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Complete spinal cord injury causes an irreversible disruption in the central nervous system, leading to motor, sensory, and autonomic function loss, and a secondary injury that constitutes a physical barrier preventing tissue repair. Tissue engineering scaffolds are presented as a permissive platform for cell migration and the reconnection of spared tissue. Iodine-doped plasma pyrrole polymer (pPPy-I), a neuroprotective material, was applied to polylactic acid (PLA) fibers and implanted in a rat complete spinal cord transection injury model to evaluate whether the resulting composite implants provided structural and functional recovery, using magnetic resonance (MR) imaging, diffusion tensor imaging and tractography, magnetic resonance spectroscopy, locomotion analysis, histology, and immunofluorescence. In vivo, MR studies evidenced a tissue response to the implant, demonstrating that the fibrillar composite scaffold moderated the structural effects of secondary damage by providing mechanical stability to the lesion core, tissue reconstruction, and significant motor recovery. Histologic analyses demonstrated that the composite scaffold provided a permissive environment for cell attachment and neural tissue guidance over the fibers, reducing cyst formation. These results supply evidence that pPPy-I enhanced the properties of PLA fibrillar scaffolds as a promising treatment for spinal cord injury recovery. [ABSTRACT FROM AUTHOR]

Introduction: Self‐repair of spinal cord injury (SCI) has been found in humans and experimental animals with partial recovery of neurological functions. However, the regulatory mechanisms underlying the spontaneous locomotion recovery after SCI are elusive. Aims: This study was aimed at evaluating the pathological changes in injured spinal cord and exploring the possible mechanism related to the spontaneous recovery. Results: Immunofluorescence staining was performed to detect GAP43 expression in lesion site after spinal cord transection (SCT) in rats. Then RNA sequencing and gene ontology (GO) analysis were employed to predict lncRNA that correlates with GAP43. LncRNA smart‐silencing was applied to verify the function of lncRNA vof16 in vitro, and knockout rats were used to evaluate its role in neurobehavioral functions after SCT. MicroRNA sequencing, target scan, and RNA22 prediction were performed to further explore the underlying regulatory mechanisms, and miR‐185‐5p stands out. A miR‐185‐5p site‐regulated relationship with GAP43 and vof16 was determined by luciferase activity analysis. GAP43‐silencing, miR‐185‐5p‐mimic/inhibitor, and miR‐185‐5p knockout rats were also applied to elucidate their effects on spinal cord neurite growth and neurobehavioral function after SCT. We found that a time‐dependent increase of GAP43 corresponded with the limited neurological recovery in rats with SCT. CRNA chip and GO analysis revealed lncRNA vof16 was the most functional in targeting GAP43 in SCT rats. Additionally, silencing vof16 suppressed neurite growth and attenuated the motor dysfunction in SCT rats. Luciferase reporter assay showed that miR‐185‐5p competitively bound the same regulatory region of vof16 and GAP43. Conclusions: Our data indicated miR‐185‐5p could be a detrimental factor in SCT, and vof16 may function as a ceRNA by competitively binding miR‐185‐5p to modulate GAP43 in the process of self‐recovery after SCT. Our study revealed a novel vof16‐miR‐185‐5p‐GAP43 regulatory network in neurological self‐repair after SCT and may underlie the potential treatment target for SCI. [ABSTRACT FROM AUTHOR]

Introduction: Severe spinal cord injury results in the loss of neurons in the relatively intact spinal cord below the injury area and skeletal muscle atrophy in the paralyzed limbs. These pathological processes are significant obstacles for motor function reconstruction. Objective: We performed tail nerve electrical stimulation (TNES) to activate the motor neural circuits below the injury site of the spinal cord to elucidate the regulatory mechanisms of the excitatory afferent neurons in promoting the reconstruction of locomotor function. Methods: Eight days after T10 spinal cord transection in rats, TNES was performed for 7 weeks. Behavioral scores were assessed weekly. Electrophysiological tests and double retrograde tracings were performed at week 8. Results: After 7 weeks of TNES treatment, there was restoration in innervation, the number of stem cells, and mitochondrial metabolism in the rats' hindlimb muscles. Double retrograde tracings of the tail nerve and sciatic nerve further confirmed the presence of synaptic connections between the tail nerve and central pattern generator (CPG) neurons in the lumbar spinal cord, as well as motor neurons innervating the hindlimb muscles. Conclusion: The mechanisms of TNES induced by the stimulation of primary afferent nerve fibers involves efficient activation of the motor neural circuits in the lumbosacral segment, alterations of synaptic plasticity, and the improvement of muscle and nerve regeneration, which provides the structural and functional foundation for the future use of cutting‐edge biological treatment strategies to restore voluntary movement of paralyzed hindlimbs. [ABSTRACT FROM AUTHOR]

Abstract A young stray entire female domestic shorthair cat was presented with symmetrical forelimb extensor rigidity, neck hyperextension and hindlimb paraplegia, characteristic of Schiff–Sherrington phenomenon (SSP), within 30 min of a motor vehicle accident. Radiographic and post‐mortem studies disclosed complete transection of the spinal cord from traumatic dorsocranial luxation of the second lumbar vertebra, displacement of the sacrum from the ilium, seventh lumbar and first caudal vertebrae and multiple pelvic fractures. Other causes of forelimb extensor rigidity and neck hyperextension such as decerebrate and decerebellate rigidity were excluded by a lack of neurological signs consistent with these entities and unremarkable findings on post‐mortem examination of the cranial cavity and brain and histological examination of the cerebrum, brainstem and cerebellum. To the best of the author's knowledge, this is the first report of SSP in the cat outside the experimental arena of decerebrate or non‐decerebrate preparations following post‐brachial spinal cord transection/cold block.

