lack of regeneration seen in CNS neurons.

Longitudinal fMRI measures of cortical reactivation and hand use with and without training after sensory loss in primates

In a series of previous studies, we demonstrated that damage to the dorsal column in the cervical spinal cord deactivates the contralateral somatosensory hand cortex and impairs hand use in a reach-to-grasp task in squirrel monkeys. Nevertheless, considerable cortical reactivation and behavioral recovery occurs over the following weeks to months after lesion. This timeframe may also be a window for targeted therapies to promote cortical reactivation and functional reorganization, aiding in the recovery process. Here we asked if and how task specific training of an impaired hand would improve behavioral recovery and cortical reorganization in predictable ways, and if recovery related cortical changes would be detectable using noninvasive functional magnetic resonance imaging (fMRI). We further asked if invasive neurophysiological mapping reflected fMRI results. A reach-to-grasp task was used to test impairment and recovery of hand use before and after dorsal column lesions (DC-lesion). The activation and organization of the affected primary somatosensory cortex (area 3b) was evaluated with two types of fMRI – either blood oxygenation level dependent (BOLD) or cerebral blood volume (CBV) with a contrast agent of monocrystalline iron oxide nanocolloid (MION) – before and after DC-lesion. At the end of the behavioral and fMRI studies, microelectrode recordings in the somatosensory areas 3a, 3b and 1 were used to characterize neuronal responses and verify the somatotopy of cortical reactivations. Our results indicate that even after nearly complete DC lesions, monkeys had both considerable post-lesion behavioral recovery, as well as cortical reactivation assessed with fMRI followed by extracellular recordings. Generalized linear regression analyses indicate that lesion extent is correlated with the behavioral outcome, as well as with the difference in the percent signal change from pre-lesion peak activation in fMRI. Monkeys showed behavioral recovery and nearly complete cortical reactivation by 9–12 weeks post-lesion (particularly when the DC-lesion was incomplete). Importantly, the specific training group revealed trends for earlier behavioral recovery and had higher magnitude of fMRI responses to digit stimulation by 5–8 weeks post-lesion. Specific kinematic measures of hand movements in the selected retrieval task predicted recovery time and related to lesion characteristics better than overall task performance success. For measures of cortical reactivation, we found that CBV scans provided stronger signals to vibrotactile digit stimulation as compared to BOLD scans, and thereby may be the preferred non-invasive way to study the cortical reactivation process after sensory deprivations from digits. When the reactivation of cortex for each of the digits was considered, the reactivation by digit 2 stimulation as measured with microelectrode maps and fMRI maps was best correlated with overall behavioral recovery.

Combination of Defined CatWalk Gait Parameters for Predictive Locomotion Recovery in Experimental Spinal Cord Injury Rat Models.

In many preclinical spinal cord injury (SCI) studies, assessment of locomotion recovery is key to understanding the effectiveness of the experimental intervention. In such rat SCI studies, the most basic locomotor recovery scoring system is a subjective observation of animals freely roaming in an open field, the Basso Beattie Bresnahan (BBB) score. In comparison, CatWalk is an automated gait analysis system, providing further parameter specifications. Although together the CatWalk parameters encompass gait, studies consistently report single parameters, which differ in significance from other behavioral assessments. Therefore, we believe no single parameter produced by the CatWalk can represent the fully-coordinated motion of gait. Typically, other locomotor assessments, such as the BBB score, combine several locomotor characteristics into a representative score. For this reason, we ranked the most distinctive CatWalk parameters between uninjured and SC injured rats. Subsequently, we combined nine of the topmost parameters into an SCI gait index score based on linear discriminant analysis (LDA). The resulting combination was applied to assess gait recovery in SCI experiments comprising of three thoracic contusions, a thoracic dorsal hemisection, and a cervical dorsal column lesion model. For thoracic lesions, our unbiased machine learning model revealed gait differences in lesion type and severity. In some instances, our LDA was found to be more sensitive in differentiating recovery than the BBB score alone. We believe the newly developed gait parameter combination presented here should be used in CatWalk gait recovery work with preclinical thoracic rat SCI models.

Corticocuneate projections are altered after spinal cord dorsal column lesions in New World monkeys.