A young stray entire female domestic shorthair cat was presented with symmetrical forelimb extensor rigidity, neck hyperextension and hindlimb paraplegia, characteristic of Schiff–Sherrington phenomenon (SSP), within 30 min of a motor vehicle accident. Radiographic and post‐mortem studies disclosed complete transection of the spinal cord from traumatic dorsocranial luxation of the second lumbar vertebra, displacement of the sacrum from the ilium, seventh lumbar and first caudal vertebrae and multiple pelvic fractures. Other causes of forelimb extensor rigidity and neck hyperextension such as decerebrate and decerebellate rigidity were excluded by a lack of neurological signs consistent with these entities and unremarkable findings on post‐mortem examination of the cranial cavity and brain and histological examination of the cerebrum, brainstem and cerebellum. To the best of the author's knowledge, this is the first report of SSP in the cat outside the experimental arena of decerebrate or non‐decerebrate preparations following post‐brachial spinal cord transection/cold block. [ABSTRACT FROM AUTHOR]

Spinal cord injuries result in the loss of motor and sensory functions controlled by neurons located at the site of the lesion and below. We hypothesized that experimentally enhanced remyelination supports axon preservation and/or growth in the total spinal cord transection in rats. Multifocal demyelination was induced by injection of ethidium bromide (EB), either at the time of transection or twice during transection and at 5 days post-injury. We demonstrated that the number of oligodendrocyte progenitor cells (OPCs) significantly increased 14 days after demyelination. Most OPCs differentiated into mature oligodendrocytes by 60–90 dpi in double-EB-injected rats; however, most axons were remyelinated by Schwann cells. A significant number of axons passed the injury epicenter and entered the distant segments of the spinal cord in the double-EB-injected rats. Moreover, some serotoninergic fibers, not detected in control animals, grew caudally through the injury site. Behavioral tests performed at 60–90 dpi revealed significant improvement in locomotor function recovery in double-EB-injected rats, which was impaired by the blockade of serotonin receptors, confirming the important role of restored serotonergic fibers in functional recovery. Our findings indicate that enhanced remyelination per se, without substantial inhibition of glial scar formation, is an important component of spinal cord injury regeneration. [ABSTRACT FROM AUTHOR]

Quad fever is a rare and sometimes fatal condition characterised by sustained high temperatures of 40.8°C (105.4°F) and above, in spinal cord injury patients. Patients are often unresponsive to routine antipyretics and diagnosis is usually one of exclusion after other causes of fever are ruled out. This condition is understood to be secondary to autonomic dysfunction leading to thermoregulatory impairment. In the present case report, a 53-year-old male patient developed a fever of 104°F two days after a traumatic spinal cord injury involving C6-C7 segments. The fever did not respond to paracetamol, empirical broad-spectrum antibiotics or thromboprophylaxis. After ruling out both infectious and non infectious causes of fever, the hyperthermia was attributed to quad fever, a type of neurogenic fever. The patient continued to have non relapsing high fever and died five days after presentation. The case highlights the need to be aware of this differential in cases of high fever following traumatic spinal cord injury, in order to better prognosticate and also avoid unnecessary antimicrobial usage.

Traumatic spinal cord injury (SCI) often leads to urinary dysfunction. Although an involuntary micturition reflex can be established to elicit voiding with time, complications arise in the form of bladder hyper-reflexia and detrusor-sphincter dyssynergia that cause incontinence and inefficient expulsion of urine. To date, the neuronal mechanisms that underlie regulation of micturition after SCI are not well understood. We recently observed an increase of a population of tyrosine hydroxylase (TH)+ cells in the rat lumbosacral cord post-SCI, which contribute to the sustention of a low level of dopamine that modulates the recovered bladder reflex. To identify whether spinal TH+ cells are involved in the micturition reflex pathway post-SCI, two isoforms of the trans-synaptic retrograde tracer, pseudorabies virus encoding green fluorescent protein (GFP; PRV-152) or red fluorescent protein (RFP; PRV-614), were injected into the bladder detrusor or the external urethral sphincter (EUS), respectively, 3 weeks after a spinal cord transection at the 10th thoracic level (T10) in rats. Immunohistochemistry was performed to examine infected TH+ cells in the caudal cord at both 48 and 72?h post-injection. As a result, double-labeled TH+/GFP+ and TH+/RFP+ cells could be found in the superficial dorsal horn, parasympathetic nuclei, and dorsal gray commissure (lamina X) at both time points. More importantly, a shared population of TH+ interneurons (TH+/GFP+/RFP+) exists between bladder and EUS circuitry. These results suggest that spinal TH+ interneurons may coordinate activity of the bladder and EUS that occurs during micturition reflexes post-SCI.

After spinal cord transection (SCT) the interaction between motoneurons (MNs) and muscle is impaired, due to reorganization of the spinal network after a loss of supraspinal inputs. Rats subjected to SCT, treated with intraspinal injection of a AAV-BDNF (brain-derived neurotrophic factor) construct, partially regained the ability to walk. The central effects of this treatment have been identified, but its impact at the neuromuscular junction (NMJ) has not been characterized. Here, we compared the ability of NMJ pre- and postsynaptic machinery in the ankle extensor (Sol) and flexor (TA) muscles to respond to intraspinal AAV-BDNF after SCT. The gene expression of cholinergic molecules (VAChT, ChAT, AChE, nAChR, mAChR) was investigated in tracer-identified, microdissected MN perikarya, and in muscle fibers with the use of qPCR. In the NMJs, a distribution of VAChT, nAChR and Schwann cells was studied by immunofluorescence, and of synaptic vesicles and membrane active zones by electron microscopy. We showed partial protection of the Sol NMJs from disintegration, and upregulation of the VAChT and AChE transcripts in the Sol, but not the TA MNs after spinal enrichment with BDNF. We propose that the observed discrepancy in response to BDNF treatment is an effect of difference in the TrkB expression setting BDNF responsiveness, and of BDNF demands in Sol and TA muscles. [ABSTRACT FROM AUTHOR]

Objective: Despite the conventional belief that motor function and sensation distal to the site of a complete spinal cord transection are irretrievable, our research has demonstrated significant motor recovery in mice, rats, and dogs by applying polyethylene glycol (PEG) topically via a syringe directly to the contact interface of transected spinal cord. However, before implementing this technology in human subjects, validating PEG's efficacy and enduring impact through experimentation on non-human primates is imperative., Methods: Two 4-year-old female Macaca fascicularis monkeys underwent complete dorsal cord transection at T10. Postoperative behavioral assessment, electrophysiologic monitoring, and neuroimaging examinations were recorded, and tissues were obtained for histological examination at the end of study., Results: The monkey whose spinal cord had been fully transected in the presence of PEG developed useful recovery already at 3 months and near-complete recovery of motor function in the hind-limbs at 18 months. The control animal without PEG remained paralyzed. Cortical somatosensory evoked potentials recovered postoperatively only in PEG-treated monkey vs none in the control. Diffusion tensor imaging showed re-establishment of continuity of the white matter in PEG-treated monkey, but not in the control. Moreover, histology revealed intact neuronal bodies, axons, and myelin tissue at the spinal cord transection site in PEG-treated monkey only., Conclusion: This report suggests that in primates, an acutely transected spinal cord can be re-fused in the presence of PEG with restoration of neural continuity and functional recovery of motor activity distal to the site of transection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc. on behalf of International Brain Research Organization.)

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor produced locally in the central nervous system which can promote axonal regeneration, protect motoneurons, and inhibit neuroinflammation. In this study, we used the zebrafish spinal transection model to investigate whether IGF-1 plays an important role in the recovery of motor function. Unlike mammals, zebrafish can regenerate axons and restore mobility in remarkably short period after spinal cord transection. Quantitative real-time PCR and immunofluorescence showed decreased IGF-1 expression in the lesion site. Double immunostaining for IGF-1 and Islet-1 (motoneuron marker)/GFAP (astrocyte marker)/Iba-1 (microglia marker) showed that IGF-1 was mainly expressed in motoneurons and was surrounded by astrocyte and microglia. Following administration of IGF-1 morpholino at the lesion site of spinal-transected zebrafish, swimming test showed retarded recovery of mobility, the number of motoneurons was reduced, and increased immunofluorescence density of microglia was caused. Our data suggested that IGF-1 enhances motoneuron survival and inhibits neuroinflammation after spinal cord transection in zebrafish, which suggested that IGF-1 might be involved in the motor recovery. [ABSTRACT FROM AUTHOR]

These data contain the details of the fabrication of the calcium ion-selective microelectrode (Ca2+-ISμEs) modified with poly(3,4-ethylenedioxythiophene)-poly(sodium 4-styrenesulfonate) (PEDOT(PSS)) as solid contact. The electrochemical impedance spectroscopy was carried out for the investigation of the resistance of the Ca2+-ISμEs. The thickness of the solid contact and the calcium ion-selective membrane was investigated by SEM. Potential-time curve of the electrodeposition of the PEDOT/PSS film onto the surface of the microelectrodes under the applied current of 0.5 μA for 200 s was recorded. The proposed Ca2+-ISμE was optimized through conditioning in different CaCl2 solutions ranged from 1.0 × 10−6 to 3.1 × 10−3 M for different time before use. The anti-fouling property of the Ca2+-ISμEs against proteins was investigated through taking BSA as the model protein. The developed Ca2+-ISμEs were used for the in vivo monitoring of the calcium ions in rat cerebrospinal fluid under the stimuli of the spinal cord transection in a living animal.

Quad fever is a rare and sometimes fatal condition characterised by sustained high temperatures of 40.8°C (105.4°F) and above, in spinal cord injury patients. Patients are often unresponsive to routine antipyretics and diagnosis is usually one of exclusion after other causes of fever are ruled out. This condition is understood to be secondary to autonomic dysfunction leading to thermoregulatory impairment. In the present case report, a 53-year-old male patient developed a fever of 104°F two days after a traumatic spinal cord injury involving C6-C7 segments. The fever did not respond to paracetamol, empirical broad-spectrum antibiotics or thromboprophylaxis. After ruling out both infectious and non infectious causes of fever, the hyperthermia was attributed to quad fever, a type of neurogenic fever. The patient continued to have non relapsing high fever and died five days after presentation. The case highlights the need to be aware of this differential in cases of high fever following traumatic spinal cord injury, in order to better prognosticate and also avoid unnecessary antimicrobial usage. [ABSTRACT FROM AUTHOR]

BackgroundIn rat models of spinal cord injury, at least 3 different strategies can be used to promote long-term cortical reorganization: (1) active exercise above the level of the lesion; (2) passive exercise below the level of the lesion; and (3) serotonergic pharmacotherapy. Whether and how these potential therapeutic strategies-and their underlying mechanisms of action-interact remains unknown. Methods In spinally transected adult rats, we compared the effects of active exercise above the level of the lesion (treadmill), passive exercise below the level of the lesion (bike), serotonergic pharmacotherapy (quipazine), and combinations of the above therapies (bike+quipazine, treadmill+quipazine, bike+treadmill+quipazine) on long-term cortical reorganization (9 weeks after the spinal transection). Cortical reorganization was measured as the percentage of cells recorded in the deafferented hindlimb cortex that responded to tactile stimulation of the contralateral forelimb. Results Bike and quipazine are "competing" therapies for cortical reorganization, in the sense that quipazine limits the cortical reorganization induced by bike, whereas treadmill and quipazine are "collaborative" therapies, in the sense that the reorganization induced by quipazine combined with treadmill is greater than the reorganization induced by either quipazine or treadmill.ConclusionsThese results uncover the interactive effects between active/passive exercise and serotonergic pharmacotherapy on cortical reorganization after spinal cord injury, emphasizing the importance of understanding the effects of therapeutic strategies in spinal cord injury (and in other forms of deafferentation) from an integrated system-level approach.