Recovery of responses to cutaneous stimuli in the area 3b hand cortex of monkeys after dorsal column lesions (DCLs) in the cervical spinal cord relies on neural rewiring in the cuneate nucleus (Cu) over time. To examine whether the corticocuneate projections are modified during recoveries after the DCL, we injected cholera toxin subunit B into the hand representation in Cu to label the cortical neurons after various recovery times, and related results to the recovery of neural responses in the affected area 3b hand cortex. In normal New World monkeys, labeled neurons were predominately distributed in the hand regions of contralateral areas 3b, 3a, 1 and 2, parietal ventral (PV), secondary somatosensory cortex (S2), and primary motor cortex (M1), with similar distributions in the ipsilateral cortex in significantly smaller numbers. In monkeys with short-term recoveries, the area 3b hand neurons were unresponsive or responded weakly to touch on the hand, while the cortical labeling pattern was largely unchanged. After longer recoveries, the area 3b hand neurons remained unresponsive, or responded to touch on the hand or somatotopically abnormal parts, depending on the lesion extent. The distributions of cortical labeled neurons were much more widespread than the normal pattern in both hemispheres, especially when lesions were incomplete. The proportion of labeled neurons in the contralateral area 3b hand cortex was not correlated with the functional reactivation in the area 3b hand cortex. Overall, our findings indicated that corticocuneate inputs increase during the functional recovery, but their functional role is uncertain.

Formation of somatosensory detour circuits mediates functional recovery following dorsal column injury

Anatomically incomplete spinal cord injuries can be followed by functional recovery mediated, in part, by the formation of intraspinal detour circuits. Here, we show that adult mice recover tactile and proprioceptive function following a unilateral dorsal column lesion. We therefore investigated the basis of this recovery and focused on the plasticity of the dorsal column-medial lemniscus pathway. We show that ascending dorsal root ganglion (DRG) axons branch in the spinal grey matter and substantially increase the number of these collaterals following injury. These sensory fibers exhibit synapsin-positive varicosities, indicating their integration into spinal networks. Using a monosynaptic circuit tracing with rabies viruses injected into the cuneate nucleus, we show the presence of spinal cord neurons that provide a detour pathway to the original target area of DRG axons. Notably the number of contacts between DRG collaterals and those spinal neurons increases by more than 300% after injury. We then characterized these interneurons and showed that the lesion triggers a remodeling of the connectivity pattern. Finally, using re-lesion experiments after initial remodeling of connections, we show that these detour circuits are responsible for the recovery of tactile and proprioceptive function. Taken together our study reveals that detour circuits represent a common blueprint for axonal rewiring after injury.

Adaptation of tape removal test for measurement of sensitivity in perineal area of rat

Regeneration after spinal cord injury is a goal of many studies. Although the most obvious target is to recover motor function, restoration of sensation can also improve the quality of life after spinal cord injury. For many patients, recovery of sensation in the perineal and genital area is a high priority. Currently there is no experimental test in rodents for measuring changes in sensation in the perineal and genital area after spinal cord injury. The aim of our study was to develop a behavioural test for measuring the sensitivity of the perineal and genital area in rats. We have modified the tape removal test used routinely to test sensorimotor deficits after stroke and spinal cord injury to test the perineal area with several variations. A small piece of tape (approximately 1 cm2) was attached to the perineal area. Time to first contact and to the removal of the tape was measured. Each rat was trained for 5 consecutive days and then tested weekly. We compared different rat strains (Wistar, Sprague-Dawley, Long-Evans and Lewis), both genders, shaving and non-shaving and different types of tape. We found that the test was suitable for all tested strains, however, Lewis rats achieved the lowest contact times, but this difference was significant only for the first few days of learning the task. There were no significant differences between gender and different types of tape or shaving. After training the animals underwent dorsal column lesion at T10 and were tested at day 3, 8, 14 and 21. The test detected a sensory deficit, the average time across all animals to sense the stimulus increased from 1′32 up to 3′20. There was a strong relationship between lesion size and tape detection time, and only lesions that extended laterally to the dorsal root entry zone produced significant sensory deficits. Other standard behavioural tests (BBB, von Frey, ladder and Plantar test) were performed in the same animals. There was a correlation between lesion size and deficit for the ladder and BBB tests, but not for the von Frey and Plantar tests. We conclude that the tape removal test is suitable for testing perineal sensation in rats, can be used in different strains and is appropriate for monitoring changes in sensation after spinal cord injury.

Longitudinally Extensive Dorsal Column Lesion in a Patient with Longstanding Anti-Hu and Anti-Amphphysin Autoimmunity (P1.2-054)

Longitudinally Extensive Dorsal Column Lesion in a Patient with Longstanding Anti-Hu and Anti-Amphphysin Autoimmunity (P1.2-054)

Metformin Activates Neural Stem and Progenitor Cells in the Spinal Cord and Improves Functional Outcomes Following Injury

Across mammals, spinal cord injuries (SCI) result in devastating functional deficits with minimal treatment options. Neural stem and progenitor cells (NSPCs) exist within the spinal cord and are located in the periventricular region lining the central canal. Although normally relatively quiescent and non‐neurogenic, these NSPCs are activated in response to injury, however their response is not sufficient to support functional recovery. Enhancing the response of resident NSPCs is an innovative approach to improve structural and functional outcomes following SCI. The FDA‐approved drug metformin (MET) has demonstrated efficacy in promoting neural repair in the injured brain where it expands the size of the NSPC pool and promotes both oligogenesis and neurogenesis from NSPCs. Here, we seek to determine whether MET can influence NSPCs within the spinal cord prior to and following SCI. Using the in vitro colony‐forming assay (neurosphere assay) we examined the size of the neural stem cell (NSC) pool in the spinal cord following 7 days of in vivo MET treatment. Females, but not males, demonstrated a three‐fold increase in the size of the NSC pool in response to MET treatment. Conversely, the differentiation profile of male and female‐derived NSPCs was not sex dependent in the presence of MET. Our results show that MET exposure led to an increase in oligogenesis across both males and females, with no change in neurogenesis. Next, we evaluated whether MET administration would improve functional outcomes following SCI using a dorsal column lesion in the thoracic spinal cord. MET was delivered to animals immediately post‐SCI and treatment resulted in a significantly reduced impairment at 7 days post‐injury (DPI) on a skilled walking task, compared to vehicle‐treated SCI mice. Strikingly, MET‐treated mice recovered to baseline by 14 DPI. Our data reveals that MET has differential effects on spinal cord NSPCs across males and females and that MET administration reduces the severity of SCI and results in improves functional outcomes post‐injury. Taken together, our results support MET as a viable therapeutic strategy for enhancing neural repair and improving recovery following SCI.Support or Funding InformationAmerican Association of AnatomistsOntario Institute for Regeneration MedicineKrembil FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Spinal cord injury transiently alters Meissner's corpuscle density in the digit pads of macaque monkeys.

Meissner's corpuscles (MCs) are cutaneous mechanoreceptors found in glabrous skin and are exquisitely sensitive to light touch. Along with other receptors, they provide continuous sensory feedback that informs the execution of fine manual behaviors. Following cervical spinal deafferentation injuries, hand use can be initially severely impaired, but substantial recovery occurs over many weeks, even when ~95% of the original input is permanently lost. While most SCI research focuses on central neural pathway responses, little is known about the role of peripheral receptors in facilitating recovery. We begin to address this by asking the following: (1) What is the normal pattern of MCs in the distal pads of all five digits in the macaque monkey (with hands similar to humans)? (2) What happens to these receptors 4-5 months following either a dorsal column lesion (DCL) or a combined dorsal root/dorsal column lesion (DRL/DCL), when functional recovery is largely complete? (3) What happens chronically, 12-14 months later? Our findings show that in normal monkeys, MCs are densest in the distal pads of the opposing thumb and index finger, with the greatest concentration on the thumb. This reflects a close functional relationship between receptor density and precision grip. At 4-5 months post-injury, there was a (~30%) loss of MCs on the deafferented digits of the injured hand compared with the contralateral side. However, 12-14 months after a DRL/DCL, receptor densities had returned to normal levels. Our findings indicate a complex peripheral response and highlight the importance of the periphery in shaping central changes.