After spinal cord transection (SCT) the interaction between motoneurons (MNs) and muscle is impaired, due to reorganization of the spinal network after a loss of supraspinal inputs. Rats subjected to SCT, treated with intraspinal injection of a AAV-BDNF (brain-derived neurotrophic factor) construct, partially regained the ability to walk. The central effects of this treatment have been identified, but its impact at the neuromuscular junction (NMJ) has not been characterized. Here, we compared the ability of NMJ pre- and postsynaptic machinery in the ankle extensor (Sol) and flexor (TA) muscles to respond to intraspinal AAV-BDNF after SCT. The gene expression of cholinergic molecules (VAChT, ChAT, AChE, nAChR, mAChR) was investigated in tracer-identified, microdissected MN perikarya, and in muscle fibers with the use of qPCR. In the NMJs, a distribution of VAChT, nAChR and Schwann cells was studied by immunofluorescence, and of synaptic vesicles and membrane active zones by electron microscopy. We showed partial protection of the Sol NMJs from disintegration, and upregulation of the VAChT and AChE transcripts in the Sol, but not the TA MNs after spinal enrichment with BDNF. We propose that the observed discrepancy in response to BDNF treatment is an effect of difference in the TrkB expression setting BDNF responsiveness, and of BDNF demands in Sol and TA muscles.

Adult cats with a complete spinal cord transection at T12-T13 can relearn over a period of days-to-weeks how to generate full weight-bearing stepping on a treadmill or standing ability if trained specifically for that task. In the present study, we assessed short-term (milliseconds to minutes) adaptations by repetitively imposing a mechanical perturbation on the hindlimb of chronic spinal cats by placing a rod in the path of the leg during the swing phase to trigger a tripping response. The kinematics and EMG were recorded during control (10 steps), trip (1-60 steps with various patterns), and then release (without any tripping stimulus, 10-20 steps) sequences. Our data show that the muscle activation patterns and kinematics of the hindlimb in the step cycle immediately following the initial trip (mechanosensory stimulation of the dorsal surface of the paw) was modified in a way that increased the probability of avoiding the obstacle in the subsequent step. This indicates that the spinal sensorimotor circuitry reprogrammed the trajectory of the swing following a perturbation prior to the initiation of the swing phase of the subsequent step, in effect "attempting" to avoid the re-occurrence of the perturbation. The average height of the release steps was elevated compared to control regardless of the pattern and the length of the trip sequences. In addition, the average impact force on the tripping rod tended to be lower with repeated exposure to the tripping stimulus. EMG recordings suggest that the semitendinosus, a primary knee flexor, was a major contributor to the adaptive tripping response. These results demonstrate that the lumbosacral locomotor circuitry can modulate the activation patterns of the hindlimb motor pools within the time frame of single step in a manner that tends to minimize repeated perturbations. Furthermore, these adaptations remained evident for a number of steps after removal of the mechanosensory stimulation.

Cardiovascular dysfunction often occurs after high-level spinal cord injury. Disrupting supraspinal vasomotor pathways affects basal hemodynamics and contributes to the development of autonomic dysreflexia (AD). Transplantation of early-stage neurons to the injured cord may reconstruct the descending projections to enhance cardiovascular performance. To determine the specific role of reestablishing serotonergic regulation of hemodynamics, we implanted serotonergic (5-HT+) neuron-enriched embryonic raphe nucleus-derived neural stem cells/progenitors (RN-NSCs) into a complete spinal cord transection lesion site in adult female rats. Grafting embryonic spinal cord-derived NSCs or injury alone served as 2 controls. Ten weeks after injury/grafting, histological analysis revealed well-survived grafts and partial integration with host tissues in the lesion site. Numerous graft-derived serotonergic axons topographically projected to the caudal autonomic regions. Neuronal tracing showed that host supraspinal vasomotor pathways regenerated into the graft, and 5-HT + neurons within graft and host brainstem neurons were transsynaptically labeled by injecting pseudorabies virus (PRV-614) into the kidney, indicating reconnected serotonergic circuits regulating autonomic activity. Using an implanted telemeter to record cardiovascular parameters, grafting RN-NSCs restored resting mean arterial pressure to normal levels and remarkably alleviated naturally occurring and colorectal distension-induced AD. Subsequent pharmacological blockade of 5-HT2A receptors with ketanserin in RN-NSCgrafted rats reduced resting mean arterial pressure and increased heart rate in all but 2 controls. Furthermore, spinal cord retransection below RN-NSC grafts partially eliminated the recovery in AD. Collectively, these data indicate that RN-NSCs grafted into a spinal cord injury site relay supraspinal control of serotonergic regulation for sympathetic activity to improve cardiovascular function. [ABSTRACT FROM AUTHOR]

The precise location and functional organization of the spinal neuronal locomotor-related networks in adult mammals remain unclear. Our recent neurophysiological findings provided empirical evidence that the rostral lumbar spinal cord segments play a critical role in the initiation and generation of the rhythmic activation patterns necessary for hindlimb locomotion in adult spinal rats. Since added epidural stimulation at the S1 segments significantly enhanced the motor output generated by L2 stimulation, these data also suggested that the sacral spinal cord provides a strong facilitory influence in rhythm initiation and generation. However, whether L2 will initiate hindlimb locomotion in the absence of S1 segments, and whether S1 segments can facilitate locomotion in the absence of L2 segments remain unknown. Herein, adult rats received complete spinal cord transections at T8 and then at either L2 or S1. Rats with spinal cord transections at T8 and S1 remained capable of generating coordinated hindlimb locomotion when receiving epidural stimulation at L2 and when ensembles of locomotor related loadbearing input were present. In contrast, minimal locomotion was observed when S1 stimulation was delivered after spinal cord transections at T8 and L2. Results were similar when the nonspecific serotonergic agonists were administered. These results demonstrate in adult rats that rostral lumbar segments are essential for the regulation of hindlimb locomotor rhythmicity. In addition, the more caudal spinal networks alone cannot control locomotion in the absence of the rostral segments around L2 even when loadbearing rhythmic proprioceptive afferent input is imposed. [ABSTRACT FROM AUTHOR]

Despite decades of animal experimentation, human translation with cell grafts, conduits, and other strategies has failed to cure patients with chronic spinal cord injury (SCI). Recent data show that motor deficits due to spinal cord transection in animal models can be reversed by local application of fusogens, such as Polyethylene glycol (PEG). Results proved superior at short term over all other treatments deployed in animal studies, opening the way to human trials. In particular, removal of the injured spinal cord segment followed by PEG fusion of the two ends along with vertebral osteotomy to shorten the spine holds the promise for a cure in many cases. [ABSTRACT FROM AUTHOR]

Background: Developmental cortical plasticity with reorganization of cerebral cortex, has been known to occur in young and adult animals after permanent, restricted elimination of afferent (visual or somatosensory) input. In animals, cortical representation of unaffected muscles or sensory areas has been shown to invade the neighboring cortex when this is deprived of its normal sensory input or motor functions. Some studies indicate that similar cortical plasticity may take place in adult humans.Methods: In patients with a high cervical spinal cord injury leaving the patient without any movements of the fingers, we performed fMRI studies of the cortical representation of an elbow flexor muscle before and after a surgical procedure that changed its function to a thumb flexor, thus providing the patient with a useful grip.Results: Preoperatively, the elbow flexion movement was elicited from a cortical area corresponding with the “elbow area” in healthy individuals. Despite the fact that an elbow flexor was used for the post-operative key-grip, this movement in the tetraplegic patients was elicited from a similar brain region as in healthy controls (the “hand area”). This supports our hypothesis that control of that muscle shifts from a brain region typically associated with elbow movement, to one typically associated with wrist movements.Conclusion: The findings presented here show with fMRI that the human cortex is capable of reorganizing itself spatially after a relatively acute change in the periphery.

To determine whether norepinephrine (NE) and galanin are coreleased during reflex activation of the sympathetic nervous system by hypoglycemia, we administered insulin to halothane-anesthetized (0.8%) dogs and measured the spillover of NE and galanin-like immunoreactivity (GLIR) into pancreatic venous plasma. Insulin injection produced hypoglycemia [plasma glucose (PG) = 34 +/- 3 mg/dl] but did not activate pancreatic noradrenergic (delta pancreatic NE output = +20 +/- 130 pg/min) or galaninergic nerves (delta GLIR output = +40 +/- 50 fmol/min). To determine whether more severe hypoglycemia would activate these nerves, insulin was administered to dogs infused with somatostatin (SS; 2.5 micrograms/min) to block the counterregulatory increase of glucagon secretion. SS reduced the glucagon response to hypoglycemia by greater than 90%, which allowed PG to decrease to 14 +/- 1 mg/dl. Pancreatic NE output increased by 470 +/- 140 pg/min (P less than 0.005); however, pancreatic GLIR output did not increase significantly (delta = +70 +/- 50 fmol/min). When SS was discontinued, pancreatic NE output increased by 490 +/- 200 pg/min (P less than 0.025), and GLIR output increased by an additional +160 +/- 70 fmol/min (P less than 0.025; total delta from baseline = +230 +/- 90 fmol/min, P less than 0.025), suggesting that SS may restrain pancreatic NE and galanin release. Pancreatic NE and GLIR spillover were also increased during severe hypoglycemia when ganglionic neurotransmission was partially impaired with hexamethonium but not when the neural pathway was interrupted by spinal cord transection. We conclude that NE and galanin are coreleased from pancreatic sympathetic nerves when these nerves are centrally activated during severe hypoglycemia in halothane-anesthetized dogs.

The Chinese herbal formula Tongluo Jiunao, containing the active components Panax notoginseng and Gardenia jasminoides, has recently been patented and is in use clinically. It is known to be neuroprotective in cerebral ischemia, but the underlying pathway remains poorly understood. In the present study, we established a rat model of cerebral ischemia by occlusion of the middle cerebral artery, and administered Tongluo Jiunao, a positive control (Xuesai Tong, containing Panax notoginseng) or saline intraperitoneally to investigate the pathway involved in the action of Tongluo Jiunao injection. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed that the cerebral infarct area was significantly smaller in model rats that received Tongluo Jiunao than in those that received saline. Enzyme-linked immunosorbent assay revealed significantly greater expression of neurotrophin 3 and growth-associated protein 43 in ischemic cerebral tissue, and serum levels of neurotrophin 3, in the Tongluo Jiunao group than in the saline group. The reverse transcription polymerase chain reaction and immunohistochemical staining showed that after treatment with Tongluo Jiunao or Xuesai Tong, tropomyosin-related kinase C gene expression and immunoreactivity were significantly elevated compared with saline, with the greatest expression observed after Tongluo Jiunao treatment. These findings suggest that Tongluo Jiunao injection exerts a neuroprotective effect in rats with cerebral ischemia by activating the neurotrophin 3/tropomyosin-related kinase C pathway.

Lung injury is the main manifestation of paraquat poisoning. Few studies have addressed brain damage after paraquat poisoning. Ulinastatin is a protease inhibitor that can effectively stabilize lysosomal membranes, prevent cell damage, and reduce the production of free radicals. This study assumed that ulinastatin would exert these effects on brain tissues that had been poisoned with paraquat. Rat models of paraquat poisoning were intraperitoneally injected with ulinastatin. Simultaneously, rats in the control group were administered normal saline. Hematoxylin-eosin staining showed that most hippocampal cells were contracted and nucleoli had disappeared in the paraquat group. Fewer cells in the hippocampus were concentrated and nucleoli had disappeared in the ulinastatin group. Western blot assay showed that expressions of GRP78 and cleaved-caspase-3 were significantly lower in the ulinastatin group than in the paraquat group. Immunohistochemical findings showed that CHOP immunoreactivity was significantly lower in the ulinastatin group than in the paraquat group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining showed that the number of apoptotic cells was reduced in the paraquat and ulinastatin groups. These data confirmed that endoplasmic reticular stress can be induced by acute paraquat poisoning. Ulinastatin can effectively inhibit this stress as well as cell apoptosis, thereby exerting a neuroprotective effect.

In this study, we investigated the effects of streptozotocin-induced type 1 diabetes on antioxidant-like protein-1 immunoreactivity, protein carbonyl levels, and malondialdehyde formation, a marker for lipid peroxidation, in the hippocampus. For this study, streptozotocin (75 mg/kg) was intraperitoneally injected into adult rats to induce type 1 diabetes. The three experimental parameters were determined at 2, 3, 4 weeks after streptozotocin treatment. Fasting blood glucose levels significantly increased by 20.7-21.9 mM after streptozotocin treatment. The number of antioxidant-like protein-1 immunoreactive neurons significantly decreased in the hippocampal CA1 region, but not the dentate gyrus, 3 weeks after streptozotocin treatment compared to the control group. Malondialdehyde and protein carbonyl levels, which are modified by oxidative stress, significantly increased with a peak at 3 weeks after malondialdehyde treatment, and then decreased 4 weeks after malondialdehyde treatment. These results suggest that neurons in the hippocampal CA1 region, but not the dentate gyrus, are susceptible to oxidative stress 3 weeks after malondialdehyde treatment.

Recent studies have shown that induced expression of endogenous antioxidative enzymes thr-ough activation of the antioxidant response element/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway may be a neuroprotective strategy. In this study, rat cerebral cortical neurons cultured in vitro were pretreated with 10 μM curcumin or post-treated with 5 μM curcumin, respectively before or after being subjected to oxygen-glucose deprivation and reoxygenation for 24 hours. Both pretreatment and post-treatment resulted in a significant decrease of cell injury as indicated by propidium iodide/Hoechst 33258 staining, a prominent increase of Nrf2 protein expression as indicated by western blot analysis, and a remarkable increase of protein expression and enzyme activity in whole cell lysates of thioredoxin before ischemia, after ischemia, and after reoxygenation. In addition, post-treatment with curcumin inhibited early DNA/RNA oxidation as indicated by immunocytochemistry and increased nuclear Nrf2 protein by inducing nuclear accumulation of Nrf2. These findings suggest that curcumin activates the expression of thioredoxin, an antioxidant protein in the Nrf2 pathway, and protects neurons from death caused by oxygen-glucose deprivation in an in vitro model of ischemia/reperfusion. We speculate that pharmacologic stimulation of antioxidant gene expression may be a promising approach to neuroprotection after cerebral ischemia.

The residual consciousness of unconscious patients can be detected by studying the P300, a wave among event-related potentials. Previous studies have applied tones, the subject′s name and other names as stimuli. However, the results were not satisfactory. In this study, we changed the constituent order of subjects′two-character names to create derived names. The subject′s derived names, together with tones and their own names, were used as auditory stimuli in event-related potential experiments. Healthy controls and unconscious patients were included in this study and made to listen to these auditory stimuli. In the two paradigms, a sine tone followed by the subject′s own name and the subject′s derived name followed by the subject′s own name were used as standard and deviant stimuli, respectively. The results showed that all healthy controls had the P300 using both paradigms, and that the P300 in the second paradigm had a longer latency and two peaks. All minimally conscious state patients had the P300 in the first paradigm and the majority of them had the P300 in the second paradigm. Most vegetative state patients had no P300. Patients who showed the P300 in the two paradigms had more residual consciousness, and patients with the two-peak P300 had a higher probability of awakening within a short time. Our experimental findings suggest that the P300 event-related potential could reflect the conscious state of unconscious patients.

Previous studies have shown that up-regulation of transforming growth factor β1 results in neuroprotective effects. However, the role of the transforming growth factor β1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1β mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways.

We speculate that cortical reactions evoked by swallowing activity may be abnormal in patients with central infarction with dysphagia. The present study aimed to detect functional imaging features of cerebral cortex in central dysphagia patients by using blood oxygen level-dependent functional magnetic resonance imaging techniques. The results showed that when normal controls swallowed, primary motor cortex (BA4), insula (BA13), premotor cortex (BA6/8), supramarginal gyrus (BA40), and anterior cingulate cortex (BA24/32) were activated, and that the size of the activated areas were larger in the left hemisphere compared with the right. In recurrent cerebral infarction patients with central dysphagia, BA4, BA13, BA40 and BA6/8 areas were activated, while the degree of activation in BA24/32 was decreased. Additionally, more areas were activated, including posterior cingulate cortex (BA23/31), visual association cortex (BA18/19), primary auditory cortex (BA41) and parahippocampal cortex (BA36). Somatosensory association cortex (BA7) and left cerebellum in patients with recurrent cerebral infarction with central dysphagia were also activated. Experimental findings suggest that the cerebral cortex has obvious hemisphere lateralization in response to swallowing, and patients with recurrent cerebral infarction with central dysphagia show compensatory recombination phenomena of neurological functions. In rehabilitative treatment, using the favorite food of patients can stimulate swallowing through visual, auditory, and other nerve conduction pathways, thus promoting compensatory recombination of the central cortex functions.

Progressive motor deficits are relatively common in acute pontine infarction and frequently associated with increased functional disability. However, the factors that affect the progression of clinical motor weakness are largely unknown. Previous studies have suggested that pontine infarctions are caused mainly by basilar artery stenosis and penetrating artery disease. Recently, lower pons lesions in patients with acute pontine infarctions have been reported to be related to progressive motor deficits, and ensuing that damage to the corticospinal tracts may be responsible for the worsening of neurological symptoms. Here, we review studies on motor weakness progression in pontine infarction and discuss the mechanisms that may underlie the neurologic worsening.

Polyethyleneimine-polyethylene glycol (PEI-PEG), a novel nanocarrier, has been used for transfection and gene therapy in a variety of cells. In our previous study, we successfully carried out PEI-PEG-mediated gene transfer in spiral ganglion cells. It remains unclear whether PEI-PEG could be used for gene therapy with X-linked inhibitor of apoptosis protein (XIAP) in the inner ear. In the present study, we performed PEI-PEG-mediated XIAP gene transfection in the cochlea of Sprague-Dawley rats, via scala tympani fenestration, before daily cisplatin injections. Auditory brainstem reflex tests demonstrated the protective effects of XIAP gene therapy on auditory function. Immunohistochemical staining revealed XIAP protein expression in the cytoplasm of cells in the spiral ganglion, the organ of Corti and the stria vascularis. Reverse transcription-PCR detected high levels of XIAP mRNA expression in the cochlea. The present findings suggest that PEI-PEG nanocarrier-mediated XIAP gene transfection results in XIAP expression in the cochlea, prevents damage to cochlear spiral ganglion cells, and protects hearing.

Glaucoma, a type of optic neuropathy, is characterized by the loss of retinal ganglion cells. It remains controversial whether c-Jun N-terminal kinase (JNK) participates in the apoptosis of retinal ganglion cells in glaucoma. This study sought to explore a possible mechanism of action of JNK signaling pathway in glaucoma-induced retinal optic nerve damage. We established a mouse model of chronic ocular hypertension by reducing the aqueous humor followed by photocoagulation using the laser ignition method. Results showed significant pathological changes in the ocular tissues after the injury. Apoptosis of retinal ganglion cells increased with increased intraocular pressure, as did JNK3 mRNA expression in the retina. These data indicated that the increased expression of JNK3 mRNA was strongly associated with the increase in intraocular pressure in the retina, and correlated positively with the apoptosis of retinal ganglion cells.

Severe edema in the endoneurium can occur after non-freezing cold injury to the peripheral nerve, which suggests damage to the blood-nerve barrier. To determine the effects of cold injury on the blood-nerve barrier, the sciatic nerve on one side of Wistar rats was treated with low temperatures (3-5°C) for 2 hours. The contralateral sciatic nerve was used as a control. We assessed changes in the nerves using Evans blue as a fluid tracer and morphological methods. Excess fluid was found in the endoneurium 1 day after cold injury, though the tight junctions between cells remained closed. From 3 to 5 days after the cold injury, the fluid was still present, but the tight junctions were open. Less tracer leakage was found from 3 to 5 days after the cold injury compared with 1 day after injury. The cold injury resulted in a breakdown of the blood-nerve barrier function, which caused endoneurial edema. However, during the early period, the breakdown of the blood-nerve barrier did not include the opening of tight junctions, but was due to other factors. Excessive fluid volume produced a large increase in the endoneurial fluid pressure, prevented liquid penetration into the endoneurium from the microvasculature. These results suggest that drug treatment to patients with cold injuries should be administered during the early period after injury because it may be more difficult for the drug to reach the injury site through the microcirculation after the tissue fluid pressure becomes elevated.

Diffusion tensor imaging is a sensitive way to reflect axonal necrosis and degeneration, glial cell regeneration and demyelination following spinal cord injury, and to display microstructure changes in the spinal cord in vivo. Diffusion tensor imaging technology is a sensitive method to diagnose spinal cord injury fiber tractography visualizes the white matter fibers, and directly displays the structural integrity and resultant damage of the fiber bundle. At present, diffusion tensor imaging is restricted to brain examinations, and is rarely applied in the evaluation of spinal cord injury. This study aimed to explore the fractional anisotropy and apparent diffusion coefficient of diffusion tensor magnetic resonance imaging and the feasibility of diffusion tensor tractography in the evaluation of complete spinal cord injury in rats. The results showed that the average combined scores were obviously decreased after spinal cord transection in rats, and then began to increase over time. The fractional anisotropy scores after spinal cord transection in rats were significantly lower than those in normal rats (P

Transcranial direct current stimulation (tDCS), an emerging technique for non-invasive brain stimulation, is increasingly used to induce changes in cortical excitability and modulate motor behavior, especially for upper limbs. The purpose of this study was to investigate the effects of tDCS of the primary motor cortex on visuomotor coordination based on three levels of task difficulty in healthy subjects. Thirty-eight healthy participants underwent real tDCS or sham tDCS. Using a single-blind, sham-controlled crossover design, tDCS was applied to the primary motor cortex. For real tDCS conditions, tDCS intensity was 1 mA while stimulation was applied for 15 minutes. For the sham tDCS, electrodes were placed in the same position, but the stimulator was turned off after 5 seconds. Visuomotor tracking task, consisting of three levels (levels 1, 2, 3) of difficulty with higher level indicating greater difficulty, was performed before and after tDCS application. At level 2, real tDCS of the primary motor cortex improved the accurate index compared to the sham tDCS. However, at levels 1 and 3, the accurate index was not significantly increased after real tDCS compared to the sham tDCS. These findings suggest that tasks of moderate difficulty may improve visuomotor coordination in healthy subjects when tDCS is applied compared with easier or more difficult tasks.

Notch pathway activation maintains neural stem cells in a proliferating state and increases nerve repair capacity. To date, studies have rarely focused on changes or damage to signal transduction pathways during cerebral hemorrhage. Here, we examined the effect of acupuncture in a rat model of cerebral hemorrhage. We examined four groups: in the control group, rats received no treatment. In the model group, cerebral hemorrhage models were established by infusing non-heparinized blood into the brain. In the acupuncture group, modeled rats had Baihui (DU20) and Qubin (GB7) acupoints treated once a day for 30 minutes. In the DAPT group, modeled rats had 0.15 μg/mL DAPT solution (10 mL) infused into the brain. Immunohistochemistry and western blot results showed that acupuncture effectively inhibits Notch1 and Hes1 protein expression in rat basal ganglia. These inhibitory effects were identical to DAPT, a Notch signaling pathway inhibitor. Our results suggest that acupuncture has a neuroprotective effect on cerebral hemorrhage by inhibiting Notch-Hes signaling pathway transduction in rat basal ganglia after cerebral hemorrhage.

Studies have shown that serum response factor is beneficial for axonal regeneration of peripheral nerves. However, its role after central nervous system injury remains unclear. In this study, we established a rat model of T9-T10 spinal cord transection injury. We found that the expression of serum response factor in injured spinal cord gray matter neurons gradually increased with time, reached its peak on the 7 th day, and then gradually decreased. To investigate the role of serum response factor, we used lentivirus vectors to overexpress and silence serum response factor in spinal cord tissue. We found that overexpression of serum response factor promoted motor function recovery in rats with spinal cord injury. Qualitative observation of biotinylated dextran amine anterograde tracing showed that overexpression of serum response factor increased nerve fibers in the injured spinal cord. Additionally, transmission electron microscopy showed that axon and myelin sheath morphology was restored. Silencing serum response factor had the opposite effects of overexpression. These findings suggest that serum response factor plays a role in the recovery of motor function after spinal cord injury. The underlying mechanism may be related to the regulation of axonal regeneration., Competing Interests: None

Background: Developmental cortical plasticity with reorganization of cerebral cortex, has been known to occur in young and adult animals after permanent, restricted elimination of afferent (visual or somatosensory) input. In animals, cortical representation of unaffected muscles or sensory areas has been shown to invade the neighboring cortex when this is deprived of its normal sensory input or motor functions. Some studies indicate that similar cortical plasticity may take place in adult humans. Methods: In patients with a high cervical spinal cord injury leaving the patient without any movements of the fingers, we performed fMRI studies of the cortical representation of an elbow flexor muscle before and after a surgical procedure that changed its function to a thumb flexor, thus providing the patient with a useful grip. Results: Preoperatively, the elbow flexion movement was elicited from a cortical area corresponding with the “elbow area” in healthy individuals. Despite the fact that an elbow flexor was used for the post-operative key-grip, this movement in the tetraplegic patients was elicited from a similar brain region as in healthy controls (the “hand area”). This supports our hypothesis that control of that muscle shifts from a brain region typically associated with elbow movement, to one typically associated with wrist movements. Conclusion: The findings presented here show with fMRI that the human cortex is capable of reorganizing itself spatially after a relatively acute change in the periphery. [ABSTRACT FROM AUTHOR]

Rats with complete spinal cord transection (SCT) can recover hindlimb locomotor function under strategies combining exercise training and 5-HT agonist treatment. This recovery is expected to result from structural and functional re-organization within the spinal cord below the lesion. To begin to understand the nature of this reorganization, we examined synaptic changes to identified gastrocnemius (GS) or tibialis anterior (TA) motoneurons (MNs) in SCT rats after a schedule of early exercise training and delayed 5-HT agonist treatment. In addition, we analyzed changes in distribution and number of lumbar interneurons (INs) presynaptic to GS MNs using retrograde transneuronal transport of rabies virus. In SCT-untrained rats, we found few changes in the density and size of inhibitory and excitatory inputs impinging on cell bodies of TA and GS MNs compared to intact rats, whereas there was a marked trend for a reduction in the number of premotor INs connected to GS MNs. In contrast, after training of SCT rats, a significant increase of the density of GABAergic and glycinergic axon terminals was observed on both GS and TA motoneuronal cell bodies, as well as of presynaptic P-boutons on VGLUT1 afferents. Despite these changes in innervation the number of premotor INs connected to GS MNs was similar to control values although some new connections to MNs were observed. These results suggest that adaptation of gait patterns in SCT-trained rats was accompanied by changes in the innervation of lumbar MNs while the distribution of the spinal premotor circuitry was relatively preserved. [ABSTRACT FROM AUTHOR]

Aims: Lumbar to sacral rerouting surgery can potentially allow voiding via a skin‐central nervous system‐bladder reflex pathway. Here, we assessed if this surgery was effective in treating neurogenic bladder dysfunction/sphincter in felines. Methods: Eight cats underwent spinal cord transection (SCT) at thoracic level 10/11. Unilateral L7 to S1 ventral root anastomosis was performed 1 month later in six cats. Two cats served as transection‐only controls. Electrical and manual stimulation of L6‐S1 dermatomes, and urodynamics were performed at 3, 5, 7, and 9/10 months post transection. At 9/10 months, cats were also evaluated by direct electrophysiological testing of anastomosed roots with urodynamics, then tissue collection and examination of the root anastomosis site and lumbosacral cord ventral horns for cells retrogradely labeled from tracer dye injected 2 weeks earlier into the bladder wall. Results: At 9/10 months, four of six rerouted cats exhibited increased detrusor pressure provoked by cutaneous stimulation, one cat bilaterally. Two cats presented with a voiding stream after ipsilateral cutaneous stimulation at 7 and 9 months. All six rerouted animals showed regrowth of axons from the L7 ventral horn to the bladder, although some aberrant axonal regrowth was also observed. Conclusion: L7 to S1 ventral root rerouting below the level of SCT showed successful axonal regrowth to the bladder from the L7 spinal cord segment in all rerouted animals, and induced increased detrusor pressure response to cutaneous stimulation in a subset. This feasibility study paves the way for future animal studies for bladder reinnervation. [ABSTRACT FROM AUTHOR]

After complete transection of the thoracic spinal segment, neonatal rats exhibit spontaneous locomotor recovery of hindlimbs, but this recovery is not found in adult rats after similar injury. The potential mechanism related to the difference in recovery of neonatal and adult rats remains unknown. In this study, 342 animals were analyzed. The vascular endothelial growth factor (VEGF) level in spinal segments below injury sites was significantly higher in postnatal day 1 rats (P1) compared with 28-day-old adult rats (P28) following a complete T9 transection. VEGF administration in P28 rats with T9 transection significantly improved the functional recovery; by contrast, treatment with VEGF receptor inhibitors in P1 rats with T9 transection slowed down the spontaneous functional recovery. Results showed more neurons reduced in the lumbar spinal cord and worse local neural network reorganization below injury sites in P28 rats than those in P1 rats. Transynaptic tracing with pseudorabies virus and double immunofluorescence analysis indicated that VEGF treatment in P28 rats alleviated the reduced number of neurons and improved their network reorganization. VEGF inhibition in neonates resulted in high neuronal death rate and deteriorated network reorganization. In in vivo studies, T9 transection induced less increase in the number of microglia in the spinal cord in P1 animals than P28 animals. VEGF treatment reduced the increase in microglial cells in P28 animals. VEGF administration in cultured spinal motoneurons prevented lipopolysaccharide (LPS)-induced neuronal death and facilitated neurite growth. Western blots of the samples of lumbar spinal cord after spinal transection and cultured spinal motoneurons showed a lower level of Erk1/2 phosphorylation after the injury or LPS induction compared with that in the control. The phosphorylation level increased after VEGF treatment. In conclusion, VEGF is a critical mediator involved in functional recovery after spinal transection and can be considered a potential target for clinical therapy.